AbstractObjectiveTo characterize the phenotype of patients with symptoms of periodic paralysis (PP) andryanodine receptor (RYR1) gene mutations
MethodsCases with a possible diagnosis of PP but additional clinicopathologic findings previouslyassociated with RYR1-related disorders were referred for a tertiary neuromuscular clinicalassessment in which they underwent detailed clinical evaluation including neurophysiologicassessment muscle biopsy and muscle MRI Genetic analysis with next-generation sequencingandor targeted Sanger sequencing was performed
ResultsThree cases with episodic muscle paralysis or weakness and additional findings compatible witha RYR1-related myopathy were identified The McManis test used in the diagnosis of PP waspositive in 2 of 3 cases Genetic analysis of known PP genes was negative RYR1 analysisconfirmed likely pathogenic variants in all 3 cases
ConclusionsRYR1 mutations can cause late-onset atypical PP both with and without associated myopathyMyalgia and cramps are prominent features The McManis test may be a useful diagnostic toolto indicate RYR1-associated PP We propose that clinicopathologic features suggestive ofRYR1-related disorders should be sought in genetically undefined PP cases and that RYR1 genetesting be considered in those in whom mutations in SCN4A CACNA1S and KCNJ2 havealready been excluded
These authors contributed equally to this work
From the MRC Centre for Neuromuscular Diseases (EM FJ RSS DF MP DRR KS HH EH RQ JLH MGH) Department of Molecular Neuroscience UCL Institute ofNeurology and National Hospital for Neurology and Neurosurgery Queen Square London UK Neuromuscular Diseases UnitALS Clinic (CN) Kantonsspital St Gallen SwitzerlandNeurogenetics Unit (RS HH) and Department of Neuropathology (JLH) National Hospital for Neurology and Neurosurgery Queen Square London UK Human GeneticsLaboratory Genetica (RS) Zurich Switzerland Genetics Department (RM) Viapath Guyrsquos Hospital London Wellcome Trust Centre for Mitochondrial Research (AS) University ofNewcastle Framlington Place Newcastle Upon Tyne UK Institute of Pathology (EH) Belfast Health and Social Care Trust Northern Ireland Department of Neurology (JP) JohnRadcliffe Hospital Oxford UK Departments of Biomedicine and Anesthesia (ST) Basel University Hospital Switzerland Department of Life Sciences (ST) Microbiology and AppliedPathology Section University of Ferrara Italy Department of Paediatric Neurology (HJ) Neuromuscular Service Evelina Childrenrsquos Hospital St ThomasrsquoHospital and Department ofBasic andClinical Neuroscience (HJ) Institute of Psychiatry Psychology andNeuroscience andRandall Division of Cell andMolecular Biophysics (HJ) Muscle Signalling Section KingrsquosCollege London UK
Go to NeurologyorgN for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article
The Article Processing Charge was funded by the Medical Research Council (UK)
This is an open access article distributed under the terms of the Creative Commons Attribution License 40 (CC BY) which permits unrestricted use distribution and reproduction in anymedium provided the original work is properly cited
e412 Copyright copy 2018 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology
The skeletal muscle ryanodine receptor (RYR1) gene enc-odes the principal sarcoplasmic reticulum calcium releasechannel with a crucial role in excitation-contraction couplingMutations in RYR1 are the most common genetic cause ofnondystrophic neuromuscular disorders12 associated witha wide spectrum of clinicopathologic features ranging fromvarious early-onset congenital myopathiesmdashcentral coredisease3 multiminicore disease (MmD)4 centronuclearmyopathy5 and congenital fiber type disproportion6mdashto themalignant hyperthermia (MH) susceptibility trait RYR1mutations may also give rise to episodic neuromuscularmanifestations including exertional myalgia and rhabdo-myolysis7 a late-onset axial myopathy89 and have recentlybeen associated with a novel bleeding disorder due to ab-normal smooth muscle cell contractility10 Episodes of atyp-ical periodic paralysis (PP) have been previously reported ina single patient with a recessive RYR1-related myopathy11
but it has been unclear whether this phenotype was unique tothe reported individual or common across different RYR1genotypes The association between RYR1 and PP is notentirely unexpected considering that dysfunction of Cav11the other key player involved in excitation-contraction cou-pling and the principal RYR1 interactor is the most commoncause of primary PP Recently both dominant and recessivefamilies with a Cav11-related myopathy have been de-scribed12 suggesting further phenotypic overlap betweenRYR1 and Cav11 dysfunction and a continuum betweenmyopathic and episodic phenotypes due to mutations inthese genes Here we report 3 additional RYR1-mutatedpatients presenting with PP episodes and variable additionalmyopathic manifestations
MethodsWe examined cases referred with a possible diagnosis of PPbut additional clinicopathologic findings previously associatedwith RYR1-related disorders to the national referral center forskeletal muscle channelopathies in the United Kingdom andto the Swiss Neuromuscular Diseases Unit Center
Standard protocol approvals registrationsand patient consentsAll procedures were conducted as part of routine clinical careThe study was performed under the ethics guidelines issuedby our institution with written informed consent obtainedfrom all participants for genetic studies
Genetic analysis for PP genes SCN4ACACNA1S andKCNJ2was performed at the Neurogenetics Unit National Hospitalfor Neurology and Neurosurgery as provided by the
Channelopathy Highly Specialized National Service for raredisease Samples underwent next-generation sequencing onan Illumina HiSeq after enrichment with an Illumina customNextera Rapid Capture panel (Illumina Inc San Diego CA)For case 2 the library preparation and enrichment wereperformed with TruSight One kit (Illumina) according toprotocol instructions allowing analysis of a panel of asymp5000genes (including PP genes and RYR1) The library wasquantified with the Qubit 20 Fluorometer system (ThermoFisher Scientific Waltham MA) and 2 times 250-bp paired-endsequencing was performed on the MiSeq sequencer(Illumina) as well as sequences alignment (Burrows-Wheeleraligner) and variant calling (Genome Analysis Toolkit variantcaller) The variants were then analyzed with VariantStudio(Illumina)
Additional targeted RYR1 Sanger sequencing of all cases wasperformed at the Diagnostic DNA Laboratory at GuyrsquosHospital London
ResultsCase 1A 54-year-old man was born 7 weeks prematurely An atrialseptal defect was noted at birth and corrected at the age of5 years Walking was delayed until the age of 2 years He wasnever able to run or to keep up with peers physically becauseof weakness of his arms and legs In early childhood he toe-walked ultimately requiring Achilles tendon lengtheningSymptoms were effectively stable throughout childhood butfrom the age of 20 years there was slowly progressive proxi-mal weakness
At the age of 34 years after a flu-like illness he complained ofa change in symptoms He reported episodes of sudden severemyalgia followed by profound muscle weakness in either1 limb or the entire body from the neck down lasting forseveral hours Examination demonstrated a waddling gait andpronounced lumbar lordosis and mild dysmorphic featureswith a long thin face and high arched palate Mild bilateralptosis with a complex ophthalmoplegia most marked onupgaze a typical finding in recessive RYR1-related myo-pathies was noted There was bilateral facial and sternoclei-domastoid weakness with additional proximal upper andlower limb weakness Reflexes were 1+ and there were nosensory abnormalities Cardiac examination demonstratedatrial fibrillation for which he underwent cardioversion Be-cause of the change in symptoms a muscle biopsy was per-formed Although core-like structures were seen theywere not felt to be typical of central core disease a common
NeurologyorgN Neurology | Volume 90 Number 5 | January 30 2018 e413
RYR1-related myopathy and no definitive diagnosis wasreached (figure 1)
From this point he continued to complain of episodes of tem-porary worsening of limb weakness 2 to 3 times a year lasting forseveral days He could identify no specific triggers At the age of38 years he presented with an episode of severe neck flexor andbulbar weakness Over the course of 9 days his neck flexorweakness improved to baseline Bulbar function remained im-paired and a percutaneous endoscopic gastrostomy (PEG) tubefor feeding was inserted However he continued to report fluc-tuant improvement in his swallow on some days being entirelyreliant on the PEG and on others managing a soft diet Fourteenmonths after the PEG insertion he attended clinic and reportedthat he no longer used it and consistentlymanaged a normal dietVideofluoroscopy demonstrated only minor persisting abnor-malities and the PEG was removed at his request
Over subsequent years he continued to experience acute attacksof myalgia followed by weakness When care was transferred tous he was reinvestigated including a repeatmuscle biopsy at theage of 42 years (figure 2) which on this occasion revealed mildloss of oxidative enzyme activity in the central region of manyfibers but classic central cores were not observed
Electrophysiologic tests showed myopathic EMG featuresnormal repetitive stimulation mildly abnormal jitter and oc-casional blocking on single-fiber EMG (including in extensordigitorum communis biceps and orbicularis oculi) Whileindicative of a mild neuromuscular junction transmission de-fect this was thought likely to be a secondary phenomenonrather than a primary myasthenic feature13 Serologic testingfor acetylcholine receptor antibodies and muscle-specific ki-nase antibodies was negative The McManis test for PP waspositive on 2 separate occasions (53 and 59 decrement in
Figure 1 Histology slides of muscle biopsies taken from case 1 at age (A) 34 and (B) 42 years
(A) Histologic examination of a right quadriceps muscle biopsy performed at age 34 years showed variation in fiber diameter and internalized nuclei withhematoxylin and eosin staining (B) ATPase histochemistry at pH 43 indicated type I fiber predominance with decreased myofibrillar ATPase activity in core-like areas in up to 15 of type I fibers (red arrow) (C) Central absence of staining suggestive of cores was apparent in type I and II fibers in the nicotinamidedinucleotide tetrazolium reductase preparation (black arrows) and central reduction in oxidative enzyme activity was confirmedby succinate dehydrogenasestaining (D black arrow) Scale bar in A represents 100 μm in (A) and (C) 200 μm in (B) and 50 μm in (D)
e414 Neurology | Volume 90 Number 5 | January 30 2018 NeurologyorgN
compound muscle action potential [CMAP] amplitude) MRIdemonstrated fatty infiltration of all thigh muscles in particularthe adductor magnus which was almost completely replacedby fat with relative sparing of the vastus lateralis rectus femorisgracilis and semitendinosus a pattern of selective involvementpreviously associated withRYR1-relatedmyopathies1415 Therewas no family history of similar symptoms Genetic analysisrevealed RYR1 variants Arg109Trp previously describedwith MmD and ophthalmoplegia416 a variant of uncertain
significance Met485Val4 and the novel although presumedtruncating variant Gln70X Testing for congenital myastheniaand PP genes was negative His unaffected mother carried theGln70X variant It was not possible to obtain DNA from hisfather
Case 2A 42-year-old Swiss woman presented with intermittentweakness of the limbs lasting from several minutes to 2 days
Figure 2 Histologic examination of a right biceps muscle biopsy
Histologic examination of a right biceps muscle biopsy performed at age 42 years showed (A) variation in fiber diameter and increased internal nuclei with (B)occasional fibers showing central basophilia (arrow) and (C) a small number of necrotic fibersGomori trichrome staining suggested regions with reducedmitochondrial staining (arrow) (E) ATPasehistochemistry indicated focal type I fiber predominance (darkly stained fibers) (F)Mild central pallor suggestive of coreswas apparent in type I and II fibers in the nicotinamide adenine dinucleotide tetrazolium reductase preparation (arrows) and (G) central reduction in oxidativeenzyme activity was confirmed by cytochrome oxidase histochemistry Scale bar in represents 260 μm in (E) 100 μm in (A) (F) and (G) and 50 μm in (BndashD)
NeurologyorgN Neurology | Volume 90 Number 5 | January 30 2018 e415
Medical history was notable for migraine and 3 caesareansections The first episode of flaccid paresis occurred duringher first pregnancy at the age of 23 years with a fall from thecouch when she could not move her right arm and leg forseveral minutes without associated disturbance of cognitionor sensory symptoms Examination at the emergency roomafter recovery was normal Brain imaging was not performedbecause of the pregnancy Two subsequent EEGs were nor-mal and no specific diagnosis was made at the time She hada history of migraine and we cannot definitively exclude thepossibility that this first episode of unilateral weakness wasa migraine aura without headache However her typical mi-graine episodes are headache and are distinct from this pre-sentation Fifteen years later while driving she notedweakness of her arms legs and trunk severe enough to war-rant stopping the car Weakness recovered slowly after 15minutes A similar episode occurred a few months later Po-tassium levels and clinical examination when asymptomaticwere normal Subsequently the frequency of similar episodeswith flaccid paresis of her limbs affecting predominantly thelegs and lasting several minutes increased and they occurreddaily always after resting No correlation with food intake orfasting was reported In addition she complained of painlesscramps in her arms and legs muscles which could becomepainful if she tried to stretch her muscles These lasted up to10 minutes and also occurred during sleep
A detailed neurologic examination at the age of 42 yearsrevealed no abnormalities A relatively thin and long face witha small lower jaw was noted but she was not overtly dys-morphic On follow-up examination she presented withflaccid weakness of her right hand lasting for 2 days Motorand sensory nerve conduction studies repetitive motor nervestimulation and EMG in the limbs and paravertebral musclesperformed after recovery from the acute episode were un-remarkable The McManis test was negative Laboratorytesting revealed no thyroid dysfunction electrolytes andcreatine kinase were normal Muscle biopsy of the tibialisanterior muscle was unremarkable Genetic testing revealedRYR1 gene variants Arg1507Gln and Gly2446Ser in transArg1507Gln is a missense variant with a minor allele fre-quency of 000001 in ExAC that has been previously found inother myopathic phenotypes Gly2446Ser although notpreviously reported localizes to a recognized MH-associatedmutational hot spot (wwwemhgorg) PP gene testing wasnegative
Case 3This 49-year-old man reported experiencing episodes of mi-nor limb weakness after strenuous exercise that lasted a fewhours from the age of 14 years He had his first full attack ofmuscle paralysis at the age of 29 years He awoke in themorning after a day of strenuous exercise to find that he wasunable to walk From this age on he experienced multiplesimilar episodes All muscles from the neck down could beweak although the legs were predominantly and mostseverely affected Symptoms usually lasted for several hours
but could persist for as long as 48 hours In the recovery phasehe reported that the limbs could be painful as strengthreturned Symptoms could be provoked by exercise intenseheat or a carbohydrate-rich meal late at night
Medical history was notable for 2 complicated general anes-thetics in childhood although the exact circumstances wereunclear and medical records unavailable His parents wereadvised after these that he may be at risk of MH and to informclinicians before any future procedures requiring generalanesthesia
Examination was unremarkable as was creatine kinase andMRI of the lower limbs EMG and nerve conduction studywere normal but theMcManis test for PP was positive with anexercise-induced reduction of CMAP of 68 A biopsy of thetibialis anterior muscle demonstrated variation in fiber size anincrease in internal nuclei and 1 ring fiber (figure e-1 httplinkslwwcomWNLA96) A type I fiber predominance wasinterpreted as normal for the muscle biopsied Genetic testingfor PP genes was negative but an RYR1 variant Arg1043Hiswas identified Another amino acid substitution at the samesite Arg1043Cys previously associated with the MH trait butnot functionally tested yet (wwwemhgorg) has beendescribed
DiscussionWe have previously reported a single patient with recessiveRYR1-related MmD with additional episodic muscle weak-nessparalysis11 Here we have described 3 additional cases(summarized in the table) One was compound heterozygousfor RYR1 nonsense and missense mutations and presentedwith later development of episodic symptoms in the context ofa congenital myopathy similar to our original patient reportedby Zhou et al17 who showed a comparable genotype andphenotype The other 2 patients had an episodic phenotypewithout myopathy and were either heterozygous for or com-pound heterozygous forRYR1missensemutations (putatively)implicated in the MH trait suggesting tentative genotype-phenotype correlations In all cases (including our originalcase) the onset of episodic muscle paralysis was from earlyadulthood onward which is later than the onset typically seenin primary PP17 Although there were variable triggers in-cluding exertion or rest after exertion which is a typical triggerfor PP there was no consistent relationship to food or tem-perature across all the cases Myalgia or cramp was a universalfeature indicating overlap with the spectrum of RYR1-relatedexertional myalgiarhabdomyolysis and this together with thelater age at onset may be a phenotypic clue for future cases
The McManis test was positive in 2 of 3 of our new cases Weretrospectively reviewed the source data for our previouslyreported case11 and found that the drop in CMAP amplitudewhen calculated from the postexercise increment was alsogt40 indicating a positive test
e416 Neurology | Volume 90 Number 5 | January 30 2018 NeurologyorgN
A positive McManis test to the best of our knowledge haspreviously been described only in primary or secondaryPP18 Given the direct interaction between the Cav11channel implicated in the majority of cases of hypokalemicPP19 and RYR1 it seems plausible that dysfunction of eachmay produce phenotypic mimics This is supported by theobservation of a profound disturbance of the normalCav11RYR1 interaction in 1 previous patient with RYR1-related PP and other patients with recessive RYR1-relatedmyopathies1120 Furthermore the recently described CAC-NA1S-associated early-onset myopathy shares features ofpredominantly axial weakness and ophthalmoplegia withRYR1-related myopathies12 and may also feature similarreductions of the Cav11 protein However the exactmechanism by which the RYR1 variants would cause anepisodically unexcitable sarcolemma as demonstrated bya positive McManis test is unclear On the basis of the recentobservation of altered BK channel activity in RYR1-mutatedsmooth muscle cells10 one possibility is via an impairment ofBK channelndashmediated membrane repolarization due toaltered intracellular calcium homeostasis but this requiresfurther study102122
Other atypical PP phenotypes associated with motor neurop-athy due to mitochondrial gene mutations have beendescribed23 demonstrating that the clinical symptoms may beseen in nonndashion channel genetic disorders Our data demon-strate that late-onset episodic muscle weakness or paralysiswith prominent myalgia and cramps may be a more commonRYR1-associated phenotype than the single case we previously
reported and may not be limited to a specific genotype Wesuggest that cases compound heterozygous for RYR1 nonsenseand missense mutations are more likely to have a concomitantearly-onset myopathy The McManis test may be a useful di-agnostic tool in these cases although a negative test does notexclude the possibility of RYR1 involvement
We propose that clinicopathologic features suggestive ofRYR1 disorders should be sought in genetically undefined PPcases and RYR1 gene testing considered in those in whommutations in SCN4A CACNA1S and KCNJ2 have alreadybeen excluded
Author contributionsE Matthews drafting the manuscript for content analysis orinterpretation of data study concept C Neuwirth andF Jaffer revising the manuscript for content analysis orinterpretation of data study concept R Scalco D FialhoM Parton R Sud R Spiegel R Mein D Raja RayanK Suetterlin H Houlden A Schaefer E Healy J PalaceR Quinlivan S Treves and JL Holton revising the man-uscript for content analysis or interpretation of dataH Jungbluth drafting the manuscript for content analysisor interpretation of data study concept MG Hannarevising the manuscript for content analysis or in-terpretation of data
AcknowledgmentThe authors are grateful to Mark Walker at Southampton forthe retrieval of muscle histology slides
Table Summary of clinicopathologic features of cases with RYR1 gene variants and episodic weaknessparalysis
Symptoms ExaminationCKIUL EMG
McManistest Muscle biopsy
RYR1variants
Previouslyreportedcase11
Hypotonia respiratory andfeeding impairment at birthdelayed motor milestonesepisodic limb weaknesslasting days from age 18 ycold- and exercise-inducedmyalgiacramp from age 26 y
High arched palatefacial weaknessophthalmoplegiasevere trunk and neckweakness moderatelimb weaknesshyperlordosis
Normalrange
Myopathic Positive Variation in fibersize increasedinternal nucleicore-like structures
Asp708AsnArg2241XArg2939Lys
Case 1 Delayed walking early onsetproximal myopathy episodicmyalgia followed by limb andneck weakness lasting hoursto days from age 34 yfluctuant bulbar weakness
Long thin face higharched palate proximalmyopathy facialweakness and ptosisophthalmoplegiahyperlordosis
101 Myopathicincreasedjitter andblocking onSFEMG
Positive Variation in fibersize increasedinternal nucleiareas of centralpallor suggestive ofcore-like structures
Gln70XArg109TrpMet485Val
Case 2 Early history anddevelopment normalepisodic limb weakness fromage 23 y cramps withmyalgia
Long thin face 120 Normal Negative Normal Arg1507GlnGly2446Ser
Case 3 Early history anddevelopment normal minorepisodic weakness from age14 y episodic limb paralysisand myalgia from age 29 y
Normal 92 Normal Positive Type 1predominance 1ragged red fiber(+COX negative)increased internalnuclei 1 ring fiber
Arg1043His
Abbreviations CK = creatine kinase SFEMG = single-fiber EMG
NeurologyorgN Neurology | Volume 90 Number 5 | January 30 2018 e417
Study fundingPart of this work was undertaken at University College LondonHospitalsUniversity College London which received aproportion of funding from the Department of HealthrsquosNational Institute for Health Research Biomedical ResearchCentres funding scheme
DisclosureE Matthews holds a post-doctoral fellowship from the Na-tional Institute for Health Research Rare Disease SchemeC Neuwirth F Jaffer and R Scalco report no disclosuresrelevant to the manuscript D Fialho is supported by theNational Highly Specialised Service Department of HealthUK M Parton R Sud R Spiegel R Mein and D Rayanreport no disclosures relevant to the manuscript K Suetterlinhas an MRC Clinical Research Training Fellowship and re-ceived funding from the European Communityrsquos SeventhFramework Programme (FP72007-2013) under grantagreement 2012-305121 ldquoIntegrated European-omics Re-search Project for Diagnosis and Therapy in Rare Neuro-muscular and Neurodegenerative Diseases (NEUROMICS)rdquoH Houlden has received funding from the European Com-munityrsquos Seventh Framework Programme (FP72007-2013)under grant agreement 2012-305121 ldquoIntegratedEuropean-omics Research Project for Diagnosis andTherapy in Rare Neuromuscular and NeurodegenerativeDiseases (NEUROMICS)rdquo A Schaefer and E Healy reportno disclosures relevant to the manuscript J Palace is partlyfunded by Highly Specialised Services to run national con-genital myasthenia and neuromyelitis optica services and hasreceived support for scientific meetings and honorariums foradvisory work from Merck Serono Biogen Idec NovartisTeva Chugai Pharma and Bayer Schering as well as un-restricted grants from Merck Serono Novartis Biogen IdecTeva and Bayer Schering Her hospital trust receives funds forher role as clinical lead for the Department of Health RiskSharing Scheme She has received grants from the MS societyand Guthy-Jackson Foundation R Quinlivan is supported bythe National Highly Specialised Service Department ofHealth UK andNational Institute for Health Research and hasgrant funding from Muscular Dystrophy UK and Associationfor Glycogen Storage Disease She has received honoraria forteaching and consultancy from PTC Therapeutics Sanofi-Genzyme and Ultragenyx S Treves reports no disclosuresrelevant to the manuscript J Holton is supported by the RetaLila Weston Institute for Neurologic Studies H Jungbluthreports no disclosures relevant to the manuscript M Hanna is
supported by a Medical Research Council Centre grant theNational Centre for Research Resources and the NationalHighly Specialised Service Department of Health UK Go toNeurologyorgN for full disclosures
Received June 9 2017 Accepted in final form October 24 2017
References1 Amburgey K McNamara N Bennett LR McCormick ME Acsadi G Dowling JJ
Prevalence of congenital myopathies in a representative pediatric United Statespopulation Ann Neurol 201170662ndash665
2 Maggi L Scoto M Cirak S et al Congenital myopathies clinical features and fre-quency of individual subtypes diagnosed over a 5-year period in the United KingdomNeuromuscul Disord 201323195ndash205
3 Zhang Y Chen HS Khanna VK et al A mutation in the human ryanodine receptorgene associated with central core disease Nat Genet 1993546ndash50
4 Jungbluth H Zhou H Hartley L et al Minicore myopathy with ophthalmoplegiacaused by mutations in the ryanodine receptor type 1 gene Neurology 2005651930ndash1935
5 Wilmshurst JM Lillis S Zhou H et al RYR1 mutations are a common cause ofcongenital myopathies with central nuclei Ann Neurol 201068717ndash726
6 Clarke NF Waddell LB Cooper ST et al Recessive mutations in RYR1 are a com-mon cause of congenital fiber type disproportion Hum Mutat 201031E1544ndashE1550
7 Dlamini N Voermans NC Lillis S et al Mutations in RYR1 are a common cause ofexertional myalgia and rhabdomyolysis Neuromuscul Disord 201323540ndash548
8 Jungbluth H Lillis S Zhou H et al Late-onset axial myopathy with cores due toa novel heterozygous dominant mutation in the skeletal muscle ryanodine receptor(RYR1) gene Neuromuscul Disord 200919344ndash347
9 Loseth S Voermans NC Torbergsen T et al A novel late-onset axial myopathyassociated with mutations in the skeletal muscle ryanodine receptor (RYR1) geneJ Neurol 20132601504ndash1510
10 Lopez RJ Byrne S Vukcevic M et al An RYR1 mutation associated with malignanthyperthermia is also associated with bleeding abnormalities Sci Signal 20169ra68
11 Zhou H Lillis S Loy RE et al Multi-minicore disease and atypical periodic paralysisassociated with novel mutations in the skeletal muscle ryanodine receptor (RYR1)gene Neuromuscul Disord 201020166ndash173
12 Schartner V Romero NB Donkervoort S et al Dihydropyridine receptor (DHPRCACNA1S) congenital myopathy Acta Neuropathol 2017133517ndash533
13 Illingworth MA Main M Pitt M et al RYR1-related congenital myopathy withfatigable weakness responding to pyridostigimine Neuromuscul Disord 201424707ndash712
14 Jungbluth H Davis MR Muller C et al Magnetic resonance imaging of muscle incongenital myopathies associated with RYR1 mutations Neuromuscul Disord 200414785ndash790
15 Klein A Jungbluth H Clement E et al Muscle magnetic resonance imaging incongenital myopathies due to ryanodine receptor type 1 gene mutations Arch Neurol2011681171ndash1179
16 Zhou H Jungbluth H Sewry CA et al Molecular mechanisms and phenotypicvariation in RYR1-related congenital myopathies Brain 20071302024ndash2036
17 Venance SL Cannon SC Fialho D et al The primary periodic paralyses diagnosispathogenesis and treatment Brain 20061298ndash17
18 McManis PG Lambert EH Daube JR The exercise test in periodic paralysis MuscleNerve 19869704ndash710
19 Matthews E Labrum R Sweeney MG et al Voltage sensor charge loss accounts formost cases of hypokalemic periodic paralysis Neurology 2009721544ndash1547
20 Zhou H Rokach O Feng L et al RyR1 deficiency in congenital myopathies disruptsexcitation-contraction coupling Hum Mutat 201334986ndash996
21 Tricarico D Mele A Conte CD Carbonic anhydrase inhibitors ameliorate thesymptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels Neuromuscul Disord 20061639ndash45
22 Kim JB Kim SJ Kang SY Yi JW Kim SM The large-conductance calcium-activatedpotassium channel holds the key to the conundrum of familial hypokalemic periodicparalysis Korean J Pediatr 201457445ndash450
23 Aure K Dubourg O Jardel C et al Episodic weakness due to mitochondrial DNAMT-ATP68 mutations Neurology 2013811810ndash1818
e418 Neurology | Volume 90 Number 5 | January 30 2018 NeurologyorgN
SOURCE ARTICLE NPuborg5fjlcp
Atypical periodic paralysis and myalgiaAnovelRYR1 phenotype
Emma Matthews MRCP Christoph Neuwirth MD Fatima Jaffer MRCP Renata S Scalco MD
Doreen Fialho MRCP Matt Parton FRCP Dipa Raja Rayan MRCP Karen Suetterlin MRCP Richa Sud PhD
Roland Spiegel MD Rachel Mein BSc Henry Houlden FRCP Andrew Schaefer MRCP Estelle Healy FRCPath
Jacqueline Palace FRCP Ros Quinlivan FRCP Susan Treves PhD Janice L Holton FRCPath
Heinz Jungbluth PhD and Michael G Hanna FRCP
Cite as Neurologyreg 201890e412ndashe418 doi101212WNL0000000000004894
Correspondence
Dr Matthews
emmamatthewsuclacuk
Study questionWhat are the phenotypic characteristics of patients with pe-riodic paralysis (PP) symptoms and RYR1 mutations
Summary answerThese patients can have late-onset atypical PP with or withoutmyopathy and with myalgia and cramps as prominent features
What is known and what this paper addsRYR1 mutations are associated with diverse neuromusculardisorders including 1 reported case of atypical PP This studydescribes the phenotypes of 3 more patients with RYR1mutations and PP episodes
Participants and settingThis study reports 3 patients with possible PP diagnosesand clinicopathologic findings typically associated withRYR1-related disorders who were referred to UK and Swissspecialist centers
Design size and durationMedical histories were collected for all 3 patients Thesehistories includedmuscle examinations at various ages Sangersequencing for RYR1 was performed on patient samples
Main results and the role of chanceCase 1 was a 54-year-old man who had lifelong muscleweakness At 34 years old he experienced worsened symp-toms including sudden severe myalgia Examinations revealedvarious neuromuscular abnormalities including positiveresults on the McManis test for PP Case 2 was a 42-year-oldwoman who had experienced episodic muscle weakness andmigraine symptoms since the age of 23 years A neurologicexamination yielded unremarkable results and the McManistest yielded negative results Case 3 was a 49-year-old man
who had experienced postexercise limb weakness episodessince 14 years of age and full muscle paralysis episodes since29 years of age Neurologic examinations yielded unremark-able results but the McManis test yielded positive results All3 patients carried various RYR1 mutations and reported my-algia andor muscle cramps
Bias confounding and other reasonsfor cautionThese case reports do not firmly establish a genotype-phenotype relationship or explain the physiologic mecha-nism by which RYR1 mutations would cause late-onsetatypical PP
Generalizability to other populationsLate-onset atypical PP may be more common in persons withRYR1 mutations than the single previous report suggested
Study fundingpotential competing interestsThis study was funded by the UK Department of HealthSome authors report receiving funding from the UKand European Union governments pharmaceutical com-panies and medical research foundations Some authorsreport receiving personal compensation from pharma-ceutical companies Go to NeurologyorgN for fulldisclosures
Patient RYR1 variants
Previously reported Asp708Asn Arg2241X Arg2939Lys
Case 1 Gln70X Arg109Trp Met485Val
Case 2 Arg1507Gln Gly2446Ser
Case 3 Arg1043His
A draft of the short-form article was written by M Dalefield a writer with Editage a division of Cactus Communications The authors of thefull-length article and the journal editors edited and approved the final version
Copyright copy 2018 American Academy of Neurology 219
SHORT-FORM ARTICLE
DOI 101212WNL0000000000004894201890e412-e418 Published Online before print January 3 2018Neurology
Emma Matthews Christoph Neuwirth Fatima Jaffer et al Atypical periodic paralysis and myalgia A novel RYR1 phenotype
This information is current as of January 3 2018
ServicesUpdated Information amp
httpnneurologyorgcontent905e412fullincluding high resolution figures can be found at
httpnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online
0028-3878 Online ISSN 1526-632XKluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print ISSN1951 it is now a weekly with 48 issues per year Copyright copy 2018 The Author(s) Published by Wolters
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
The skeletal muscle ryanodine receptor (RYR1) gene enc-odes the principal sarcoplasmic reticulum calcium releasechannel with a crucial role in excitation-contraction couplingMutations in RYR1 are the most common genetic cause ofnondystrophic neuromuscular disorders12 associated witha wide spectrum of clinicopathologic features ranging fromvarious early-onset congenital myopathiesmdashcentral coredisease3 multiminicore disease (MmD)4 centronuclearmyopathy5 and congenital fiber type disproportion6mdashto themalignant hyperthermia (MH) susceptibility trait RYR1mutations may also give rise to episodic neuromuscularmanifestations including exertional myalgia and rhabdo-myolysis7 a late-onset axial myopathy89 and have recentlybeen associated with a novel bleeding disorder due to ab-normal smooth muscle cell contractility10 Episodes of atyp-ical periodic paralysis (PP) have been previously reported ina single patient with a recessive RYR1-related myopathy11
but it has been unclear whether this phenotype was unique tothe reported individual or common across different RYR1genotypes The association between RYR1 and PP is notentirely unexpected considering that dysfunction of Cav11the other key player involved in excitation-contraction cou-pling and the principal RYR1 interactor is the most commoncause of primary PP Recently both dominant and recessivefamilies with a Cav11-related myopathy have been de-scribed12 suggesting further phenotypic overlap betweenRYR1 and Cav11 dysfunction and a continuum betweenmyopathic and episodic phenotypes due to mutations inthese genes Here we report 3 additional RYR1-mutatedpatients presenting with PP episodes and variable additionalmyopathic manifestations
MethodsWe examined cases referred with a possible diagnosis of PPbut additional clinicopathologic findings previously associatedwith RYR1-related disorders to the national referral center forskeletal muscle channelopathies in the United Kingdom andto the Swiss Neuromuscular Diseases Unit Center
Standard protocol approvals registrationsand patient consentsAll procedures were conducted as part of routine clinical careThe study was performed under the ethics guidelines issuedby our institution with written informed consent obtainedfrom all participants for genetic studies
Genetic analysis for PP genes SCN4ACACNA1S andKCNJ2was performed at the Neurogenetics Unit National Hospitalfor Neurology and Neurosurgery as provided by the
Channelopathy Highly Specialized National Service for raredisease Samples underwent next-generation sequencing onan Illumina HiSeq after enrichment with an Illumina customNextera Rapid Capture panel (Illumina Inc San Diego CA)For case 2 the library preparation and enrichment wereperformed with TruSight One kit (Illumina) according toprotocol instructions allowing analysis of a panel of asymp5000genes (including PP genes and RYR1) The library wasquantified with the Qubit 20 Fluorometer system (ThermoFisher Scientific Waltham MA) and 2 times 250-bp paired-endsequencing was performed on the MiSeq sequencer(Illumina) as well as sequences alignment (Burrows-Wheeleraligner) and variant calling (Genome Analysis Toolkit variantcaller) The variants were then analyzed with VariantStudio(Illumina)
Additional targeted RYR1 Sanger sequencing of all cases wasperformed at the Diagnostic DNA Laboratory at GuyrsquosHospital London
ResultsCase 1A 54-year-old man was born 7 weeks prematurely An atrialseptal defect was noted at birth and corrected at the age of5 years Walking was delayed until the age of 2 years He wasnever able to run or to keep up with peers physically becauseof weakness of his arms and legs In early childhood he toe-walked ultimately requiring Achilles tendon lengtheningSymptoms were effectively stable throughout childhood butfrom the age of 20 years there was slowly progressive proxi-mal weakness
At the age of 34 years after a flu-like illness he complained ofa change in symptoms He reported episodes of sudden severemyalgia followed by profound muscle weakness in either1 limb or the entire body from the neck down lasting forseveral hours Examination demonstrated a waddling gait andpronounced lumbar lordosis and mild dysmorphic featureswith a long thin face and high arched palate Mild bilateralptosis with a complex ophthalmoplegia most marked onupgaze a typical finding in recessive RYR1-related myo-pathies was noted There was bilateral facial and sternoclei-domastoid weakness with additional proximal upper andlower limb weakness Reflexes were 1+ and there were nosensory abnormalities Cardiac examination demonstratedatrial fibrillation for which he underwent cardioversion Be-cause of the change in symptoms a muscle biopsy was per-formed Although core-like structures were seen theywere not felt to be typical of central core disease a common
NeurologyorgN Neurology | Volume 90 Number 5 | January 30 2018 e413
RYR1-related myopathy and no definitive diagnosis wasreached (figure 1)
From this point he continued to complain of episodes of tem-porary worsening of limb weakness 2 to 3 times a year lasting forseveral days He could identify no specific triggers At the age of38 years he presented with an episode of severe neck flexor andbulbar weakness Over the course of 9 days his neck flexorweakness improved to baseline Bulbar function remained im-paired and a percutaneous endoscopic gastrostomy (PEG) tubefor feeding was inserted However he continued to report fluc-tuant improvement in his swallow on some days being entirelyreliant on the PEG and on others managing a soft diet Fourteenmonths after the PEG insertion he attended clinic and reportedthat he no longer used it and consistentlymanaged a normal dietVideofluoroscopy demonstrated only minor persisting abnor-malities and the PEG was removed at his request
Over subsequent years he continued to experience acute attacksof myalgia followed by weakness When care was transferred tous he was reinvestigated including a repeatmuscle biopsy at theage of 42 years (figure 2) which on this occasion revealed mildloss of oxidative enzyme activity in the central region of manyfibers but classic central cores were not observed
Electrophysiologic tests showed myopathic EMG featuresnormal repetitive stimulation mildly abnormal jitter and oc-casional blocking on single-fiber EMG (including in extensordigitorum communis biceps and orbicularis oculi) Whileindicative of a mild neuromuscular junction transmission de-fect this was thought likely to be a secondary phenomenonrather than a primary myasthenic feature13 Serologic testingfor acetylcholine receptor antibodies and muscle-specific ki-nase antibodies was negative The McManis test for PP waspositive on 2 separate occasions (53 and 59 decrement in
Figure 1 Histology slides of muscle biopsies taken from case 1 at age (A) 34 and (B) 42 years
(A) Histologic examination of a right quadriceps muscle biopsy performed at age 34 years showed variation in fiber diameter and internalized nuclei withhematoxylin and eosin staining (B) ATPase histochemistry at pH 43 indicated type I fiber predominance with decreased myofibrillar ATPase activity in core-like areas in up to 15 of type I fibers (red arrow) (C) Central absence of staining suggestive of cores was apparent in type I and II fibers in the nicotinamidedinucleotide tetrazolium reductase preparation (black arrows) and central reduction in oxidative enzyme activity was confirmedby succinate dehydrogenasestaining (D black arrow) Scale bar in A represents 100 μm in (A) and (C) 200 μm in (B) and 50 μm in (D)
e414 Neurology | Volume 90 Number 5 | January 30 2018 NeurologyorgN
compound muscle action potential [CMAP] amplitude) MRIdemonstrated fatty infiltration of all thigh muscles in particularthe adductor magnus which was almost completely replacedby fat with relative sparing of the vastus lateralis rectus femorisgracilis and semitendinosus a pattern of selective involvementpreviously associated withRYR1-relatedmyopathies1415 Therewas no family history of similar symptoms Genetic analysisrevealed RYR1 variants Arg109Trp previously describedwith MmD and ophthalmoplegia416 a variant of uncertain
significance Met485Val4 and the novel although presumedtruncating variant Gln70X Testing for congenital myastheniaand PP genes was negative His unaffected mother carried theGln70X variant It was not possible to obtain DNA from hisfather
Case 2A 42-year-old Swiss woman presented with intermittentweakness of the limbs lasting from several minutes to 2 days
Figure 2 Histologic examination of a right biceps muscle biopsy
Histologic examination of a right biceps muscle biopsy performed at age 42 years showed (A) variation in fiber diameter and increased internal nuclei with (B)occasional fibers showing central basophilia (arrow) and (C) a small number of necrotic fibersGomori trichrome staining suggested regions with reducedmitochondrial staining (arrow) (E) ATPasehistochemistry indicated focal type I fiber predominance (darkly stained fibers) (F)Mild central pallor suggestive of coreswas apparent in type I and II fibers in the nicotinamide adenine dinucleotide tetrazolium reductase preparation (arrows) and (G) central reduction in oxidativeenzyme activity was confirmed by cytochrome oxidase histochemistry Scale bar in represents 260 μm in (E) 100 μm in (A) (F) and (G) and 50 μm in (BndashD)
NeurologyorgN Neurology | Volume 90 Number 5 | January 30 2018 e415
Medical history was notable for migraine and 3 caesareansections The first episode of flaccid paresis occurred duringher first pregnancy at the age of 23 years with a fall from thecouch when she could not move her right arm and leg forseveral minutes without associated disturbance of cognitionor sensory symptoms Examination at the emergency roomafter recovery was normal Brain imaging was not performedbecause of the pregnancy Two subsequent EEGs were nor-mal and no specific diagnosis was made at the time She hada history of migraine and we cannot definitively exclude thepossibility that this first episode of unilateral weakness wasa migraine aura without headache However her typical mi-graine episodes are headache and are distinct from this pre-sentation Fifteen years later while driving she notedweakness of her arms legs and trunk severe enough to war-rant stopping the car Weakness recovered slowly after 15minutes A similar episode occurred a few months later Po-tassium levels and clinical examination when asymptomaticwere normal Subsequently the frequency of similar episodeswith flaccid paresis of her limbs affecting predominantly thelegs and lasting several minutes increased and they occurreddaily always after resting No correlation with food intake orfasting was reported In addition she complained of painlesscramps in her arms and legs muscles which could becomepainful if she tried to stretch her muscles These lasted up to10 minutes and also occurred during sleep
A detailed neurologic examination at the age of 42 yearsrevealed no abnormalities A relatively thin and long face witha small lower jaw was noted but she was not overtly dys-morphic On follow-up examination she presented withflaccid weakness of her right hand lasting for 2 days Motorand sensory nerve conduction studies repetitive motor nervestimulation and EMG in the limbs and paravertebral musclesperformed after recovery from the acute episode were un-remarkable The McManis test was negative Laboratorytesting revealed no thyroid dysfunction electrolytes andcreatine kinase were normal Muscle biopsy of the tibialisanterior muscle was unremarkable Genetic testing revealedRYR1 gene variants Arg1507Gln and Gly2446Ser in transArg1507Gln is a missense variant with a minor allele fre-quency of 000001 in ExAC that has been previously found inother myopathic phenotypes Gly2446Ser although notpreviously reported localizes to a recognized MH-associatedmutational hot spot (wwwemhgorg) PP gene testing wasnegative
Case 3This 49-year-old man reported experiencing episodes of mi-nor limb weakness after strenuous exercise that lasted a fewhours from the age of 14 years He had his first full attack ofmuscle paralysis at the age of 29 years He awoke in themorning after a day of strenuous exercise to find that he wasunable to walk From this age on he experienced multiplesimilar episodes All muscles from the neck down could beweak although the legs were predominantly and mostseverely affected Symptoms usually lasted for several hours
but could persist for as long as 48 hours In the recovery phasehe reported that the limbs could be painful as strengthreturned Symptoms could be provoked by exercise intenseheat or a carbohydrate-rich meal late at night
Medical history was notable for 2 complicated general anes-thetics in childhood although the exact circumstances wereunclear and medical records unavailable His parents wereadvised after these that he may be at risk of MH and to informclinicians before any future procedures requiring generalanesthesia
Examination was unremarkable as was creatine kinase andMRI of the lower limbs EMG and nerve conduction studywere normal but theMcManis test for PP was positive with anexercise-induced reduction of CMAP of 68 A biopsy of thetibialis anterior muscle demonstrated variation in fiber size anincrease in internal nuclei and 1 ring fiber (figure e-1 httplinkslwwcomWNLA96) A type I fiber predominance wasinterpreted as normal for the muscle biopsied Genetic testingfor PP genes was negative but an RYR1 variant Arg1043Hiswas identified Another amino acid substitution at the samesite Arg1043Cys previously associated with the MH trait butnot functionally tested yet (wwwemhgorg) has beendescribed
DiscussionWe have previously reported a single patient with recessiveRYR1-related MmD with additional episodic muscle weak-nessparalysis11 Here we have described 3 additional cases(summarized in the table) One was compound heterozygousfor RYR1 nonsense and missense mutations and presentedwith later development of episodic symptoms in the context ofa congenital myopathy similar to our original patient reportedby Zhou et al17 who showed a comparable genotype andphenotype The other 2 patients had an episodic phenotypewithout myopathy and were either heterozygous for or com-pound heterozygous forRYR1missensemutations (putatively)implicated in the MH trait suggesting tentative genotype-phenotype correlations In all cases (including our originalcase) the onset of episodic muscle paralysis was from earlyadulthood onward which is later than the onset typically seenin primary PP17 Although there were variable triggers in-cluding exertion or rest after exertion which is a typical triggerfor PP there was no consistent relationship to food or tem-perature across all the cases Myalgia or cramp was a universalfeature indicating overlap with the spectrum of RYR1-relatedexertional myalgiarhabdomyolysis and this together with thelater age at onset may be a phenotypic clue for future cases
The McManis test was positive in 2 of 3 of our new cases Weretrospectively reviewed the source data for our previouslyreported case11 and found that the drop in CMAP amplitudewhen calculated from the postexercise increment was alsogt40 indicating a positive test
e416 Neurology | Volume 90 Number 5 | January 30 2018 NeurologyorgN
A positive McManis test to the best of our knowledge haspreviously been described only in primary or secondaryPP18 Given the direct interaction between the Cav11channel implicated in the majority of cases of hypokalemicPP19 and RYR1 it seems plausible that dysfunction of eachmay produce phenotypic mimics This is supported by theobservation of a profound disturbance of the normalCav11RYR1 interaction in 1 previous patient with RYR1-related PP and other patients with recessive RYR1-relatedmyopathies1120 Furthermore the recently described CAC-NA1S-associated early-onset myopathy shares features ofpredominantly axial weakness and ophthalmoplegia withRYR1-related myopathies12 and may also feature similarreductions of the Cav11 protein However the exactmechanism by which the RYR1 variants would cause anepisodically unexcitable sarcolemma as demonstrated bya positive McManis test is unclear On the basis of the recentobservation of altered BK channel activity in RYR1-mutatedsmooth muscle cells10 one possibility is via an impairment ofBK channelndashmediated membrane repolarization due toaltered intracellular calcium homeostasis but this requiresfurther study102122
Other atypical PP phenotypes associated with motor neurop-athy due to mitochondrial gene mutations have beendescribed23 demonstrating that the clinical symptoms may beseen in nonndashion channel genetic disorders Our data demon-strate that late-onset episodic muscle weakness or paralysiswith prominent myalgia and cramps may be a more commonRYR1-associated phenotype than the single case we previously
reported and may not be limited to a specific genotype Wesuggest that cases compound heterozygous for RYR1 nonsenseand missense mutations are more likely to have a concomitantearly-onset myopathy The McManis test may be a useful di-agnostic tool in these cases although a negative test does notexclude the possibility of RYR1 involvement
We propose that clinicopathologic features suggestive ofRYR1 disorders should be sought in genetically undefined PPcases and RYR1 gene testing considered in those in whommutations in SCN4A CACNA1S and KCNJ2 have alreadybeen excluded
Author contributionsE Matthews drafting the manuscript for content analysis orinterpretation of data study concept C Neuwirth andF Jaffer revising the manuscript for content analysis orinterpretation of data study concept R Scalco D FialhoM Parton R Sud R Spiegel R Mein D Raja RayanK Suetterlin H Houlden A Schaefer E Healy J PalaceR Quinlivan S Treves and JL Holton revising the man-uscript for content analysis or interpretation of dataH Jungbluth drafting the manuscript for content analysisor interpretation of data study concept MG Hannarevising the manuscript for content analysis or in-terpretation of data
AcknowledgmentThe authors are grateful to Mark Walker at Southampton forthe retrieval of muscle histology slides
Table Summary of clinicopathologic features of cases with RYR1 gene variants and episodic weaknessparalysis
Symptoms ExaminationCKIUL EMG
McManistest Muscle biopsy
RYR1variants
Previouslyreportedcase11
Hypotonia respiratory andfeeding impairment at birthdelayed motor milestonesepisodic limb weaknesslasting days from age 18 ycold- and exercise-inducedmyalgiacramp from age 26 y
High arched palatefacial weaknessophthalmoplegiasevere trunk and neckweakness moderatelimb weaknesshyperlordosis
Normalrange
Myopathic Positive Variation in fibersize increasedinternal nucleicore-like structures
Asp708AsnArg2241XArg2939Lys
Case 1 Delayed walking early onsetproximal myopathy episodicmyalgia followed by limb andneck weakness lasting hoursto days from age 34 yfluctuant bulbar weakness
Long thin face higharched palate proximalmyopathy facialweakness and ptosisophthalmoplegiahyperlordosis
101 Myopathicincreasedjitter andblocking onSFEMG
Positive Variation in fibersize increasedinternal nucleiareas of centralpallor suggestive ofcore-like structures
Gln70XArg109TrpMet485Val
Case 2 Early history anddevelopment normalepisodic limb weakness fromage 23 y cramps withmyalgia
Long thin face 120 Normal Negative Normal Arg1507GlnGly2446Ser
Case 3 Early history anddevelopment normal minorepisodic weakness from age14 y episodic limb paralysisand myalgia from age 29 y
Normal 92 Normal Positive Type 1predominance 1ragged red fiber(+COX negative)increased internalnuclei 1 ring fiber
Arg1043His
Abbreviations CK = creatine kinase SFEMG = single-fiber EMG
NeurologyorgN Neurology | Volume 90 Number 5 | January 30 2018 e417
Study fundingPart of this work was undertaken at University College LondonHospitalsUniversity College London which received aproportion of funding from the Department of HealthrsquosNational Institute for Health Research Biomedical ResearchCentres funding scheme
DisclosureE Matthews holds a post-doctoral fellowship from the Na-tional Institute for Health Research Rare Disease SchemeC Neuwirth F Jaffer and R Scalco report no disclosuresrelevant to the manuscript D Fialho is supported by theNational Highly Specialised Service Department of HealthUK M Parton R Sud R Spiegel R Mein and D Rayanreport no disclosures relevant to the manuscript K Suetterlinhas an MRC Clinical Research Training Fellowship and re-ceived funding from the European Communityrsquos SeventhFramework Programme (FP72007-2013) under grantagreement 2012-305121 ldquoIntegrated European-omics Re-search Project for Diagnosis and Therapy in Rare Neuro-muscular and Neurodegenerative Diseases (NEUROMICS)rdquoH Houlden has received funding from the European Com-munityrsquos Seventh Framework Programme (FP72007-2013)under grant agreement 2012-305121 ldquoIntegratedEuropean-omics Research Project for Diagnosis andTherapy in Rare Neuromuscular and NeurodegenerativeDiseases (NEUROMICS)rdquo A Schaefer and E Healy reportno disclosures relevant to the manuscript J Palace is partlyfunded by Highly Specialised Services to run national con-genital myasthenia and neuromyelitis optica services and hasreceived support for scientific meetings and honorariums foradvisory work from Merck Serono Biogen Idec NovartisTeva Chugai Pharma and Bayer Schering as well as un-restricted grants from Merck Serono Novartis Biogen IdecTeva and Bayer Schering Her hospital trust receives funds forher role as clinical lead for the Department of Health RiskSharing Scheme She has received grants from the MS societyand Guthy-Jackson Foundation R Quinlivan is supported bythe National Highly Specialised Service Department ofHealth UK andNational Institute for Health Research and hasgrant funding from Muscular Dystrophy UK and Associationfor Glycogen Storage Disease She has received honoraria forteaching and consultancy from PTC Therapeutics Sanofi-Genzyme and Ultragenyx S Treves reports no disclosuresrelevant to the manuscript J Holton is supported by the RetaLila Weston Institute for Neurologic Studies H Jungbluthreports no disclosures relevant to the manuscript M Hanna is
supported by a Medical Research Council Centre grant theNational Centre for Research Resources and the NationalHighly Specialised Service Department of Health UK Go toNeurologyorgN for full disclosures
Received June 9 2017 Accepted in final form October 24 2017
References1 Amburgey K McNamara N Bennett LR McCormick ME Acsadi G Dowling JJ
Prevalence of congenital myopathies in a representative pediatric United Statespopulation Ann Neurol 201170662ndash665
2 Maggi L Scoto M Cirak S et al Congenital myopathies clinical features and fre-quency of individual subtypes diagnosed over a 5-year period in the United KingdomNeuromuscul Disord 201323195ndash205
3 Zhang Y Chen HS Khanna VK et al A mutation in the human ryanodine receptorgene associated with central core disease Nat Genet 1993546ndash50
4 Jungbluth H Zhou H Hartley L et al Minicore myopathy with ophthalmoplegiacaused by mutations in the ryanodine receptor type 1 gene Neurology 2005651930ndash1935
5 Wilmshurst JM Lillis S Zhou H et al RYR1 mutations are a common cause ofcongenital myopathies with central nuclei Ann Neurol 201068717ndash726
6 Clarke NF Waddell LB Cooper ST et al Recessive mutations in RYR1 are a com-mon cause of congenital fiber type disproportion Hum Mutat 201031E1544ndashE1550
7 Dlamini N Voermans NC Lillis S et al Mutations in RYR1 are a common cause ofexertional myalgia and rhabdomyolysis Neuromuscul Disord 201323540ndash548
8 Jungbluth H Lillis S Zhou H et al Late-onset axial myopathy with cores due toa novel heterozygous dominant mutation in the skeletal muscle ryanodine receptor(RYR1) gene Neuromuscul Disord 200919344ndash347
9 Loseth S Voermans NC Torbergsen T et al A novel late-onset axial myopathyassociated with mutations in the skeletal muscle ryanodine receptor (RYR1) geneJ Neurol 20132601504ndash1510
10 Lopez RJ Byrne S Vukcevic M et al An RYR1 mutation associated with malignanthyperthermia is also associated with bleeding abnormalities Sci Signal 20169ra68
11 Zhou H Lillis S Loy RE et al Multi-minicore disease and atypical periodic paralysisassociated with novel mutations in the skeletal muscle ryanodine receptor (RYR1)gene Neuromuscul Disord 201020166ndash173
12 Schartner V Romero NB Donkervoort S et al Dihydropyridine receptor (DHPRCACNA1S) congenital myopathy Acta Neuropathol 2017133517ndash533
13 Illingworth MA Main M Pitt M et al RYR1-related congenital myopathy withfatigable weakness responding to pyridostigimine Neuromuscul Disord 201424707ndash712
14 Jungbluth H Davis MR Muller C et al Magnetic resonance imaging of muscle incongenital myopathies associated with RYR1 mutations Neuromuscul Disord 200414785ndash790
15 Klein A Jungbluth H Clement E et al Muscle magnetic resonance imaging incongenital myopathies due to ryanodine receptor type 1 gene mutations Arch Neurol2011681171ndash1179
16 Zhou H Jungbluth H Sewry CA et al Molecular mechanisms and phenotypicvariation in RYR1-related congenital myopathies Brain 20071302024ndash2036
17 Venance SL Cannon SC Fialho D et al The primary periodic paralyses diagnosispathogenesis and treatment Brain 20061298ndash17
18 McManis PG Lambert EH Daube JR The exercise test in periodic paralysis MuscleNerve 19869704ndash710
19 Matthews E Labrum R Sweeney MG et al Voltage sensor charge loss accounts formost cases of hypokalemic periodic paralysis Neurology 2009721544ndash1547
20 Zhou H Rokach O Feng L et al RyR1 deficiency in congenital myopathies disruptsexcitation-contraction coupling Hum Mutat 201334986ndash996
21 Tricarico D Mele A Conte CD Carbonic anhydrase inhibitors ameliorate thesymptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels Neuromuscul Disord 20061639ndash45
22 Kim JB Kim SJ Kang SY Yi JW Kim SM The large-conductance calcium-activatedpotassium channel holds the key to the conundrum of familial hypokalemic periodicparalysis Korean J Pediatr 201457445ndash450
23 Aure K Dubourg O Jardel C et al Episodic weakness due to mitochondrial DNAMT-ATP68 mutations Neurology 2013811810ndash1818
e418 Neurology | Volume 90 Number 5 | January 30 2018 NeurologyorgN
SOURCE ARTICLE NPuborg5fjlcp
Atypical periodic paralysis and myalgiaAnovelRYR1 phenotype
Emma Matthews MRCP Christoph Neuwirth MD Fatima Jaffer MRCP Renata S Scalco MD
Doreen Fialho MRCP Matt Parton FRCP Dipa Raja Rayan MRCP Karen Suetterlin MRCP Richa Sud PhD
Roland Spiegel MD Rachel Mein BSc Henry Houlden FRCP Andrew Schaefer MRCP Estelle Healy FRCPath
Jacqueline Palace FRCP Ros Quinlivan FRCP Susan Treves PhD Janice L Holton FRCPath
Heinz Jungbluth PhD and Michael G Hanna FRCP
Cite as Neurologyreg 201890e412ndashe418 doi101212WNL0000000000004894
Correspondence
Dr Matthews
emmamatthewsuclacuk
Study questionWhat are the phenotypic characteristics of patients with pe-riodic paralysis (PP) symptoms and RYR1 mutations
Summary answerThese patients can have late-onset atypical PP with or withoutmyopathy and with myalgia and cramps as prominent features
What is known and what this paper addsRYR1 mutations are associated with diverse neuromusculardisorders including 1 reported case of atypical PP This studydescribes the phenotypes of 3 more patients with RYR1mutations and PP episodes
Participants and settingThis study reports 3 patients with possible PP diagnosesand clinicopathologic findings typically associated withRYR1-related disorders who were referred to UK and Swissspecialist centers
Design size and durationMedical histories were collected for all 3 patients Thesehistories includedmuscle examinations at various ages Sangersequencing for RYR1 was performed on patient samples
Main results and the role of chanceCase 1 was a 54-year-old man who had lifelong muscleweakness At 34 years old he experienced worsened symp-toms including sudden severe myalgia Examinations revealedvarious neuromuscular abnormalities including positiveresults on the McManis test for PP Case 2 was a 42-year-oldwoman who had experienced episodic muscle weakness andmigraine symptoms since the age of 23 years A neurologicexamination yielded unremarkable results and the McManistest yielded negative results Case 3 was a 49-year-old man
who had experienced postexercise limb weakness episodessince 14 years of age and full muscle paralysis episodes since29 years of age Neurologic examinations yielded unremark-able results but the McManis test yielded positive results All3 patients carried various RYR1 mutations and reported my-algia andor muscle cramps
Bias confounding and other reasonsfor cautionThese case reports do not firmly establish a genotype-phenotype relationship or explain the physiologic mecha-nism by which RYR1 mutations would cause late-onsetatypical PP
Generalizability to other populationsLate-onset atypical PP may be more common in persons withRYR1 mutations than the single previous report suggested
Study fundingpotential competing interestsThis study was funded by the UK Department of HealthSome authors report receiving funding from the UKand European Union governments pharmaceutical com-panies and medical research foundations Some authorsreport receiving personal compensation from pharma-ceutical companies Go to NeurologyorgN for fulldisclosures
Patient RYR1 variants
Previously reported Asp708Asn Arg2241X Arg2939Lys
Case 1 Gln70X Arg109Trp Met485Val
Case 2 Arg1507Gln Gly2446Ser
Case 3 Arg1043His
A draft of the short-form article was written by M Dalefield a writer with Editage a division of Cactus Communications The authors of thefull-length article and the journal editors edited and approved the final version
Copyright copy 2018 American Academy of Neurology 219
SHORT-FORM ARTICLE
DOI 101212WNL0000000000004894201890e412-e418 Published Online before print January 3 2018Neurology
Emma Matthews Christoph Neuwirth Fatima Jaffer et al Atypical periodic paralysis and myalgia A novel RYR1 phenotype
This information is current as of January 3 2018
ServicesUpdated Information amp
httpnneurologyorgcontent905e412fullincluding high resolution figures can be found at
httpnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online
0028-3878 Online ISSN 1526-632XKluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print ISSN1951 it is now a weekly with 48 issues per year Copyright copy 2018 The Author(s) Published by Wolters
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
RYR1-related myopathy and no definitive diagnosis wasreached (figure 1)
From this point he continued to complain of episodes of tem-porary worsening of limb weakness 2 to 3 times a year lasting forseveral days He could identify no specific triggers At the age of38 years he presented with an episode of severe neck flexor andbulbar weakness Over the course of 9 days his neck flexorweakness improved to baseline Bulbar function remained im-paired and a percutaneous endoscopic gastrostomy (PEG) tubefor feeding was inserted However he continued to report fluc-tuant improvement in his swallow on some days being entirelyreliant on the PEG and on others managing a soft diet Fourteenmonths after the PEG insertion he attended clinic and reportedthat he no longer used it and consistentlymanaged a normal dietVideofluoroscopy demonstrated only minor persisting abnor-malities and the PEG was removed at his request
Over subsequent years he continued to experience acute attacksof myalgia followed by weakness When care was transferred tous he was reinvestigated including a repeatmuscle biopsy at theage of 42 years (figure 2) which on this occasion revealed mildloss of oxidative enzyme activity in the central region of manyfibers but classic central cores were not observed
Electrophysiologic tests showed myopathic EMG featuresnormal repetitive stimulation mildly abnormal jitter and oc-casional blocking on single-fiber EMG (including in extensordigitorum communis biceps and orbicularis oculi) Whileindicative of a mild neuromuscular junction transmission de-fect this was thought likely to be a secondary phenomenonrather than a primary myasthenic feature13 Serologic testingfor acetylcholine receptor antibodies and muscle-specific ki-nase antibodies was negative The McManis test for PP waspositive on 2 separate occasions (53 and 59 decrement in
Figure 1 Histology slides of muscle biopsies taken from case 1 at age (A) 34 and (B) 42 years
(A) Histologic examination of a right quadriceps muscle biopsy performed at age 34 years showed variation in fiber diameter and internalized nuclei withhematoxylin and eosin staining (B) ATPase histochemistry at pH 43 indicated type I fiber predominance with decreased myofibrillar ATPase activity in core-like areas in up to 15 of type I fibers (red arrow) (C) Central absence of staining suggestive of cores was apparent in type I and II fibers in the nicotinamidedinucleotide tetrazolium reductase preparation (black arrows) and central reduction in oxidative enzyme activity was confirmedby succinate dehydrogenasestaining (D black arrow) Scale bar in A represents 100 μm in (A) and (C) 200 μm in (B) and 50 μm in (D)
e414 Neurology | Volume 90 Number 5 | January 30 2018 NeurologyorgN
compound muscle action potential [CMAP] amplitude) MRIdemonstrated fatty infiltration of all thigh muscles in particularthe adductor magnus which was almost completely replacedby fat with relative sparing of the vastus lateralis rectus femorisgracilis and semitendinosus a pattern of selective involvementpreviously associated withRYR1-relatedmyopathies1415 Therewas no family history of similar symptoms Genetic analysisrevealed RYR1 variants Arg109Trp previously describedwith MmD and ophthalmoplegia416 a variant of uncertain
significance Met485Val4 and the novel although presumedtruncating variant Gln70X Testing for congenital myastheniaand PP genes was negative His unaffected mother carried theGln70X variant It was not possible to obtain DNA from hisfather
Case 2A 42-year-old Swiss woman presented with intermittentweakness of the limbs lasting from several minutes to 2 days
Figure 2 Histologic examination of a right biceps muscle biopsy
Histologic examination of a right biceps muscle biopsy performed at age 42 years showed (A) variation in fiber diameter and increased internal nuclei with (B)occasional fibers showing central basophilia (arrow) and (C) a small number of necrotic fibersGomori trichrome staining suggested regions with reducedmitochondrial staining (arrow) (E) ATPasehistochemistry indicated focal type I fiber predominance (darkly stained fibers) (F)Mild central pallor suggestive of coreswas apparent in type I and II fibers in the nicotinamide adenine dinucleotide tetrazolium reductase preparation (arrows) and (G) central reduction in oxidativeenzyme activity was confirmed by cytochrome oxidase histochemistry Scale bar in represents 260 μm in (E) 100 μm in (A) (F) and (G) and 50 μm in (BndashD)
NeurologyorgN Neurology | Volume 90 Number 5 | January 30 2018 e415
Medical history was notable for migraine and 3 caesareansections The first episode of flaccid paresis occurred duringher first pregnancy at the age of 23 years with a fall from thecouch when she could not move her right arm and leg forseveral minutes without associated disturbance of cognitionor sensory symptoms Examination at the emergency roomafter recovery was normal Brain imaging was not performedbecause of the pregnancy Two subsequent EEGs were nor-mal and no specific diagnosis was made at the time She hada history of migraine and we cannot definitively exclude thepossibility that this first episode of unilateral weakness wasa migraine aura without headache However her typical mi-graine episodes are headache and are distinct from this pre-sentation Fifteen years later while driving she notedweakness of her arms legs and trunk severe enough to war-rant stopping the car Weakness recovered slowly after 15minutes A similar episode occurred a few months later Po-tassium levels and clinical examination when asymptomaticwere normal Subsequently the frequency of similar episodeswith flaccid paresis of her limbs affecting predominantly thelegs and lasting several minutes increased and they occurreddaily always after resting No correlation with food intake orfasting was reported In addition she complained of painlesscramps in her arms and legs muscles which could becomepainful if she tried to stretch her muscles These lasted up to10 minutes and also occurred during sleep
A detailed neurologic examination at the age of 42 yearsrevealed no abnormalities A relatively thin and long face witha small lower jaw was noted but she was not overtly dys-morphic On follow-up examination she presented withflaccid weakness of her right hand lasting for 2 days Motorand sensory nerve conduction studies repetitive motor nervestimulation and EMG in the limbs and paravertebral musclesperformed after recovery from the acute episode were un-remarkable The McManis test was negative Laboratorytesting revealed no thyroid dysfunction electrolytes andcreatine kinase were normal Muscle biopsy of the tibialisanterior muscle was unremarkable Genetic testing revealedRYR1 gene variants Arg1507Gln and Gly2446Ser in transArg1507Gln is a missense variant with a minor allele fre-quency of 000001 in ExAC that has been previously found inother myopathic phenotypes Gly2446Ser although notpreviously reported localizes to a recognized MH-associatedmutational hot spot (wwwemhgorg) PP gene testing wasnegative
Case 3This 49-year-old man reported experiencing episodes of mi-nor limb weakness after strenuous exercise that lasted a fewhours from the age of 14 years He had his first full attack ofmuscle paralysis at the age of 29 years He awoke in themorning after a day of strenuous exercise to find that he wasunable to walk From this age on he experienced multiplesimilar episodes All muscles from the neck down could beweak although the legs were predominantly and mostseverely affected Symptoms usually lasted for several hours
but could persist for as long as 48 hours In the recovery phasehe reported that the limbs could be painful as strengthreturned Symptoms could be provoked by exercise intenseheat or a carbohydrate-rich meal late at night
Medical history was notable for 2 complicated general anes-thetics in childhood although the exact circumstances wereunclear and medical records unavailable His parents wereadvised after these that he may be at risk of MH and to informclinicians before any future procedures requiring generalanesthesia
Examination was unremarkable as was creatine kinase andMRI of the lower limbs EMG and nerve conduction studywere normal but theMcManis test for PP was positive with anexercise-induced reduction of CMAP of 68 A biopsy of thetibialis anterior muscle demonstrated variation in fiber size anincrease in internal nuclei and 1 ring fiber (figure e-1 httplinkslwwcomWNLA96) A type I fiber predominance wasinterpreted as normal for the muscle biopsied Genetic testingfor PP genes was negative but an RYR1 variant Arg1043Hiswas identified Another amino acid substitution at the samesite Arg1043Cys previously associated with the MH trait butnot functionally tested yet (wwwemhgorg) has beendescribed
DiscussionWe have previously reported a single patient with recessiveRYR1-related MmD with additional episodic muscle weak-nessparalysis11 Here we have described 3 additional cases(summarized in the table) One was compound heterozygousfor RYR1 nonsense and missense mutations and presentedwith later development of episodic symptoms in the context ofa congenital myopathy similar to our original patient reportedby Zhou et al17 who showed a comparable genotype andphenotype The other 2 patients had an episodic phenotypewithout myopathy and were either heterozygous for or com-pound heterozygous forRYR1missensemutations (putatively)implicated in the MH trait suggesting tentative genotype-phenotype correlations In all cases (including our originalcase) the onset of episodic muscle paralysis was from earlyadulthood onward which is later than the onset typically seenin primary PP17 Although there were variable triggers in-cluding exertion or rest after exertion which is a typical triggerfor PP there was no consistent relationship to food or tem-perature across all the cases Myalgia or cramp was a universalfeature indicating overlap with the spectrum of RYR1-relatedexertional myalgiarhabdomyolysis and this together with thelater age at onset may be a phenotypic clue for future cases
The McManis test was positive in 2 of 3 of our new cases Weretrospectively reviewed the source data for our previouslyreported case11 and found that the drop in CMAP amplitudewhen calculated from the postexercise increment was alsogt40 indicating a positive test
e416 Neurology | Volume 90 Number 5 | January 30 2018 NeurologyorgN
A positive McManis test to the best of our knowledge haspreviously been described only in primary or secondaryPP18 Given the direct interaction between the Cav11channel implicated in the majority of cases of hypokalemicPP19 and RYR1 it seems plausible that dysfunction of eachmay produce phenotypic mimics This is supported by theobservation of a profound disturbance of the normalCav11RYR1 interaction in 1 previous patient with RYR1-related PP and other patients with recessive RYR1-relatedmyopathies1120 Furthermore the recently described CAC-NA1S-associated early-onset myopathy shares features ofpredominantly axial weakness and ophthalmoplegia withRYR1-related myopathies12 and may also feature similarreductions of the Cav11 protein However the exactmechanism by which the RYR1 variants would cause anepisodically unexcitable sarcolemma as demonstrated bya positive McManis test is unclear On the basis of the recentobservation of altered BK channel activity in RYR1-mutatedsmooth muscle cells10 one possibility is via an impairment ofBK channelndashmediated membrane repolarization due toaltered intracellular calcium homeostasis but this requiresfurther study102122
Other atypical PP phenotypes associated with motor neurop-athy due to mitochondrial gene mutations have beendescribed23 demonstrating that the clinical symptoms may beseen in nonndashion channel genetic disorders Our data demon-strate that late-onset episodic muscle weakness or paralysiswith prominent myalgia and cramps may be a more commonRYR1-associated phenotype than the single case we previously
reported and may not be limited to a specific genotype Wesuggest that cases compound heterozygous for RYR1 nonsenseand missense mutations are more likely to have a concomitantearly-onset myopathy The McManis test may be a useful di-agnostic tool in these cases although a negative test does notexclude the possibility of RYR1 involvement
We propose that clinicopathologic features suggestive ofRYR1 disorders should be sought in genetically undefined PPcases and RYR1 gene testing considered in those in whommutations in SCN4A CACNA1S and KCNJ2 have alreadybeen excluded
Author contributionsE Matthews drafting the manuscript for content analysis orinterpretation of data study concept C Neuwirth andF Jaffer revising the manuscript for content analysis orinterpretation of data study concept R Scalco D FialhoM Parton R Sud R Spiegel R Mein D Raja RayanK Suetterlin H Houlden A Schaefer E Healy J PalaceR Quinlivan S Treves and JL Holton revising the man-uscript for content analysis or interpretation of dataH Jungbluth drafting the manuscript for content analysisor interpretation of data study concept MG Hannarevising the manuscript for content analysis or in-terpretation of data
AcknowledgmentThe authors are grateful to Mark Walker at Southampton forthe retrieval of muscle histology slides
Table Summary of clinicopathologic features of cases with RYR1 gene variants and episodic weaknessparalysis
Symptoms ExaminationCKIUL EMG
McManistest Muscle biopsy
RYR1variants
Previouslyreportedcase11
Hypotonia respiratory andfeeding impairment at birthdelayed motor milestonesepisodic limb weaknesslasting days from age 18 ycold- and exercise-inducedmyalgiacramp from age 26 y
High arched palatefacial weaknessophthalmoplegiasevere trunk and neckweakness moderatelimb weaknesshyperlordosis
Normalrange
Myopathic Positive Variation in fibersize increasedinternal nucleicore-like structures
Asp708AsnArg2241XArg2939Lys
Case 1 Delayed walking early onsetproximal myopathy episodicmyalgia followed by limb andneck weakness lasting hoursto days from age 34 yfluctuant bulbar weakness
Long thin face higharched palate proximalmyopathy facialweakness and ptosisophthalmoplegiahyperlordosis
101 Myopathicincreasedjitter andblocking onSFEMG
Positive Variation in fibersize increasedinternal nucleiareas of centralpallor suggestive ofcore-like structures
Gln70XArg109TrpMet485Val
Case 2 Early history anddevelopment normalepisodic limb weakness fromage 23 y cramps withmyalgia
Long thin face 120 Normal Negative Normal Arg1507GlnGly2446Ser
Case 3 Early history anddevelopment normal minorepisodic weakness from age14 y episodic limb paralysisand myalgia from age 29 y
Normal 92 Normal Positive Type 1predominance 1ragged red fiber(+COX negative)increased internalnuclei 1 ring fiber
Arg1043His
Abbreviations CK = creatine kinase SFEMG = single-fiber EMG
NeurologyorgN Neurology | Volume 90 Number 5 | January 30 2018 e417
Study fundingPart of this work was undertaken at University College LondonHospitalsUniversity College London which received aproportion of funding from the Department of HealthrsquosNational Institute for Health Research Biomedical ResearchCentres funding scheme
DisclosureE Matthews holds a post-doctoral fellowship from the Na-tional Institute for Health Research Rare Disease SchemeC Neuwirth F Jaffer and R Scalco report no disclosuresrelevant to the manuscript D Fialho is supported by theNational Highly Specialised Service Department of HealthUK M Parton R Sud R Spiegel R Mein and D Rayanreport no disclosures relevant to the manuscript K Suetterlinhas an MRC Clinical Research Training Fellowship and re-ceived funding from the European Communityrsquos SeventhFramework Programme (FP72007-2013) under grantagreement 2012-305121 ldquoIntegrated European-omics Re-search Project for Diagnosis and Therapy in Rare Neuro-muscular and Neurodegenerative Diseases (NEUROMICS)rdquoH Houlden has received funding from the European Com-munityrsquos Seventh Framework Programme (FP72007-2013)under grant agreement 2012-305121 ldquoIntegratedEuropean-omics Research Project for Diagnosis andTherapy in Rare Neuromuscular and NeurodegenerativeDiseases (NEUROMICS)rdquo A Schaefer and E Healy reportno disclosures relevant to the manuscript J Palace is partlyfunded by Highly Specialised Services to run national con-genital myasthenia and neuromyelitis optica services and hasreceived support for scientific meetings and honorariums foradvisory work from Merck Serono Biogen Idec NovartisTeva Chugai Pharma and Bayer Schering as well as un-restricted grants from Merck Serono Novartis Biogen IdecTeva and Bayer Schering Her hospital trust receives funds forher role as clinical lead for the Department of Health RiskSharing Scheme She has received grants from the MS societyand Guthy-Jackson Foundation R Quinlivan is supported bythe National Highly Specialised Service Department ofHealth UK andNational Institute for Health Research and hasgrant funding from Muscular Dystrophy UK and Associationfor Glycogen Storage Disease She has received honoraria forteaching and consultancy from PTC Therapeutics Sanofi-Genzyme and Ultragenyx S Treves reports no disclosuresrelevant to the manuscript J Holton is supported by the RetaLila Weston Institute for Neurologic Studies H Jungbluthreports no disclosures relevant to the manuscript M Hanna is
supported by a Medical Research Council Centre grant theNational Centre for Research Resources and the NationalHighly Specialised Service Department of Health UK Go toNeurologyorgN for full disclosures
Received June 9 2017 Accepted in final form October 24 2017
References1 Amburgey K McNamara N Bennett LR McCormick ME Acsadi G Dowling JJ
Prevalence of congenital myopathies in a representative pediatric United Statespopulation Ann Neurol 201170662ndash665
2 Maggi L Scoto M Cirak S et al Congenital myopathies clinical features and fre-quency of individual subtypes diagnosed over a 5-year period in the United KingdomNeuromuscul Disord 201323195ndash205
3 Zhang Y Chen HS Khanna VK et al A mutation in the human ryanodine receptorgene associated with central core disease Nat Genet 1993546ndash50
4 Jungbluth H Zhou H Hartley L et al Minicore myopathy with ophthalmoplegiacaused by mutations in the ryanodine receptor type 1 gene Neurology 2005651930ndash1935
5 Wilmshurst JM Lillis S Zhou H et al RYR1 mutations are a common cause ofcongenital myopathies with central nuclei Ann Neurol 201068717ndash726
6 Clarke NF Waddell LB Cooper ST et al Recessive mutations in RYR1 are a com-mon cause of congenital fiber type disproportion Hum Mutat 201031E1544ndashE1550
7 Dlamini N Voermans NC Lillis S et al Mutations in RYR1 are a common cause ofexertional myalgia and rhabdomyolysis Neuromuscul Disord 201323540ndash548
8 Jungbluth H Lillis S Zhou H et al Late-onset axial myopathy with cores due toa novel heterozygous dominant mutation in the skeletal muscle ryanodine receptor(RYR1) gene Neuromuscul Disord 200919344ndash347
9 Loseth S Voermans NC Torbergsen T et al A novel late-onset axial myopathyassociated with mutations in the skeletal muscle ryanodine receptor (RYR1) geneJ Neurol 20132601504ndash1510
10 Lopez RJ Byrne S Vukcevic M et al An RYR1 mutation associated with malignanthyperthermia is also associated with bleeding abnormalities Sci Signal 20169ra68
11 Zhou H Lillis S Loy RE et al Multi-minicore disease and atypical periodic paralysisassociated with novel mutations in the skeletal muscle ryanodine receptor (RYR1)gene Neuromuscul Disord 201020166ndash173
12 Schartner V Romero NB Donkervoort S et al Dihydropyridine receptor (DHPRCACNA1S) congenital myopathy Acta Neuropathol 2017133517ndash533
13 Illingworth MA Main M Pitt M et al RYR1-related congenital myopathy withfatigable weakness responding to pyridostigimine Neuromuscul Disord 201424707ndash712
14 Jungbluth H Davis MR Muller C et al Magnetic resonance imaging of muscle incongenital myopathies associated with RYR1 mutations Neuromuscul Disord 200414785ndash790
15 Klein A Jungbluth H Clement E et al Muscle magnetic resonance imaging incongenital myopathies due to ryanodine receptor type 1 gene mutations Arch Neurol2011681171ndash1179
16 Zhou H Jungbluth H Sewry CA et al Molecular mechanisms and phenotypicvariation in RYR1-related congenital myopathies Brain 20071302024ndash2036
17 Venance SL Cannon SC Fialho D et al The primary periodic paralyses diagnosispathogenesis and treatment Brain 20061298ndash17
18 McManis PG Lambert EH Daube JR The exercise test in periodic paralysis MuscleNerve 19869704ndash710
19 Matthews E Labrum R Sweeney MG et al Voltage sensor charge loss accounts formost cases of hypokalemic periodic paralysis Neurology 2009721544ndash1547
20 Zhou H Rokach O Feng L et al RyR1 deficiency in congenital myopathies disruptsexcitation-contraction coupling Hum Mutat 201334986ndash996
21 Tricarico D Mele A Conte CD Carbonic anhydrase inhibitors ameliorate thesymptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels Neuromuscul Disord 20061639ndash45
22 Kim JB Kim SJ Kang SY Yi JW Kim SM The large-conductance calcium-activatedpotassium channel holds the key to the conundrum of familial hypokalemic periodicparalysis Korean J Pediatr 201457445ndash450
23 Aure K Dubourg O Jardel C et al Episodic weakness due to mitochondrial DNAMT-ATP68 mutations Neurology 2013811810ndash1818
e418 Neurology | Volume 90 Number 5 | January 30 2018 NeurologyorgN
SOURCE ARTICLE NPuborg5fjlcp
Atypical periodic paralysis and myalgiaAnovelRYR1 phenotype
Emma Matthews MRCP Christoph Neuwirth MD Fatima Jaffer MRCP Renata S Scalco MD
Doreen Fialho MRCP Matt Parton FRCP Dipa Raja Rayan MRCP Karen Suetterlin MRCP Richa Sud PhD
Roland Spiegel MD Rachel Mein BSc Henry Houlden FRCP Andrew Schaefer MRCP Estelle Healy FRCPath
Jacqueline Palace FRCP Ros Quinlivan FRCP Susan Treves PhD Janice L Holton FRCPath
Heinz Jungbluth PhD and Michael G Hanna FRCP
Cite as Neurologyreg 201890e412ndashe418 doi101212WNL0000000000004894
Correspondence
Dr Matthews
emmamatthewsuclacuk
Study questionWhat are the phenotypic characteristics of patients with pe-riodic paralysis (PP) symptoms and RYR1 mutations
Summary answerThese patients can have late-onset atypical PP with or withoutmyopathy and with myalgia and cramps as prominent features
What is known and what this paper addsRYR1 mutations are associated with diverse neuromusculardisorders including 1 reported case of atypical PP This studydescribes the phenotypes of 3 more patients with RYR1mutations and PP episodes
Participants and settingThis study reports 3 patients with possible PP diagnosesand clinicopathologic findings typically associated withRYR1-related disorders who were referred to UK and Swissspecialist centers
Design size and durationMedical histories were collected for all 3 patients Thesehistories includedmuscle examinations at various ages Sangersequencing for RYR1 was performed on patient samples
Main results and the role of chanceCase 1 was a 54-year-old man who had lifelong muscleweakness At 34 years old he experienced worsened symp-toms including sudden severe myalgia Examinations revealedvarious neuromuscular abnormalities including positiveresults on the McManis test for PP Case 2 was a 42-year-oldwoman who had experienced episodic muscle weakness andmigraine symptoms since the age of 23 years A neurologicexamination yielded unremarkable results and the McManistest yielded negative results Case 3 was a 49-year-old man
who had experienced postexercise limb weakness episodessince 14 years of age and full muscle paralysis episodes since29 years of age Neurologic examinations yielded unremark-able results but the McManis test yielded positive results All3 patients carried various RYR1 mutations and reported my-algia andor muscle cramps
Bias confounding and other reasonsfor cautionThese case reports do not firmly establish a genotype-phenotype relationship or explain the physiologic mecha-nism by which RYR1 mutations would cause late-onsetatypical PP
Generalizability to other populationsLate-onset atypical PP may be more common in persons withRYR1 mutations than the single previous report suggested
Study fundingpotential competing interestsThis study was funded by the UK Department of HealthSome authors report receiving funding from the UKand European Union governments pharmaceutical com-panies and medical research foundations Some authorsreport receiving personal compensation from pharma-ceutical companies Go to NeurologyorgN for fulldisclosures
Patient RYR1 variants
Previously reported Asp708Asn Arg2241X Arg2939Lys
Case 1 Gln70X Arg109Trp Met485Val
Case 2 Arg1507Gln Gly2446Ser
Case 3 Arg1043His
A draft of the short-form article was written by M Dalefield a writer with Editage a division of Cactus Communications The authors of thefull-length article and the journal editors edited and approved the final version
Copyright copy 2018 American Academy of Neurology 219
SHORT-FORM ARTICLE
DOI 101212WNL0000000000004894201890e412-e418 Published Online before print January 3 2018Neurology
Emma Matthews Christoph Neuwirth Fatima Jaffer et al Atypical periodic paralysis and myalgia A novel RYR1 phenotype
This information is current as of January 3 2018
ServicesUpdated Information amp
httpnneurologyorgcontent905e412fullincluding high resolution figures can be found at
httpnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online
0028-3878 Online ISSN 1526-632XKluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print ISSN1951 it is now a weekly with 48 issues per year Copyright copy 2018 The Author(s) Published by Wolters
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
compound muscle action potential [CMAP] amplitude) MRIdemonstrated fatty infiltration of all thigh muscles in particularthe adductor magnus which was almost completely replacedby fat with relative sparing of the vastus lateralis rectus femorisgracilis and semitendinosus a pattern of selective involvementpreviously associated withRYR1-relatedmyopathies1415 Therewas no family history of similar symptoms Genetic analysisrevealed RYR1 variants Arg109Trp previously describedwith MmD and ophthalmoplegia416 a variant of uncertain
significance Met485Val4 and the novel although presumedtruncating variant Gln70X Testing for congenital myastheniaand PP genes was negative His unaffected mother carried theGln70X variant It was not possible to obtain DNA from hisfather
Case 2A 42-year-old Swiss woman presented with intermittentweakness of the limbs lasting from several minutes to 2 days
Figure 2 Histologic examination of a right biceps muscle biopsy
Histologic examination of a right biceps muscle biopsy performed at age 42 years showed (A) variation in fiber diameter and increased internal nuclei with (B)occasional fibers showing central basophilia (arrow) and (C) a small number of necrotic fibersGomori trichrome staining suggested regions with reducedmitochondrial staining (arrow) (E) ATPasehistochemistry indicated focal type I fiber predominance (darkly stained fibers) (F)Mild central pallor suggestive of coreswas apparent in type I and II fibers in the nicotinamide adenine dinucleotide tetrazolium reductase preparation (arrows) and (G) central reduction in oxidativeenzyme activity was confirmed by cytochrome oxidase histochemistry Scale bar in represents 260 μm in (E) 100 μm in (A) (F) and (G) and 50 μm in (BndashD)
NeurologyorgN Neurology | Volume 90 Number 5 | January 30 2018 e415
Medical history was notable for migraine and 3 caesareansections The first episode of flaccid paresis occurred duringher first pregnancy at the age of 23 years with a fall from thecouch when she could not move her right arm and leg forseveral minutes without associated disturbance of cognitionor sensory symptoms Examination at the emergency roomafter recovery was normal Brain imaging was not performedbecause of the pregnancy Two subsequent EEGs were nor-mal and no specific diagnosis was made at the time She hada history of migraine and we cannot definitively exclude thepossibility that this first episode of unilateral weakness wasa migraine aura without headache However her typical mi-graine episodes are headache and are distinct from this pre-sentation Fifteen years later while driving she notedweakness of her arms legs and trunk severe enough to war-rant stopping the car Weakness recovered slowly after 15minutes A similar episode occurred a few months later Po-tassium levels and clinical examination when asymptomaticwere normal Subsequently the frequency of similar episodeswith flaccid paresis of her limbs affecting predominantly thelegs and lasting several minutes increased and they occurreddaily always after resting No correlation with food intake orfasting was reported In addition she complained of painlesscramps in her arms and legs muscles which could becomepainful if she tried to stretch her muscles These lasted up to10 minutes and also occurred during sleep
A detailed neurologic examination at the age of 42 yearsrevealed no abnormalities A relatively thin and long face witha small lower jaw was noted but she was not overtly dys-morphic On follow-up examination she presented withflaccid weakness of her right hand lasting for 2 days Motorand sensory nerve conduction studies repetitive motor nervestimulation and EMG in the limbs and paravertebral musclesperformed after recovery from the acute episode were un-remarkable The McManis test was negative Laboratorytesting revealed no thyroid dysfunction electrolytes andcreatine kinase were normal Muscle biopsy of the tibialisanterior muscle was unremarkable Genetic testing revealedRYR1 gene variants Arg1507Gln and Gly2446Ser in transArg1507Gln is a missense variant with a minor allele fre-quency of 000001 in ExAC that has been previously found inother myopathic phenotypes Gly2446Ser although notpreviously reported localizes to a recognized MH-associatedmutational hot spot (wwwemhgorg) PP gene testing wasnegative
Case 3This 49-year-old man reported experiencing episodes of mi-nor limb weakness after strenuous exercise that lasted a fewhours from the age of 14 years He had his first full attack ofmuscle paralysis at the age of 29 years He awoke in themorning after a day of strenuous exercise to find that he wasunable to walk From this age on he experienced multiplesimilar episodes All muscles from the neck down could beweak although the legs were predominantly and mostseverely affected Symptoms usually lasted for several hours
but could persist for as long as 48 hours In the recovery phasehe reported that the limbs could be painful as strengthreturned Symptoms could be provoked by exercise intenseheat or a carbohydrate-rich meal late at night
Medical history was notable for 2 complicated general anes-thetics in childhood although the exact circumstances wereunclear and medical records unavailable His parents wereadvised after these that he may be at risk of MH and to informclinicians before any future procedures requiring generalanesthesia
Examination was unremarkable as was creatine kinase andMRI of the lower limbs EMG and nerve conduction studywere normal but theMcManis test for PP was positive with anexercise-induced reduction of CMAP of 68 A biopsy of thetibialis anterior muscle demonstrated variation in fiber size anincrease in internal nuclei and 1 ring fiber (figure e-1 httplinkslwwcomWNLA96) A type I fiber predominance wasinterpreted as normal for the muscle biopsied Genetic testingfor PP genes was negative but an RYR1 variant Arg1043Hiswas identified Another amino acid substitution at the samesite Arg1043Cys previously associated with the MH trait butnot functionally tested yet (wwwemhgorg) has beendescribed
DiscussionWe have previously reported a single patient with recessiveRYR1-related MmD with additional episodic muscle weak-nessparalysis11 Here we have described 3 additional cases(summarized in the table) One was compound heterozygousfor RYR1 nonsense and missense mutations and presentedwith later development of episodic symptoms in the context ofa congenital myopathy similar to our original patient reportedby Zhou et al17 who showed a comparable genotype andphenotype The other 2 patients had an episodic phenotypewithout myopathy and were either heterozygous for or com-pound heterozygous forRYR1missensemutations (putatively)implicated in the MH trait suggesting tentative genotype-phenotype correlations In all cases (including our originalcase) the onset of episodic muscle paralysis was from earlyadulthood onward which is later than the onset typically seenin primary PP17 Although there were variable triggers in-cluding exertion or rest after exertion which is a typical triggerfor PP there was no consistent relationship to food or tem-perature across all the cases Myalgia or cramp was a universalfeature indicating overlap with the spectrum of RYR1-relatedexertional myalgiarhabdomyolysis and this together with thelater age at onset may be a phenotypic clue for future cases
The McManis test was positive in 2 of 3 of our new cases Weretrospectively reviewed the source data for our previouslyreported case11 and found that the drop in CMAP amplitudewhen calculated from the postexercise increment was alsogt40 indicating a positive test
e416 Neurology | Volume 90 Number 5 | January 30 2018 NeurologyorgN
A positive McManis test to the best of our knowledge haspreviously been described only in primary or secondaryPP18 Given the direct interaction between the Cav11channel implicated in the majority of cases of hypokalemicPP19 and RYR1 it seems plausible that dysfunction of eachmay produce phenotypic mimics This is supported by theobservation of a profound disturbance of the normalCav11RYR1 interaction in 1 previous patient with RYR1-related PP and other patients with recessive RYR1-relatedmyopathies1120 Furthermore the recently described CAC-NA1S-associated early-onset myopathy shares features ofpredominantly axial weakness and ophthalmoplegia withRYR1-related myopathies12 and may also feature similarreductions of the Cav11 protein However the exactmechanism by which the RYR1 variants would cause anepisodically unexcitable sarcolemma as demonstrated bya positive McManis test is unclear On the basis of the recentobservation of altered BK channel activity in RYR1-mutatedsmooth muscle cells10 one possibility is via an impairment ofBK channelndashmediated membrane repolarization due toaltered intracellular calcium homeostasis but this requiresfurther study102122
Other atypical PP phenotypes associated with motor neurop-athy due to mitochondrial gene mutations have beendescribed23 demonstrating that the clinical symptoms may beseen in nonndashion channel genetic disorders Our data demon-strate that late-onset episodic muscle weakness or paralysiswith prominent myalgia and cramps may be a more commonRYR1-associated phenotype than the single case we previously
reported and may not be limited to a specific genotype Wesuggest that cases compound heterozygous for RYR1 nonsenseand missense mutations are more likely to have a concomitantearly-onset myopathy The McManis test may be a useful di-agnostic tool in these cases although a negative test does notexclude the possibility of RYR1 involvement
We propose that clinicopathologic features suggestive ofRYR1 disorders should be sought in genetically undefined PPcases and RYR1 gene testing considered in those in whommutations in SCN4A CACNA1S and KCNJ2 have alreadybeen excluded
Author contributionsE Matthews drafting the manuscript for content analysis orinterpretation of data study concept C Neuwirth andF Jaffer revising the manuscript for content analysis orinterpretation of data study concept R Scalco D FialhoM Parton R Sud R Spiegel R Mein D Raja RayanK Suetterlin H Houlden A Schaefer E Healy J PalaceR Quinlivan S Treves and JL Holton revising the man-uscript for content analysis or interpretation of dataH Jungbluth drafting the manuscript for content analysisor interpretation of data study concept MG Hannarevising the manuscript for content analysis or in-terpretation of data
AcknowledgmentThe authors are grateful to Mark Walker at Southampton forthe retrieval of muscle histology slides
Table Summary of clinicopathologic features of cases with RYR1 gene variants and episodic weaknessparalysis
Symptoms ExaminationCKIUL EMG
McManistest Muscle biopsy
RYR1variants
Previouslyreportedcase11
Hypotonia respiratory andfeeding impairment at birthdelayed motor milestonesepisodic limb weaknesslasting days from age 18 ycold- and exercise-inducedmyalgiacramp from age 26 y
High arched palatefacial weaknessophthalmoplegiasevere trunk and neckweakness moderatelimb weaknesshyperlordosis
Normalrange
Myopathic Positive Variation in fibersize increasedinternal nucleicore-like structures
Asp708AsnArg2241XArg2939Lys
Case 1 Delayed walking early onsetproximal myopathy episodicmyalgia followed by limb andneck weakness lasting hoursto days from age 34 yfluctuant bulbar weakness
Long thin face higharched palate proximalmyopathy facialweakness and ptosisophthalmoplegiahyperlordosis
101 Myopathicincreasedjitter andblocking onSFEMG
Positive Variation in fibersize increasedinternal nucleiareas of centralpallor suggestive ofcore-like structures
Gln70XArg109TrpMet485Val
Case 2 Early history anddevelopment normalepisodic limb weakness fromage 23 y cramps withmyalgia
Long thin face 120 Normal Negative Normal Arg1507GlnGly2446Ser
Case 3 Early history anddevelopment normal minorepisodic weakness from age14 y episodic limb paralysisand myalgia from age 29 y
Normal 92 Normal Positive Type 1predominance 1ragged red fiber(+COX negative)increased internalnuclei 1 ring fiber
Arg1043His
Abbreviations CK = creatine kinase SFEMG = single-fiber EMG
NeurologyorgN Neurology | Volume 90 Number 5 | January 30 2018 e417
Study fundingPart of this work was undertaken at University College LondonHospitalsUniversity College London which received aproportion of funding from the Department of HealthrsquosNational Institute for Health Research Biomedical ResearchCentres funding scheme
DisclosureE Matthews holds a post-doctoral fellowship from the Na-tional Institute for Health Research Rare Disease SchemeC Neuwirth F Jaffer and R Scalco report no disclosuresrelevant to the manuscript D Fialho is supported by theNational Highly Specialised Service Department of HealthUK M Parton R Sud R Spiegel R Mein and D Rayanreport no disclosures relevant to the manuscript K Suetterlinhas an MRC Clinical Research Training Fellowship and re-ceived funding from the European Communityrsquos SeventhFramework Programme (FP72007-2013) under grantagreement 2012-305121 ldquoIntegrated European-omics Re-search Project for Diagnosis and Therapy in Rare Neuro-muscular and Neurodegenerative Diseases (NEUROMICS)rdquoH Houlden has received funding from the European Com-munityrsquos Seventh Framework Programme (FP72007-2013)under grant agreement 2012-305121 ldquoIntegratedEuropean-omics Research Project for Diagnosis andTherapy in Rare Neuromuscular and NeurodegenerativeDiseases (NEUROMICS)rdquo A Schaefer and E Healy reportno disclosures relevant to the manuscript J Palace is partlyfunded by Highly Specialised Services to run national con-genital myasthenia and neuromyelitis optica services and hasreceived support for scientific meetings and honorariums foradvisory work from Merck Serono Biogen Idec NovartisTeva Chugai Pharma and Bayer Schering as well as un-restricted grants from Merck Serono Novartis Biogen IdecTeva and Bayer Schering Her hospital trust receives funds forher role as clinical lead for the Department of Health RiskSharing Scheme She has received grants from the MS societyand Guthy-Jackson Foundation R Quinlivan is supported bythe National Highly Specialised Service Department ofHealth UK andNational Institute for Health Research and hasgrant funding from Muscular Dystrophy UK and Associationfor Glycogen Storage Disease She has received honoraria forteaching and consultancy from PTC Therapeutics Sanofi-Genzyme and Ultragenyx S Treves reports no disclosuresrelevant to the manuscript J Holton is supported by the RetaLila Weston Institute for Neurologic Studies H Jungbluthreports no disclosures relevant to the manuscript M Hanna is
supported by a Medical Research Council Centre grant theNational Centre for Research Resources and the NationalHighly Specialised Service Department of Health UK Go toNeurologyorgN for full disclosures
Received June 9 2017 Accepted in final form October 24 2017
References1 Amburgey K McNamara N Bennett LR McCormick ME Acsadi G Dowling JJ
Prevalence of congenital myopathies in a representative pediatric United Statespopulation Ann Neurol 201170662ndash665
2 Maggi L Scoto M Cirak S et al Congenital myopathies clinical features and fre-quency of individual subtypes diagnosed over a 5-year period in the United KingdomNeuromuscul Disord 201323195ndash205
3 Zhang Y Chen HS Khanna VK et al A mutation in the human ryanodine receptorgene associated with central core disease Nat Genet 1993546ndash50
4 Jungbluth H Zhou H Hartley L et al Minicore myopathy with ophthalmoplegiacaused by mutations in the ryanodine receptor type 1 gene Neurology 2005651930ndash1935
5 Wilmshurst JM Lillis S Zhou H et al RYR1 mutations are a common cause ofcongenital myopathies with central nuclei Ann Neurol 201068717ndash726
6 Clarke NF Waddell LB Cooper ST et al Recessive mutations in RYR1 are a com-mon cause of congenital fiber type disproportion Hum Mutat 201031E1544ndashE1550
7 Dlamini N Voermans NC Lillis S et al Mutations in RYR1 are a common cause ofexertional myalgia and rhabdomyolysis Neuromuscul Disord 201323540ndash548
8 Jungbluth H Lillis S Zhou H et al Late-onset axial myopathy with cores due toa novel heterozygous dominant mutation in the skeletal muscle ryanodine receptor(RYR1) gene Neuromuscul Disord 200919344ndash347
9 Loseth S Voermans NC Torbergsen T et al A novel late-onset axial myopathyassociated with mutations in the skeletal muscle ryanodine receptor (RYR1) geneJ Neurol 20132601504ndash1510
10 Lopez RJ Byrne S Vukcevic M et al An RYR1 mutation associated with malignanthyperthermia is also associated with bleeding abnormalities Sci Signal 20169ra68
11 Zhou H Lillis S Loy RE et al Multi-minicore disease and atypical periodic paralysisassociated with novel mutations in the skeletal muscle ryanodine receptor (RYR1)gene Neuromuscul Disord 201020166ndash173
12 Schartner V Romero NB Donkervoort S et al Dihydropyridine receptor (DHPRCACNA1S) congenital myopathy Acta Neuropathol 2017133517ndash533
13 Illingworth MA Main M Pitt M et al RYR1-related congenital myopathy withfatigable weakness responding to pyridostigimine Neuromuscul Disord 201424707ndash712
14 Jungbluth H Davis MR Muller C et al Magnetic resonance imaging of muscle incongenital myopathies associated with RYR1 mutations Neuromuscul Disord 200414785ndash790
15 Klein A Jungbluth H Clement E et al Muscle magnetic resonance imaging incongenital myopathies due to ryanodine receptor type 1 gene mutations Arch Neurol2011681171ndash1179
16 Zhou H Jungbluth H Sewry CA et al Molecular mechanisms and phenotypicvariation in RYR1-related congenital myopathies Brain 20071302024ndash2036
17 Venance SL Cannon SC Fialho D et al The primary periodic paralyses diagnosispathogenesis and treatment Brain 20061298ndash17
18 McManis PG Lambert EH Daube JR The exercise test in periodic paralysis MuscleNerve 19869704ndash710
19 Matthews E Labrum R Sweeney MG et al Voltage sensor charge loss accounts formost cases of hypokalemic periodic paralysis Neurology 2009721544ndash1547
20 Zhou H Rokach O Feng L et al RyR1 deficiency in congenital myopathies disruptsexcitation-contraction coupling Hum Mutat 201334986ndash996
21 Tricarico D Mele A Conte CD Carbonic anhydrase inhibitors ameliorate thesymptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels Neuromuscul Disord 20061639ndash45
22 Kim JB Kim SJ Kang SY Yi JW Kim SM The large-conductance calcium-activatedpotassium channel holds the key to the conundrum of familial hypokalemic periodicparalysis Korean J Pediatr 201457445ndash450
23 Aure K Dubourg O Jardel C et al Episodic weakness due to mitochondrial DNAMT-ATP68 mutations Neurology 2013811810ndash1818
e418 Neurology | Volume 90 Number 5 | January 30 2018 NeurologyorgN
SOURCE ARTICLE NPuborg5fjlcp
Atypical periodic paralysis and myalgiaAnovelRYR1 phenotype
Emma Matthews MRCP Christoph Neuwirth MD Fatima Jaffer MRCP Renata S Scalco MD
Doreen Fialho MRCP Matt Parton FRCP Dipa Raja Rayan MRCP Karen Suetterlin MRCP Richa Sud PhD
Roland Spiegel MD Rachel Mein BSc Henry Houlden FRCP Andrew Schaefer MRCP Estelle Healy FRCPath
Jacqueline Palace FRCP Ros Quinlivan FRCP Susan Treves PhD Janice L Holton FRCPath
Heinz Jungbluth PhD and Michael G Hanna FRCP
Cite as Neurologyreg 201890e412ndashe418 doi101212WNL0000000000004894
Correspondence
Dr Matthews
emmamatthewsuclacuk
Study questionWhat are the phenotypic characteristics of patients with pe-riodic paralysis (PP) symptoms and RYR1 mutations
Summary answerThese patients can have late-onset atypical PP with or withoutmyopathy and with myalgia and cramps as prominent features
What is known and what this paper addsRYR1 mutations are associated with diverse neuromusculardisorders including 1 reported case of atypical PP This studydescribes the phenotypes of 3 more patients with RYR1mutations and PP episodes
Participants and settingThis study reports 3 patients with possible PP diagnosesand clinicopathologic findings typically associated withRYR1-related disorders who were referred to UK and Swissspecialist centers
Design size and durationMedical histories were collected for all 3 patients Thesehistories includedmuscle examinations at various ages Sangersequencing for RYR1 was performed on patient samples
Main results and the role of chanceCase 1 was a 54-year-old man who had lifelong muscleweakness At 34 years old he experienced worsened symp-toms including sudden severe myalgia Examinations revealedvarious neuromuscular abnormalities including positiveresults on the McManis test for PP Case 2 was a 42-year-oldwoman who had experienced episodic muscle weakness andmigraine symptoms since the age of 23 years A neurologicexamination yielded unremarkable results and the McManistest yielded negative results Case 3 was a 49-year-old man
who had experienced postexercise limb weakness episodessince 14 years of age and full muscle paralysis episodes since29 years of age Neurologic examinations yielded unremark-able results but the McManis test yielded positive results All3 patients carried various RYR1 mutations and reported my-algia andor muscle cramps
Bias confounding and other reasonsfor cautionThese case reports do not firmly establish a genotype-phenotype relationship or explain the physiologic mecha-nism by which RYR1 mutations would cause late-onsetatypical PP
Generalizability to other populationsLate-onset atypical PP may be more common in persons withRYR1 mutations than the single previous report suggested
Study fundingpotential competing interestsThis study was funded by the UK Department of HealthSome authors report receiving funding from the UKand European Union governments pharmaceutical com-panies and medical research foundations Some authorsreport receiving personal compensation from pharma-ceutical companies Go to NeurologyorgN for fulldisclosures
Patient RYR1 variants
Previously reported Asp708Asn Arg2241X Arg2939Lys
Case 1 Gln70X Arg109Trp Met485Val
Case 2 Arg1507Gln Gly2446Ser
Case 3 Arg1043His
A draft of the short-form article was written by M Dalefield a writer with Editage a division of Cactus Communications The authors of thefull-length article and the journal editors edited and approved the final version
Copyright copy 2018 American Academy of Neurology 219
SHORT-FORM ARTICLE
DOI 101212WNL0000000000004894201890e412-e418 Published Online before print January 3 2018Neurology
Emma Matthews Christoph Neuwirth Fatima Jaffer et al Atypical periodic paralysis and myalgia A novel RYR1 phenotype
This information is current as of January 3 2018
ServicesUpdated Information amp
httpnneurologyorgcontent905e412fullincluding high resolution figures can be found at
httpnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online
0028-3878 Online ISSN 1526-632XKluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print ISSN1951 it is now a weekly with 48 issues per year Copyright copy 2018 The Author(s) Published by Wolters
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
Medical history was notable for migraine and 3 caesareansections The first episode of flaccid paresis occurred duringher first pregnancy at the age of 23 years with a fall from thecouch when she could not move her right arm and leg forseveral minutes without associated disturbance of cognitionor sensory symptoms Examination at the emergency roomafter recovery was normal Brain imaging was not performedbecause of the pregnancy Two subsequent EEGs were nor-mal and no specific diagnosis was made at the time She hada history of migraine and we cannot definitively exclude thepossibility that this first episode of unilateral weakness wasa migraine aura without headache However her typical mi-graine episodes are headache and are distinct from this pre-sentation Fifteen years later while driving she notedweakness of her arms legs and trunk severe enough to war-rant stopping the car Weakness recovered slowly after 15minutes A similar episode occurred a few months later Po-tassium levels and clinical examination when asymptomaticwere normal Subsequently the frequency of similar episodeswith flaccid paresis of her limbs affecting predominantly thelegs and lasting several minutes increased and they occurreddaily always after resting No correlation with food intake orfasting was reported In addition she complained of painlesscramps in her arms and legs muscles which could becomepainful if she tried to stretch her muscles These lasted up to10 minutes and also occurred during sleep
A detailed neurologic examination at the age of 42 yearsrevealed no abnormalities A relatively thin and long face witha small lower jaw was noted but she was not overtly dys-morphic On follow-up examination she presented withflaccid weakness of her right hand lasting for 2 days Motorand sensory nerve conduction studies repetitive motor nervestimulation and EMG in the limbs and paravertebral musclesperformed after recovery from the acute episode were un-remarkable The McManis test was negative Laboratorytesting revealed no thyroid dysfunction electrolytes andcreatine kinase were normal Muscle biopsy of the tibialisanterior muscle was unremarkable Genetic testing revealedRYR1 gene variants Arg1507Gln and Gly2446Ser in transArg1507Gln is a missense variant with a minor allele fre-quency of 000001 in ExAC that has been previously found inother myopathic phenotypes Gly2446Ser although notpreviously reported localizes to a recognized MH-associatedmutational hot spot (wwwemhgorg) PP gene testing wasnegative
Case 3This 49-year-old man reported experiencing episodes of mi-nor limb weakness after strenuous exercise that lasted a fewhours from the age of 14 years He had his first full attack ofmuscle paralysis at the age of 29 years He awoke in themorning after a day of strenuous exercise to find that he wasunable to walk From this age on he experienced multiplesimilar episodes All muscles from the neck down could beweak although the legs were predominantly and mostseverely affected Symptoms usually lasted for several hours
but could persist for as long as 48 hours In the recovery phasehe reported that the limbs could be painful as strengthreturned Symptoms could be provoked by exercise intenseheat or a carbohydrate-rich meal late at night
Medical history was notable for 2 complicated general anes-thetics in childhood although the exact circumstances wereunclear and medical records unavailable His parents wereadvised after these that he may be at risk of MH and to informclinicians before any future procedures requiring generalanesthesia
Examination was unremarkable as was creatine kinase andMRI of the lower limbs EMG and nerve conduction studywere normal but theMcManis test for PP was positive with anexercise-induced reduction of CMAP of 68 A biopsy of thetibialis anterior muscle demonstrated variation in fiber size anincrease in internal nuclei and 1 ring fiber (figure e-1 httplinkslwwcomWNLA96) A type I fiber predominance wasinterpreted as normal for the muscle biopsied Genetic testingfor PP genes was negative but an RYR1 variant Arg1043Hiswas identified Another amino acid substitution at the samesite Arg1043Cys previously associated with the MH trait butnot functionally tested yet (wwwemhgorg) has beendescribed
DiscussionWe have previously reported a single patient with recessiveRYR1-related MmD with additional episodic muscle weak-nessparalysis11 Here we have described 3 additional cases(summarized in the table) One was compound heterozygousfor RYR1 nonsense and missense mutations and presentedwith later development of episodic symptoms in the context ofa congenital myopathy similar to our original patient reportedby Zhou et al17 who showed a comparable genotype andphenotype The other 2 patients had an episodic phenotypewithout myopathy and were either heterozygous for or com-pound heterozygous forRYR1missensemutations (putatively)implicated in the MH trait suggesting tentative genotype-phenotype correlations In all cases (including our originalcase) the onset of episodic muscle paralysis was from earlyadulthood onward which is later than the onset typically seenin primary PP17 Although there were variable triggers in-cluding exertion or rest after exertion which is a typical triggerfor PP there was no consistent relationship to food or tem-perature across all the cases Myalgia or cramp was a universalfeature indicating overlap with the spectrum of RYR1-relatedexertional myalgiarhabdomyolysis and this together with thelater age at onset may be a phenotypic clue for future cases
The McManis test was positive in 2 of 3 of our new cases Weretrospectively reviewed the source data for our previouslyreported case11 and found that the drop in CMAP amplitudewhen calculated from the postexercise increment was alsogt40 indicating a positive test
e416 Neurology | Volume 90 Number 5 | January 30 2018 NeurologyorgN
A positive McManis test to the best of our knowledge haspreviously been described only in primary or secondaryPP18 Given the direct interaction between the Cav11channel implicated in the majority of cases of hypokalemicPP19 and RYR1 it seems plausible that dysfunction of eachmay produce phenotypic mimics This is supported by theobservation of a profound disturbance of the normalCav11RYR1 interaction in 1 previous patient with RYR1-related PP and other patients with recessive RYR1-relatedmyopathies1120 Furthermore the recently described CAC-NA1S-associated early-onset myopathy shares features ofpredominantly axial weakness and ophthalmoplegia withRYR1-related myopathies12 and may also feature similarreductions of the Cav11 protein However the exactmechanism by which the RYR1 variants would cause anepisodically unexcitable sarcolemma as demonstrated bya positive McManis test is unclear On the basis of the recentobservation of altered BK channel activity in RYR1-mutatedsmooth muscle cells10 one possibility is via an impairment ofBK channelndashmediated membrane repolarization due toaltered intracellular calcium homeostasis but this requiresfurther study102122
Other atypical PP phenotypes associated with motor neurop-athy due to mitochondrial gene mutations have beendescribed23 demonstrating that the clinical symptoms may beseen in nonndashion channel genetic disorders Our data demon-strate that late-onset episodic muscle weakness or paralysiswith prominent myalgia and cramps may be a more commonRYR1-associated phenotype than the single case we previously
reported and may not be limited to a specific genotype Wesuggest that cases compound heterozygous for RYR1 nonsenseand missense mutations are more likely to have a concomitantearly-onset myopathy The McManis test may be a useful di-agnostic tool in these cases although a negative test does notexclude the possibility of RYR1 involvement
We propose that clinicopathologic features suggestive ofRYR1 disorders should be sought in genetically undefined PPcases and RYR1 gene testing considered in those in whommutations in SCN4A CACNA1S and KCNJ2 have alreadybeen excluded
Author contributionsE Matthews drafting the manuscript for content analysis orinterpretation of data study concept C Neuwirth andF Jaffer revising the manuscript for content analysis orinterpretation of data study concept R Scalco D FialhoM Parton R Sud R Spiegel R Mein D Raja RayanK Suetterlin H Houlden A Schaefer E Healy J PalaceR Quinlivan S Treves and JL Holton revising the man-uscript for content analysis or interpretation of dataH Jungbluth drafting the manuscript for content analysisor interpretation of data study concept MG Hannarevising the manuscript for content analysis or in-terpretation of data
AcknowledgmentThe authors are grateful to Mark Walker at Southampton forthe retrieval of muscle histology slides
Table Summary of clinicopathologic features of cases with RYR1 gene variants and episodic weaknessparalysis
Symptoms ExaminationCKIUL EMG
McManistest Muscle biopsy
RYR1variants
Previouslyreportedcase11
Hypotonia respiratory andfeeding impairment at birthdelayed motor milestonesepisodic limb weaknesslasting days from age 18 ycold- and exercise-inducedmyalgiacramp from age 26 y
High arched palatefacial weaknessophthalmoplegiasevere trunk and neckweakness moderatelimb weaknesshyperlordosis
Normalrange
Myopathic Positive Variation in fibersize increasedinternal nucleicore-like structures
Asp708AsnArg2241XArg2939Lys
Case 1 Delayed walking early onsetproximal myopathy episodicmyalgia followed by limb andneck weakness lasting hoursto days from age 34 yfluctuant bulbar weakness
Long thin face higharched palate proximalmyopathy facialweakness and ptosisophthalmoplegiahyperlordosis
101 Myopathicincreasedjitter andblocking onSFEMG
Positive Variation in fibersize increasedinternal nucleiareas of centralpallor suggestive ofcore-like structures
Gln70XArg109TrpMet485Val
Case 2 Early history anddevelopment normalepisodic limb weakness fromage 23 y cramps withmyalgia
Long thin face 120 Normal Negative Normal Arg1507GlnGly2446Ser
Case 3 Early history anddevelopment normal minorepisodic weakness from age14 y episodic limb paralysisand myalgia from age 29 y
Normal 92 Normal Positive Type 1predominance 1ragged red fiber(+COX negative)increased internalnuclei 1 ring fiber
Arg1043His
Abbreviations CK = creatine kinase SFEMG = single-fiber EMG
NeurologyorgN Neurology | Volume 90 Number 5 | January 30 2018 e417
Study fundingPart of this work was undertaken at University College LondonHospitalsUniversity College London which received aproportion of funding from the Department of HealthrsquosNational Institute for Health Research Biomedical ResearchCentres funding scheme
DisclosureE Matthews holds a post-doctoral fellowship from the Na-tional Institute for Health Research Rare Disease SchemeC Neuwirth F Jaffer and R Scalco report no disclosuresrelevant to the manuscript D Fialho is supported by theNational Highly Specialised Service Department of HealthUK M Parton R Sud R Spiegel R Mein and D Rayanreport no disclosures relevant to the manuscript K Suetterlinhas an MRC Clinical Research Training Fellowship and re-ceived funding from the European Communityrsquos SeventhFramework Programme (FP72007-2013) under grantagreement 2012-305121 ldquoIntegrated European-omics Re-search Project for Diagnosis and Therapy in Rare Neuro-muscular and Neurodegenerative Diseases (NEUROMICS)rdquoH Houlden has received funding from the European Com-munityrsquos Seventh Framework Programme (FP72007-2013)under grant agreement 2012-305121 ldquoIntegratedEuropean-omics Research Project for Diagnosis andTherapy in Rare Neuromuscular and NeurodegenerativeDiseases (NEUROMICS)rdquo A Schaefer and E Healy reportno disclosures relevant to the manuscript J Palace is partlyfunded by Highly Specialised Services to run national con-genital myasthenia and neuromyelitis optica services and hasreceived support for scientific meetings and honorariums foradvisory work from Merck Serono Biogen Idec NovartisTeva Chugai Pharma and Bayer Schering as well as un-restricted grants from Merck Serono Novartis Biogen IdecTeva and Bayer Schering Her hospital trust receives funds forher role as clinical lead for the Department of Health RiskSharing Scheme She has received grants from the MS societyand Guthy-Jackson Foundation R Quinlivan is supported bythe National Highly Specialised Service Department ofHealth UK andNational Institute for Health Research and hasgrant funding from Muscular Dystrophy UK and Associationfor Glycogen Storage Disease She has received honoraria forteaching and consultancy from PTC Therapeutics Sanofi-Genzyme and Ultragenyx S Treves reports no disclosuresrelevant to the manuscript J Holton is supported by the RetaLila Weston Institute for Neurologic Studies H Jungbluthreports no disclosures relevant to the manuscript M Hanna is
supported by a Medical Research Council Centre grant theNational Centre for Research Resources and the NationalHighly Specialised Service Department of Health UK Go toNeurologyorgN for full disclosures
Received June 9 2017 Accepted in final form October 24 2017
References1 Amburgey K McNamara N Bennett LR McCormick ME Acsadi G Dowling JJ
Prevalence of congenital myopathies in a representative pediatric United Statespopulation Ann Neurol 201170662ndash665
2 Maggi L Scoto M Cirak S et al Congenital myopathies clinical features and fre-quency of individual subtypes diagnosed over a 5-year period in the United KingdomNeuromuscul Disord 201323195ndash205
3 Zhang Y Chen HS Khanna VK et al A mutation in the human ryanodine receptorgene associated with central core disease Nat Genet 1993546ndash50
4 Jungbluth H Zhou H Hartley L et al Minicore myopathy with ophthalmoplegiacaused by mutations in the ryanodine receptor type 1 gene Neurology 2005651930ndash1935
5 Wilmshurst JM Lillis S Zhou H et al RYR1 mutations are a common cause ofcongenital myopathies with central nuclei Ann Neurol 201068717ndash726
6 Clarke NF Waddell LB Cooper ST et al Recessive mutations in RYR1 are a com-mon cause of congenital fiber type disproportion Hum Mutat 201031E1544ndashE1550
7 Dlamini N Voermans NC Lillis S et al Mutations in RYR1 are a common cause ofexertional myalgia and rhabdomyolysis Neuromuscul Disord 201323540ndash548
8 Jungbluth H Lillis S Zhou H et al Late-onset axial myopathy with cores due toa novel heterozygous dominant mutation in the skeletal muscle ryanodine receptor(RYR1) gene Neuromuscul Disord 200919344ndash347
9 Loseth S Voermans NC Torbergsen T et al A novel late-onset axial myopathyassociated with mutations in the skeletal muscle ryanodine receptor (RYR1) geneJ Neurol 20132601504ndash1510
10 Lopez RJ Byrne S Vukcevic M et al An RYR1 mutation associated with malignanthyperthermia is also associated with bleeding abnormalities Sci Signal 20169ra68
11 Zhou H Lillis S Loy RE et al Multi-minicore disease and atypical periodic paralysisassociated with novel mutations in the skeletal muscle ryanodine receptor (RYR1)gene Neuromuscul Disord 201020166ndash173
12 Schartner V Romero NB Donkervoort S et al Dihydropyridine receptor (DHPRCACNA1S) congenital myopathy Acta Neuropathol 2017133517ndash533
13 Illingworth MA Main M Pitt M et al RYR1-related congenital myopathy withfatigable weakness responding to pyridostigimine Neuromuscul Disord 201424707ndash712
14 Jungbluth H Davis MR Muller C et al Magnetic resonance imaging of muscle incongenital myopathies associated with RYR1 mutations Neuromuscul Disord 200414785ndash790
15 Klein A Jungbluth H Clement E et al Muscle magnetic resonance imaging incongenital myopathies due to ryanodine receptor type 1 gene mutations Arch Neurol2011681171ndash1179
16 Zhou H Jungbluth H Sewry CA et al Molecular mechanisms and phenotypicvariation in RYR1-related congenital myopathies Brain 20071302024ndash2036
17 Venance SL Cannon SC Fialho D et al The primary periodic paralyses diagnosispathogenesis and treatment Brain 20061298ndash17
18 McManis PG Lambert EH Daube JR The exercise test in periodic paralysis MuscleNerve 19869704ndash710
19 Matthews E Labrum R Sweeney MG et al Voltage sensor charge loss accounts formost cases of hypokalemic periodic paralysis Neurology 2009721544ndash1547
20 Zhou H Rokach O Feng L et al RyR1 deficiency in congenital myopathies disruptsexcitation-contraction coupling Hum Mutat 201334986ndash996
21 Tricarico D Mele A Conte CD Carbonic anhydrase inhibitors ameliorate thesymptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels Neuromuscul Disord 20061639ndash45
22 Kim JB Kim SJ Kang SY Yi JW Kim SM The large-conductance calcium-activatedpotassium channel holds the key to the conundrum of familial hypokalemic periodicparalysis Korean J Pediatr 201457445ndash450
23 Aure K Dubourg O Jardel C et al Episodic weakness due to mitochondrial DNAMT-ATP68 mutations Neurology 2013811810ndash1818
e418 Neurology | Volume 90 Number 5 | January 30 2018 NeurologyorgN
SOURCE ARTICLE NPuborg5fjlcp
Atypical periodic paralysis and myalgiaAnovelRYR1 phenotype
Emma Matthews MRCP Christoph Neuwirth MD Fatima Jaffer MRCP Renata S Scalco MD
Doreen Fialho MRCP Matt Parton FRCP Dipa Raja Rayan MRCP Karen Suetterlin MRCP Richa Sud PhD
Roland Spiegel MD Rachel Mein BSc Henry Houlden FRCP Andrew Schaefer MRCP Estelle Healy FRCPath
Jacqueline Palace FRCP Ros Quinlivan FRCP Susan Treves PhD Janice L Holton FRCPath
Heinz Jungbluth PhD and Michael G Hanna FRCP
Cite as Neurologyreg 201890e412ndashe418 doi101212WNL0000000000004894
Correspondence
Dr Matthews
emmamatthewsuclacuk
Study questionWhat are the phenotypic characteristics of patients with pe-riodic paralysis (PP) symptoms and RYR1 mutations
Summary answerThese patients can have late-onset atypical PP with or withoutmyopathy and with myalgia and cramps as prominent features
What is known and what this paper addsRYR1 mutations are associated with diverse neuromusculardisorders including 1 reported case of atypical PP This studydescribes the phenotypes of 3 more patients with RYR1mutations and PP episodes
Participants and settingThis study reports 3 patients with possible PP diagnosesand clinicopathologic findings typically associated withRYR1-related disorders who were referred to UK and Swissspecialist centers
Design size and durationMedical histories were collected for all 3 patients Thesehistories includedmuscle examinations at various ages Sangersequencing for RYR1 was performed on patient samples
Main results and the role of chanceCase 1 was a 54-year-old man who had lifelong muscleweakness At 34 years old he experienced worsened symp-toms including sudden severe myalgia Examinations revealedvarious neuromuscular abnormalities including positiveresults on the McManis test for PP Case 2 was a 42-year-oldwoman who had experienced episodic muscle weakness andmigraine symptoms since the age of 23 years A neurologicexamination yielded unremarkable results and the McManistest yielded negative results Case 3 was a 49-year-old man
who had experienced postexercise limb weakness episodessince 14 years of age and full muscle paralysis episodes since29 years of age Neurologic examinations yielded unremark-able results but the McManis test yielded positive results All3 patients carried various RYR1 mutations and reported my-algia andor muscle cramps
Bias confounding and other reasonsfor cautionThese case reports do not firmly establish a genotype-phenotype relationship or explain the physiologic mecha-nism by which RYR1 mutations would cause late-onsetatypical PP
Generalizability to other populationsLate-onset atypical PP may be more common in persons withRYR1 mutations than the single previous report suggested
Study fundingpotential competing interestsThis study was funded by the UK Department of HealthSome authors report receiving funding from the UKand European Union governments pharmaceutical com-panies and medical research foundations Some authorsreport receiving personal compensation from pharma-ceutical companies Go to NeurologyorgN for fulldisclosures
Patient RYR1 variants
Previously reported Asp708Asn Arg2241X Arg2939Lys
Case 1 Gln70X Arg109Trp Met485Val
Case 2 Arg1507Gln Gly2446Ser
Case 3 Arg1043His
A draft of the short-form article was written by M Dalefield a writer with Editage a division of Cactus Communications The authors of thefull-length article and the journal editors edited and approved the final version
Copyright copy 2018 American Academy of Neurology 219
SHORT-FORM ARTICLE
DOI 101212WNL0000000000004894201890e412-e418 Published Online before print January 3 2018Neurology
Emma Matthews Christoph Neuwirth Fatima Jaffer et al Atypical periodic paralysis and myalgia A novel RYR1 phenotype
This information is current as of January 3 2018
ServicesUpdated Information amp
httpnneurologyorgcontent905e412fullincluding high resolution figures can be found at
httpnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online
0028-3878 Online ISSN 1526-632XKluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print ISSN1951 it is now a weekly with 48 issues per year Copyright copy 2018 The Author(s) Published by Wolters
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
A positive McManis test to the best of our knowledge haspreviously been described only in primary or secondaryPP18 Given the direct interaction between the Cav11channel implicated in the majority of cases of hypokalemicPP19 and RYR1 it seems plausible that dysfunction of eachmay produce phenotypic mimics This is supported by theobservation of a profound disturbance of the normalCav11RYR1 interaction in 1 previous patient with RYR1-related PP and other patients with recessive RYR1-relatedmyopathies1120 Furthermore the recently described CAC-NA1S-associated early-onset myopathy shares features ofpredominantly axial weakness and ophthalmoplegia withRYR1-related myopathies12 and may also feature similarreductions of the Cav11 protein However the exactmechanism by which the RYR1 variants would cause anepisodically unexcitable sarcolemma as demonstrated bya positive McManis test is unclear On the basis of the recentobservation of altered BK channel activity in RYR1-mutatedsmooth muscle cells10 one possibility is via an impairment ofBK channelndashmediated membrane repolarization due toaltered intracellular calcium homeostasis but this requiresfurther study102122
Other atypical PP phenotypes associated with motor neurop-athy due to mitochondrial gene mutations have beendescribed23 demonstrating that the clinical symptoms may beseen in nonndashion channel genetic disorders Our data demon-strate that late-onset episodic muscle weakness or paralysiswith prominent myalgia and cramps may be a more commonRYR1-associated phenotype than the single case we previously
reported and may not be limited to a specific genotype Wesuggest that cases compound heterozygous for RYR1 nonsenseand missense mutations are more likely to have a concomitantearly-onset myopathy The McManis test may be a useful di-agnostic tool in these cases although a negative test does notexclude the possibility of RYR1 involvement
We propose that clinicopathologic features suggestive ofRYR1 disorders should be sought in genetically undefined PPcases and RYR1 gene testing considered in those in whommutations in SCN4A CACNA1S and KCNJ2 have alreadybeen excluded
Author contributionsE Matthews drafting the manuscript for content analysis orinterpretation of data study concept C Neuwirth andF Jaffer revising the manuscript for content analysis orinterpretation of data study concept R Scalco D FialhoM Parton R Sud R Spiegel R Mein D Raja RayanK Suetterlin H Houlden A Schaefer E Healy J PalaceR Quinlivan S Treves and JL Holton revising the man-uscript for content analysis or interpretation of dataH Jungbluth drafting the manuscript for content analysisor interpretation of data study concept MG Hannarevising the manuscript for content analysis or in-terpretation of data
AcknowledgmentThe authors are grateful to Mark Walker at Southampton forthe retrieval of muscle histology slides
Table Summary of clinicopathologic features of cases with RYR1 gene variants and episodic weaknessparalysis
Symptoms ExaminationCKIUL EMG
McManistest Muscle biopsy
RYR1variants
Previouslyreportedcase11
Hypotonia respiratory andfeeding impairment at birthdelayed motor milestonesepisodic limb weaknesslasting days from age 18 ycold- and exercise-inducedmyalgiacramp from age 26 y
High arched palatefacial weaknessophthalmoplegiasevere trunk and neckweakness moderatelimb weaknesshyperlordosis
Normalrange
Myopathic Positive Variation in fibersize increasedinternal nucleicore-like structures
Asp708AsnArg2241XArg2939Lys
Case 1 Delayed walking early onsetproximal myopathy episodicmyalgia followed by limb andneck weakness lasting hoursto days from age 34 yfluctuant bulbar weakness
Long thin face higharched palate proximalmyopathy facialweakness and ptosisophthalmoplegiahyperlordosis
101 Myopathicincreasedjitter andblocking onSFEMG
Positive Variation in fibersize increasedinternal nucleiareas of centralpallor suggestive ofcore-like structures
Gln70XArg109TrpMet485Val
Case 2 Early history anddevelopment normalepisodic limb weakness fromage 23 y cramps withmyalgia
Long thin face 120 Normal Negative Normal Arg1507GlnGly2446Ser
Case 3 Early history anddevelopment normal minorepisodic weakness from age14 y episodic limb paralysisand myalgia from age 29 y
Normal 92 Normal Positive Type 1predominance 1ragged red fiber(+COX negative)increased internalnuclei 1 ring fiber
Arg1043His
Abbreviations CK = creatine kinase SFEMG = single-fiber EMG
NeurologyorgN Neurology | Volume 90 Number 5 | January 30 2018 e417
Study fundingPart of this work was undertaken at University College LondonHospitalsUniversity College London which received aproportion of funding from the Department of HealthrsquosNational Institute for Health Research Biomedical ResearchCentres funding scheme
DisclosureE Matthews holds a post-doctoral fellowship from the Na-tional Institute for Health Research Rare Disease SchemeC Neuwirth F Jaffer and R Scalco report no disclosuresrelevant to the manuscript D Fialho is supported by theNational Highly Specialised Service Department of HealthUK M Parton R Sud R Spiegel R Mein and D Rayanreport no disclosures relevant to the manuscript K Suetterlinhas an MRC Clinical Research Training Fellowship and re-ceived funding from the European Communityrsquos SeventhFramework Programme (FP72007-2013) under grantagreement 2012-305121 ldquoIntegrated European-omics Re-search Project for Diagnosis and Therapy in Rare Neuro-muscular and Neurodegenerative Diseases (NEUROMICS)rdquoH Houlden has received funding from the European Com-munityrsquos Seventh Framework Programme (FP72007-2013)under grant agreement 2012-305121 ldquoIntegratedEuropean-omics Research Project for Diagnosis andTherapy in Rare Neuromuscular and NeurodegenerativeDiseases (NEUROMICS)rdquo A Schaefer and E Healy reportno disclosures relevant to the manuscript J Palace is partlyfunded by Highly Specialised Services to run national con-genital myasthenia and neuromyelitis optica services and hasreceived support for scientific meetings and honorariums foradvisory work from Merck Serono Biogen Idec NovartisTeva Chugai Pharma and Bayer Schering as well as un-restricted grants from Merck Serono Novartis Biogen IdecTeva and Bayer Schering Her hospital trust receives funds forher role as clinical lead for the Department of Health RiskSharing Scheme She has received grants from the MS societyand Guthy-Jackson Foundation R Quinlivan is supported bythe National Highly Specialised Service Department ofHealth UK andNational Institute for Health Research and hasgrant funding from Muscular Dystrophy UK and Associationfor Glycogen Storage Disease She has received honoraria forteaching and consultancy from PTC Therapeutics Sanofi-Genzyme and Ultragenyx S Treves reports no disclosuresrelevant to the manuscript J Holton is supported by the RetaLila Weston Institute for Neurologic Studies H Jungbluthreports no disclosures relevant to the manuscript M Hanna is
supported by a Medical Research Council Centre grant theNational Centre for Research Resources and the NationalHighly Specialised Service Department of Health UK Go toNeurologyorgN for full disclosures
Received June 9 2017 Accepted in final form October 24 2017
References1 Amburgey K McNamara N Bennett LR McCormick ME Acsadi G Dowling JJ
Prevalence of congenital myopathies in a representative pediatric United Statespopulation Ann Neurol 201170662ndash665
2 Maggi L Scoto M Cirak S et al Congenital myopathies clinical features and fre-quency of individual subtypes diagnosed over a 5-year period in the United KingdomNeuromuscul Disord 201323195ndash205
3 Zhang Y Chen HS Khanna VK et al A mutation in the human ryanodine receptorgene associated with central core disease Nat Genet 1993546ndash50
4 Jungbluth H Zhou H Hartley L et al Minicore myopathy with ophthalmoplegiacaused by mutations in the ryanodine receptor type 1 gene Neurology 2005651930ndash1935
5 Wilmshurst JM Lillis S Zhou H et al RYR1 mutations are a common cause ofcongenital myopathies with central nuclei Ann Neurol 201068717ndash726
6 Clarke NF Waddell LB Cooper ST et al Recessive mutations in RYR1 are a com-mon cause of congenital fiber type disproportion Hum Mutat 201031E1544ndashE1550
7 Dlamini N Voermans NC Lillis S et al Mutations in RYR1 are a common cause ofexertional myalgia and rhabdomyolysis Neuromuscul Disord 201323540ndash548
8 Jungbluth H Lillis S Zhou H et al Late-onset axial myopathy with cores due toa novel heterozygous dominant mutation in the skeletal muscle ryanodine receptor(RYR1) gene Neuromuscul Disord 200919344ndash347
9 Loseth S Voermans NC Torbergsen T et al A novel late-onset axial myopathyassociated with mutations in the skeletal muscle ryanodine receptor (RYR1) geneJ Neurol 20132601504ndash1510
10 Lopez RJ Byrne S Vukcevic M et al An RYR1 mutation associated with malignanthyperthermia is also associated with bleeding abnormalities Sci Signal 20169ra68
11 Zhou H Lillis S Loy RE et al Multi-minicore disease and atypical periodic paralysisassociated with novel mutations in the skeletal muscle ryanodine receptor (RYR1)gene Neuromuscul Disord 201020166ndash173
12 Schartner V Romero NB Donkervoort S et al Dihydropyridine receptor (DHPRCACNA1S) congenital myopathy Acta Neuropathol 2017133517ndash533
13 Illingworth MA Main M Pitt M et al RYR1-related congenital myopathy withfatigable weakness responding to pyridostigimine Neuromuscul Disord 201424707ndash712
14 Jungbluth H Davis MR Muller C et al Magnetic resonance imaging of muscle incongenital myopathies associated with RYR1 mutations Neuromuscul Disord 200414785ndash790
15 Klein A Jungbluth H Clement E et al Muscle magnetic resonance imaging incongenital myopathies due to ryanodine receptor type 1 gene mutations Arch Neurol2011681171ndash1179
16 Zhou H Jungbluth H Sewry CA et al Molecular mechanisms and phenotypicvariation in RYR1-related congenital myopathies Brain 20071302024ndash2036
17 Venance SL Cannon SC Fialho D et al The primary periodic paralyses diagnosispathogenesis and treatment Brain 20061298ndash17
18 McManis PG Lambert EH Daube JR The exercise test in periodic paralysis MuscleNerve 19869704ndash710
19 Matthews E Labrum R Sweeney MG et al Voltage sensor charge loss accounts formost cases of hypokalemic periodic paralysis Neurology 2009721544ndash1547
20 Zhou H Rokach O Feng L et al RyR1 deficiency in congenital myopathies disruptsexcitation-contraction coupling Hum Mutat 201334986ndash996
21 Tricarico D Mele A Conte CD Carbonic anhydrase inhibitors ameliorate thesymptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels Neuromuscul Disord 20061639ndash45
22 Kim JB Kim SJ Kang SY Yi JW Kim SM The large-conductance calcium-activatedpotassium channel holds the key to the conundrum of familial hypokalemic periodicparalysis Korean J Pediatr 201457445ndash450
23 Aure K Dubourg O Jardel C et al Episodic weakness due to mitochondrial DNAMT-ATP68 mutations Neurology 2013811810ndash1818
e418 Neurology | Volume 90 Number 5 | January 30 2018 NeurologyorgN
SOURCE ARTICLE NPuborg5fjlcp
Atypical periodic paralysis and myalgiaAnovelRYR1 phenotype
Emma Matthews MRCP Christoph Neuwirth MD Fatima Jaffer MRCP Renata S Scalco MD
Doreen Fialho MRCP Matt Parton FRCP Dipa Raja Rayan MRCP Karen Suetterlin MRCP Richa Sud PhD
Roland Spiegel MD Rachel Mein BSc Henry Houlden FRCP Andrew Schaefer MRCP Estelle Healy FRCPath
Jacqueline Palace FRCP Ros Quinlivan FRCP Susan Treves PhD Janice L Holton FRCPath
Heinz Jungbluth PhD and Michael G Hanna FRCP
Cite as Neurologyreg 201890e412ndashe418 doi101212WNL0000000000004894
Correspondence
Dr Matthews
emmamatthewsuclacuk
Study questionWhat are the phenotypic characteristics of patients with pe-riodic paralysis (PP) symptoms and RYR1 mutations
Summary answerThese patients can have late-onset atypical PP with or withoutmyopathy and with myalgia and cramps as prominent features
What is known and what this paper addsRYR1 mutations are associated with diverse neuromusculardisorders including 1 reported case of atypical PP This studydescribes the phenotypes of 3 more patients with RYR1mutations and PP episodes
Participants and settingThis study reports 3 patients with possible PP diagnosesand clinicopathologic findings typically associated withRYR1-related disorders who were referred to UK and Swissspecialist centers
Design size and durationMedical histories were collected for all 3 patients Thesehistories includedmuscle examinations at various ages Sangersequencing for RYR1 was performed on patient samples
Main results and the role of chanceCase 1 was a 54-year-old man who had lifelong muscleweakness At 34 years old he experienced worsened symp-toms including sudden severe myalgia Examinations revealedvarious neuromuscular abnormalities including positiveresults on the McManis test for PP Case 2 was a 42-year-oldwoman who had experienced episodic muscle weakness andmigraine symptoms since the age of 23 years A neurologicexamination yielded unremarkable results and the McManistest yielded negative results Case 3 was a 49-year-old man
who had experienced postexercise limb weakness episodessince 14 years of age and full muscle paralysis episodes since29 years of age Neurologic examinations yielded unremark-able results but the McManis test yielded positive results All3 patients carried various RYR1 mutations and reported my-algia andor muscle cramps
Bias confounding and other reasonsfor cautionThese case reports do not firmly establish a genotype-phenotype relationship or explain the physiologic mecha-nism by which RYR1 mutations would cause late-onsetatypical PP
Generalizability to other populationsLate-onset atypical PP may be more common in persons withRYR1 mutations than the single previous report suggested
Study fundingpotential competing interestsThis study was funded by the UK Department of HealthSome authors report receiving funding from the UKand European Union governments pharmaceutical com-panies and medical research foundations Some authorsreport receiving personal compensation from pharma-ceutical companies Go to NeurologyorgN for fulldisclosures
Patient RYR1 variants
Previously reported Asp708Asn Arg2241X Arg2939Lys
Case 1 Gln70X Arg109Trp Met485Val
Case 2 Arg1507Gln Gly2446Ser
Case 3 Arg1043His
A draft of the short-form article was written by M Dalefield a writer with Editage a division of Cactus Communications The authors of thefull-length article and the journal editors edited and approved the final version
Copyright copy 2018 American Academy of Neurology 219
SHORT-FORM ARTICLE
DOI 101212WNL0000000000004894201890e412-e418 Published Online before print January 3 2018Neurology
Emma Matthews Christoph Neuwirth Fatima Jaffer et al Atypical periodic paralysis and myalgia A novel RYR1 phenotype
This information is current as of January 3 2018
ServicesUpdated Information amp
httpnneurologyorgcontent905e412fullincluding high resolution figures can be found at
httpnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online
0028-3878 Online ISSN 1526-632XKluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print ISSN1951 it is now a weekly with 48 issues per year Copyright copy 2018 The Author(s) Published by Wolters
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
Study fundingPart of this work was undertaken at University College LondonHospitalsUniversity College London which received aproportion of funding from the Department of HealthrsquosNational Institute for Health Research Biomedical ResearchCentres funding scheme
DisclosureE Matthews holds a post-doctoral fellowship from the Na-tional Institute for Health Research Rare Disease SchemeC Neuwirth F Jaffer and R Scalco report no disclosuresrelevant to the manuscript D Fialho is supported by theNational Highly Specialised Service Department of HealthUK M Parton R Sud R Spiegel R Mein and D Rayanreport no disclosures relevant to the manuscript K Suetterlinhas an MRC Clinical Research Training Fellowship and re-ceived funding from the European Communityrsquos SeventhFramework Programme (FP72007-2013) under grantagreement 2012-305121 ldquoIntegrated European-omics Re-search Project for Diagnosis and Therapy in Rare Neuro-muscular and Neurodegenerative Diseases (NEUROMICS)rdquoH Houlden has received funding from the European Com-munityrsquos Seventh Framework Programme (FP72007-2013)under grant agreement 2012-305121 ldquoIntegratedEuropean-omics Research Project for Diagnosis andTherapy in Rare Neuromuscular and NeurodegenerativeDiseases (NEUROMICS)rdquo A Schaefer and E Healy reportno disclosures relevant to the manuscript J Palace is partlyfunded by Highly Specialised Services to run national con-genital myasthenia and neuromyelitis optica services and hasreceived support for scientific meetings and honorariums foradvisory work from Merck Serono Biogen Idec NovartisTeva Chugai Pharma and Bayer Schering as well as un-restricted grants from Merck Serono Novartis Biogen IdecTeva and Bayer Schering Her hospital trust receives funds forher role as clinical lead for the Department of Health RiskSharing Scheme She has received grants from the MS societyand Guthy-Jackson Foundation R Quinlivan is supported bythe National Highly Specialised Service Department ofHealth UK andNational Institute for Health Research and hasgrant funding from Muscular Dystrophy UK and Associationfor Glycogen Storage Disease She has received honoraria forteaching and consultancy from PTC Therapeutics Sanofi-Genzyme and Ultragenyx S Treves reports no disclosuresrelevant to the manuscript J Holton is supported by the RetaLila Weston Institute for Neurologic Studies H Jungbluthreports no disclosures relevant to the manuscript M Hanna is
supported by a Medical Research Council Centre grant theNational Centre for Research Resources and the NationalHighly Specialised Service Department of Health UK Go toNeurologyorgN for full disclosures
Received June 9 2017 Accepted in final form October 24 2017
References1 Amburgey K McNamara N Bennett LR McCormick ME Acsadi G Dowling JJ
Prevalence of congenital myopathies in a representative pediatric United Statespopulation Ann Neurol 201170662ndash665
2 Maggi L Scoto M Cirak S et al Congenital myopathies clinical features and fre-quency of individual subtypes diagnosed over a 5-year period in the United KingdomNeuromuscul Disord 201323195ndash205
3 Zhang Y Chen HS Khanna VK et al A mutation in the human ryanodine receptorgene associated with central core disease Nat Genet 1993546ndash50
4 Jungbluth H Zhou H Hartley L et al Minicore myopathy with ophthalmoplegiacaused by mutations in the ryanodine receptor type 1 gene Neurology 2005651930ndash1935
5 Wilmshurst JM Lillis S Zhou H et al RYR1 mutations are a common cause ofcongenital myopathies with central nuclei Ann Neurol 201068717ndash726
6 Clarke NF Waddell LB Cooper ST et al Recessive mutations in RYR1 are a com-mon cause of congenital fiber type disproportion Hum Mutat 201031E1544ndashE1550
7 Dlamini N Voermans NC Lillis S et al Mutations in RYR1 are a common cause ofexertional myalgia and rhabdomyolysis Neuromuscul Disord 201323540ndash548
8 Jungbluth H Lillis S Zhou H et al Late-onset axial myopathy with cores due toa novel heterozygous dominant mutation in the skeletal muscle ryanodine receptor(RYR1) gene Neuromuscul Disord 200919344ndash347
9 Loseth S Voermans NC Torbergsen T et al A novel late-onset axial myopathyassociated with mutations in the skeletal muscle ryanodine receptor (RYR1) geneJ Neurol 20132601504ndash1510
10 Lopez RJ Byrne S Vukcevic M et al An RYR1 mutation associated with malignanthyperthermia is also associated with bleeding abnormalities Sci Signal 20169ra68
11 Zhou H Lillis S Loy RE et al Multi-minicore disease and atypical periodic paralysisassociated with novel mutations in the skeletal muscle ryanodine receptor (RYR1)gene Neuromuscul Disord 201020166ndash173
12 Schartner V Romero NB Donkervoort S et al Dihydropyridine receptor (DHPRCACNA1S) congenital myopathy Acta Neuropathol 2017133517ndash533
13 Illingworth MA Main M Pitt M et al RYR1-related congenital myopathy withfatigable weakness responding to pyridostigimine Neuromuscul Disord 201424707ndash712
14 Jungbluth H Davis MR Muller C et al Magnetic resonance imaging of muscle incongenital myopathies associated with RYR1 mutations Neuromuscul Disord 200414785ndash790
15 Klein A Jungbluth H Clement E et al Muscle magnetic resonance imaging incongenital myopathies due to ryanodine receptor type 1 gene mutations Arch Neurol2011681171ndash1179
16 Zhou H Jungbluth H Sewry CA et al Molecular mechanisms and phenotypicvariation in RYR1-related congenital myopathies Brain 20071302024ndash2036
17 Venance SL Cannon SC Fialho D et al The primary periodic paralyses diagnosispathogenesis and treatment Brain 20061298ndash17
18 McManis PG Lambert EH Daube JR The exercise test in periodic paralysis MuscleNerve 19869704ndash710
19 Matthews E Labrum R Sweeney MG et al Voltage sensor charge loss accounts formost cases of hypokalemic periodic paralysis Neurology 2009721544ndash1547
20 Zhou H Rokach O Feng L et al RyR1 deficiency in congenital myopathies disruptsexcitation-contraction coupling Hum Mutat 201334986ndash996
21 Tricarico D Mele A Conte CD Carbonic anhydrase inhibitors ameliorate thesymptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels Neuromuscul Disord 20061639ndash45
22 Kim JB Kim SJ Kang SY Yi JW Kim SM The large-conductance calcium-activatedpotassium channel holds the key to the conundrum of familial hypokalemic periodicparalysis Korean J Pediatr 201457445ndash450
23 Aure K Dubourg O Jardel C et al Episodic weakness due to mitochondrial DNAMT-ATP68 mutations Neurology 2013811810ndash1818
e418 Neurology | Volume 90 Number 5 | January 30 2018 NeurologyorgN
SOURCE ARTICLE NPuborg5fjlcp
Atypical periodic paralysis and myalgiaAnovelRYR1 phenotype
Emma Matthews MRCP Christoph Neuwirth MD Fatima Jaffer MRCP Renata S Scalco MD
Doreen Fialho MRCP Matt Parton FRCP Dipa Raja Rayan MRCP Karen Suetterlin MRCP Richa Sud PhD
Roland Spiegel MD Rachel Mein BSc Henry Houlden FRCP Andrew Schaefer MRCP Estelle Healy FRCPath
Jacqueline Palace FRCP Ros Quinlivan FRCP Susan Treves PhD Janice L Holton FRCPath
Heinz Jungbluth PhD and Michael G Hanna FRCP
Cite as Neurologyreg 201890e412ndashe418 doi101212WNL0000000000004894
Correspondence
Dr Matthews
emmamatthewsuclacuk
Study questionWhat are the phenotypic characteristics of patients with pe-riodic paralysis (PP) symptoms and RYR1 mutations
Summary answerThese patients can have late-onset atypical PP with or withoutmyopathy and with myalgia and cramps as prominent features
What is known and what this paper addsRYR1 mutations are associated with diverse neuromusculardisorders including 1 reported case of atypical PP This studydescribes the phenotypes of 3 more patients with RYR1mutations and PP episodes
Participants and settingThis study reports 3 patients with possible PP diagnosesand clinicopathologic findings typically associated withRYR1-related disorders who were referred to UK and Swissspecialist centers
Design size and durationMedical histories were collected for all 3 patients Thesehistories includedmuscle examinations at various ages Sangersequencing for RYR1 was performed on patient samples
Main results and the role of chanceCase 1 was a 54-year-old man who had lifelong muscleweakness At 34 years old he experienced worsened symp-toms including sudden severe myalgia Examinations revealedvarious neuromuscular abnormalities including positiveresults on the McManis test for PP Case 2 was a 42-year-oldwoman who had experienced episodic muscle weakness andmigraine symptoms since the age of 23 years A neurologicexamination yielded unremarkable results and the McManistest yielded negative results Case 3 was a 49-year-old man
who had experienced postexercise limb weakness episodessince 14 years of age and full muscle paralysis episodes since29 years of age Neurologic examinations yielded unremark-able results but the McManis test yielded positive results All3 patients carried various RYR1 mutations and reported my-algia andor muscle cramps
Bias confounding and other reasonsfor cautionThese case reports do not firmly establish a genotype-phenotype relationship or explain the physiologic mecha-nism by which RYR1 mutations would cause late-onsetatypical PP
Generalizability to other populationsLate-onset atypical PP may be more common in persons withRYR1 mutations than the single previous report suggested
Study fundingpotential competing interestsThis study was funded by the UK Department of HealthSome authors report receiving funding from the UKand European Union governments pharmaceutical com-panies and medical research foundations Some authorsreport receiving personal compensation from pharma-ceutical companies Go to NeurologyorgN for fulldisclosures
Patient RYR1 variants
Previously reported Asp708Asn Arg2241X Arg2939Lys
Case 1 Gln70X Arg109Trp Met485Val
Case 2 Arg1507Gln Gly2446Ser
Case 3 Arg1043His
A draft of the short-form article was written by M Dalefield a writer with Editage a division of Cactus Communications The authors of thefull-length article and the journal editors edited and approved the final version
Copyright copy 2018 American Academy of Neurology 219
SHORT-FORM ARTICLE
DOI 101212WNL0000000000004894201890e412-e418 Published Online before print January 3 2018Neurology
Emma Matthews Christoph Neuwirth Fatima Jaffer et al Atypical periodic paralysis and myalgia A novel RYR1 phenotype
This information is current as of January 3 2018
ServicesUpdated Information amp
httpnneurologyorgcontent905e412fullincluding high resolution figures can be found at
httpnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online
0028-3878 Online ISSN 1526-632XKluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print ISSN1951 it is now a weekly with 48 issues per year Copyright copy 2018 The Author(s) Published by Wolters
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
SOURCE ARTICLE NPuborg5fjlcp
Atypical periodic paralysis and myalgiaAnovelRYR1 phenotype
Emma Matthews MRCP Christoph Neuwirth MD Fatima Jaffer MRCP Renata S Scalco MD
Doreen Fialho MRCP Matt Parton FRCP Dipa Raja Rayan MRCP Karen Suetterlin MRCP Richa Sud PhD
Roland Spiegel MD Rachel Mein BSc Henry Houlden FRCP Andrew Schaefer MRCP Estelle Healy FRCPath
Jacqueline Palace FRCP Ros Quinlivan FRCP Susan Treves PhD Janice L Holton FRCPath
Heinz Jungbluth PhD and Michael G Hanna FRCP
Cite as Neurologyreg 201890e412ndashe418 doi101212WNL0000000000004894
Correspondence
Dr Matthews
emmamatthewsuclacuk
Study questionWhat are the phenotypic characteristics of patients with pe-riodic paralysis (PP) symptoms and RYR1 mutations
Summary answerThese patients can have late-onset atypical PP with or withoutmyopathy and with myalgia and cramps as prominent features
What is known and what this paper addsRYR1 mutations are associated with diverse neuromusculardisorders including 1 reported case of atypical PP This studydescribes the phenotypes of 3 more patients with RYR1mutations and PP episodes
Participants and settingThis study reports 3 patients with possible PP diagnosesand clinicopathologic findings typically associated withRYR1-related disorders who were referred to UK and Swissspecialist centers
Design size and durationMedical histories were collected for all 3 patients Thesehistories includedmuscle examinations at various ages Sangersequencing for RYR1 was performed on patient samples
Main results and the role of chanceCase 1 was a 54-year-old man who had lifelong muscleweakness At 34 years old he experienced worsened symp-toms including sudden severe myalgia Examinations revealedvarious neuromuscular abnormalities including positiveresults on the McManis test for PP Case 2 was a 42-year-oldwoman who had experienced episodic muscle weakness andmigraine symptoms since the age of 23 years A neurologicexamination yielded unremarkable results and the McManistest yielded negative results Case 3 was a 49-year-old man
who had experienced postexercise limb weakness episodessince 14 years of age and full muscle paralysis episodes since29 years of age Neurologic examinations yielded unremark-able results but the McManis test yielded positive results All3 patients carried various RYR1 mutations and reported my-algia andor muscle cramps
Bias confounding and other reasonsfor cautionThese case reports do not firmly establish a genotype-phenotype relationship or explain the physiologic mecha-nism by which RYR1 mutations would cause late-onsetatypical PP
Generalizability to other populationsLate-onset atypical PP may be more common in persons withRYR1 mutations than the single previous report suggested
Study fundingpotential competing interestsThis study was funded by the UK Department of HealthSome authors report receiving funding from the UKand European Union governments pharmaceutical com-panies and medical research foundations Some authorsreport receiving personal compensation from pharma-ceutical companies Go to NeurologyorgN for fulldisclosures
Patient RYR1 variants
Previously reported Asp708Asn Arg2241X Arg2939Lys
Case 1 Gln70X Arg109Trp Met485Val
Case 2 Arg1507Gln Gly2446Ser
Case 3 Arg1043His
A draft of the short-form article was written by M Dalefield a writer with Editage a division of Cactus Communications The authors of thefull-length article and the journal editors edited and approved the final version
Copyright copy 2018 American Academy of Neurology 219
SHORT-FORM ARTICLE
DOI 101212WNL0000000000004894201890e412-e418 Published Online before print January 3 2018Neurology
Emma Matthews Christoph Neuwirth Fatima Jaffer et al Atypical periodic paralysis and myalgia A novel RYR1 phenotype
This information is current as of January 3 2018
ServicesUpdated Information amp
httpnneurologyorgcontent905e412fullincluding high resolution figures can be found at
httpnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online
0028-3878 Online ISSN 1526-632XKluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print ISSN1951 it is now a weekly with 48 issues per year Copyright copy 2018 The Author(s) Published by Wolters
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
DOI 101212WNL0000000000004894201890e412-e418 Published Online before print January 3 2018Neurology
Emma Matthews Christoph Neuwirth Fatima Jaffer et al Atypical periodic paralysis and myalgia A novel RYR1 phenotype
This information is current as of January 3 2018
ServicesUpdated Information amp
httpnneurologyorgcontent905e412fullincluding high resolution figures can be found at
httpnneurologyorgcgicollectionall_clinical_neurologyAll Clinical Neurologyfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online
0028-3878 Online ISSN 1526-632XKluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print ISSN1951 it is now a weekly with 48 issues per year Copyright copy 2018 The Author(s) Published by Wolters
reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology
