Handbook of Clinical Neurology, Vol. 100 (3rd series)Hyperkinetic Movement DisordersW.J. Weiner and E. Tolosa, Editors# 2011 Elsevier B.V. All rights reserved

Chapter 41

Myoclonus-dystonia syndrome

NARDO NARDOCCI *

Department of Child Neurology, Fondazione IRCCS Istituto Neurologico �C. Besta,� Milan, Italy

INTRODUCTION

Dystonia is defined as “a syndrome of sustained invol-untary muscle contractions frequently causing repeti-tive twisting movements or abnormal postures” (Fahnet al., 1998).

Dystonia can be classified by age at onset, distri-bution, and etiology. The etiological classificationdistinguishes five main categories: (1) primary;(2) dystonia-plus; (3) secondary; (4) heredodegenera-tive; and (5) psychogenetic dystonia (Bressman, 2004).

Myoclonus is defined as a sudden, brief, “shock-like”involuntary movement caused by muscular contractions(positive myoclonus) or inhibitions (negative myoclonusor asterixis) (Marsden et al., 1982). It may be spontane-ous or induced by action or various stimuli. Myoclonusis classified on the basis of distribution (focal, segmental,multifocal, or generalized), pathophysiology (cortical,subcortical, spinal, and peripheral) and etiology. Theetiological classification distinguishes four categories:(1) physiologic; (2) essential; (3) epileptic; (4) and symp-tomatic. Physiologicmyoclonus occurs in normal subjectsand may be induced by anxiety and exercise. Essentialmyoclonus defines a clinical syndrome where myoclonusis the most prominent or the only clinical finding and iseither familial or sporadic. Epileptic myoclonus is a partof complex chronic seizure disorders including Lennox–Gastaut syndrome, Unverricht–Lundborg syndromes,and others. Symptomatic myoclonus manifests in thesetting of a specific underlying disorder, including meta-bolic or degenerative diseases, infections, and trauma.

The nosology and clinical classification of patientswith myoclonus and dystonia have been the subject ofdebate. Such patients have been previously reportedin the literature under terms such as “myoclonic-dystonia,” “essential myoclonus (familial or sporadic),”

*Correspondence to: Nardo Nardocci, MD, Department of C

“C. Besta,” via Celoria 11, 20133 Milan, Italy. Tel. 0039-2-239422

“alcohol-responsive myoclonic dystonia,” “hereditarymyoclonic dystonia,” and “hereditary dystonia withlightning jerks responding to alcohol,” and this differ-ence in nomenclature has contributed to confusion(Quinn et al., 1988). Furthermore myoclonus may bepresent in patients with primary dystonia, addingdifficulties to the classification of patients.

The term “myoclonus-dystonia syndrome,” used inthis chapter, refers to a group of nondegenerative con-ditions characterized by the association of myoclonusand dystonia as the sole or prominent symptoms(Table 41.1). They will be described in detail, togetherwith the most relevant differential diagnoses.

INHERITEDMYOCLONUS-DYSTONIA

Inherited myoclonus-dystonia (M-D) is a term rec-ently introduced to define a movement disorder withautosomal-dominant inheritance and reduced pene-trance, beginning in early childhood, with a relativelybenign course, with myoclonus as the most predomi-nant and disabling symptom (Gasser, 1998). M-D iscurrently included in the category of a dystonia-plussyndrome (Fahn et al., 1998).

The condition is genetically heterogeneous. Muta-tions in the epsilon-sarcoglycan gene (SGCE, MIM604149; DYT11) represent the major genetic cause,but other genes and loci are associated with the diseaseand in a proportion of patients no genetic alteration isfound.

Diagnosis of M-D is based upon clinical findings.Diagnostic criteria were first proposed by Mahloudjiand Pickienly (1967) and subsequently updated (Gasser,1998; Klein, 2002).

The following diagnostic criteria have been slightlymodified from Asmus and Gasser (2004):

hild Neurology, Fondazione IRCCS Istituto Neurologico

23, Fax: 0039-2-23942181, E-mail: nnardocci@istituto-besta.it

Table 41.1

Causes of myoclonus dystonia syndrome (MDS)

Inherited myoclonus-dystonia (M-D)

DYT11 myoclonus-dystonia (SGCE gene)

DYT15 myoclonus-dystonia (18p11, unknown gene)Non-DYT11 myoclonus-dystonia (unknown gene/loci)

Primary dystonias with myoclonus (“myoclonic dystonia”)

DYT1 primary dystonia

Other primary dystonias, early- or late-onset

Autosomal-dominant guanosine triphosphate

cyclohydrolase I deficiency (DYT5)Vitamin E deficiency

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● Brief, “lightning-like” myoclonus as the primaryfeature; focal or segmental dystonia of subtle tomarked severity may be also seen; rarely, dystoniais the only feature.

● Autosomal-dominant inheritance with incompletepenetrance and variable expressivity, but it may alsooccur in sporadic patients.

● Onset is usually in the first or second decade.● Additional neurological features, such as cerebellar

ataxia, spasticity, or dementia, are absent.● No structural abnormalities are found in cranial

imaging; there are no cortical events related to themuscle jerks and normal somatosensory evokedpotentials.

● Usually the condition follows a benign clinical coursewith no progression of symptoms and normal lifeexpectancy.

Myoclonus-dystonia due to SGCEmutations (DYT11 M-D): clinical features

More than 100 patients with proven SGCE mutationshave been reported, resulting in a precise clinicalspectrum.

Onset of the disease is during childhood or adoles-cence, but earlier (<1 year) or later (up to 40 years)onset has been described. Earlier onset seems to occurmore frequently in females (Raymond et al., 2008).

The presenting symptom is usually myoclonus,which characteristically involves the upper part of thebody (neck, trunk, limb), with predominance of proxi-mal muscles. Cranial muscles can also be affected,including laryngeal muscles. Leg involvement wasthought to be a rare feature of M-D, but in large seriesof patients it is not so exceptional, and may also be thepresenting symptom (Tezenas du Montcel et al., 2006;Koukouni et al., 2008; Nardocci et al., 2008; Raymondet al., 2008; Roze et al., 2008). The movements are

brisk, lightning, shock-like jerks which may be presentat rest and are typically aggravated or elicited byvoluntary movement. Other factors that enhance theabnormal movements are stress, fever, and differentstimuli, such as sound and touch (Nardocci et al.,2008).

Dystonia is associated with myoclonus in morethan half of the patients, usually causing little or nodisability. The dystonia typically involves neck orarms (torticollis, writer’s cramp) and has the charac-teristics of an action dystonia. Many patients withM-D do not complain of dystonia, which is detectedonly on neurological examination.

The majority of patients with DYT11 M-D presentwith a combination of myoclonus and dystonia orisolated myoclonus. The phenotype of pure dystoniain M-D has been described in a few patients (Asmuset al., 2002; Doheny et al., 2002; Valente et al., 2005,Koukouni et al., 2008; Nardocci et al., 2008).

The marked amelioration of motor symptoms (mainlymyoclonus) following alcohol ingestion was noticedin the first reports of patients and families with M-D(Lindenmuldre, 1933; Daube and Peters, 1966). Prior to theavailability of genetic testing, this response to alcoholwas used to differentiate patients with idiopathic dysto-nia into a subgroup of patients identified in the literatureunder the term “inherited dystonia with lightning jerksresponding to alcohol” (Quinn and Marsden, 1984; Quinnet al., 1988). The alcohol responsiveness is a striking featureof DYT11 M-D, but it has not been systematicallyverified in all mutation-positive cases and in some hasnot been confirmed (Asmus et al., 2002; Gerrits et al.,2006; Nardocci et al., 2008; Roze et al., 2008). Further-more, alcohol-responsiveness has also been reported innon-DTY11 M-D patients (Han et al., 2003; Valenteet al., 2003; Gerrits et al., 2006). Usually the effect ofalcohol is dose-dependent, but there is great variabilityand several patients have developed alcohol problemsdue to excessive drinking.

The presence of psychiatric symptoms, such asobsessive-compulsive disorders, alcohol abuse, depres-sion, and anxiety, is another typical feature of the con-dition (Asmus et al., 2002; Marechal et al., 2003;Misbahuddin et al., 2007). In 2002 the first systematicstudy in three largeDYT11M-D families was published,demonstrating that manifesting mutation carriers havean increased rate of obsessive-compulsive disorders ver-sus nonmanifesting mutation carriers and noncarriers.Alcohol dependence is due to the suppressor effect onthe motor symptoms (Saunders-Pullman et al., 2002).Similar results were obtained in a more recent study,in which psychiatric features were assessed by meansof the Composite International Diagnostic Interview(CIDI) in a cohort of 64 individuals from five M-D

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families. Other psychiatric symptoms, such as anxietyand depression, were frequent among manifestingmutation carriers, but with no statistically significantdifference (Hess et al., 2007).

The disease course of DYT11 M-D is usually benignand compatible with an active life, but there is a widevariability of outcomes among patients, even withinthe same family. In some patients the disease stabi-lizes, causing little disability, and some patients areseverely affected, with symptom progression over time(Nardocci et al., 2008). In most patients, diseaseprogression correlates with a worsening of myoclonuswhereas the dystonia tends to remain unchanged interms of distribution and severity (Nardocci et al.,2008). Dystonia may appear any time during thecourse of the disease (Roze et al., 2008). In a fewpatients, the initial presentation can be predominantdystonia that subsequently improves (Thobois et al.,2007; Roze et al., 2008). Rarely, spontaneous remis-sion of both myoclonus ad dystonia has been observed(Kyllerman et al., 1990; Nardocci et al., 2008).

Conventional neuroradiological investigations areunrevealing in DYT11 M-D. In a single-photon emis-sion computed tomography (SPECT) study on 15DYT11 mutation carriers (11 clinically affected), bilat-eral lower dopamine D2 receptor (D2R) binding wasdetected compared to controls (Beukers et al., 2009).These data seem to be in line with similar observationsin other types of dystonia (Naumann et al., 1998;Asanuma et al., 2005).

The clinical phenotype outlined above is relativelyhomogeneous; however, a few patients with additionalfeatures have been described, expanding the clinicalspectrum.

Some patients have a postural upper-limb tremor inaddition to dystonia and myoclonus (Asmus et al.,2002; Schule et al., 2004). Two patients from differentfamilies displayed mild parkinsonian features (reducedarm swing, postural instability, and rest tremor); in onea reduction of cerebrospinal fluid homovanillic acidwas detected and treatment with L-dopa/carbidopacaused improvement of all motor symptoms, includingmyoclonus (Raymond et al., 2008).

Epilepsy and electroencephalographic (EEG)abnormalities have been described in affected mem-bers from two unrelated families with SGCEmutations.In a large Dutch family, three out of five carriers of anovel SGCE mutation had partial seizures (Fonckeet al., 2003). In a second family from Ireland, twopatients with M-D had recurrent complex partialseizures with secondary generalization and anotherexperienced a prolonged febrile convulsion. All thesepatients were carrying a nonsense mutation that waspreviously described in two other families without

MYOCLONUS-DYS

seizures (O’Riordan et al., 2004). Presence of seizuresand/or EEG abnormalities is not considered an exclu-sion criterion of M-D.

One adult patient, with genetically confirmed M-D,suffered seizure-like episodes and on angiographyfocal stenosis of both internal carotid arteries with col-lateral circulation was found, suggesting a moyamoyadisease (Chung et al., 2007).

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Myoclonus-dystonia not associated withSGCE mutations (non DYT11 M-D):

clinical features

Since the discovery of mutations in SGCE as a causeof M-D, it has emerged that a proportion of patientswith a clinical phenotype of M-D do not carry anymutation in the DYT11 gene.

The proportion of DYT11-negative patients varies(Han et al., 2003; Valente et al., 2005; Tezenas duMontcel et al., 2006; Nardocci et al., 2008) and this varia-bility is dependent upon the presence or absence of posi-tive familial history. In familial cases the proportion ofSGCE mutation-positive patients is much higher (65%),while it is very low in sporadic patients. However, theabsence of clinical history can be due to the reduced pen-etrance of the gene and patients with de novo mutationshave been described (Hedrich et al., 2004; Borges et al.,2007; Nardocci et al., 2008), indicating that sporadiccases should be screened for SGCE mutations when thephenotype is consistent with M-D.

Patients with non-DYT 11 M-D seem to have a clini-cal phenotype indistinguishable from positive patients,including the nonmotor features (Gerrits et al., 2006).Electrophysiological features have been comparedbetween gene-positive and gene-negative patients andno difference was found (Nardocci et al., 2008). As inDYT11-positive patients, familial cases have a dominantpattern of inheritance, but maternal imprinting is rarelyseen (Valente et al., 2003; Tezeans du Montcel et al.,2006; Nardocci et al., 2008). In one study, SGCE muta-tion carriers had earlier onset and more frequent legdystonia compared to nonmutation carriers (Tezenasdu Montcel et al., 2006). Other authors found that,besides early onset and positive family history, axialdystonia and truncal myoclonus were predictive forthe presence of SGCE mutations (Gerrits et al., 2006).

Two main reasons account for the relatively lowrate of detection of SGCE mutations in clinicallyaffected M-D patients.

Firstly, there is definitive evidence that the conditionis genetically heterogeneous. The DYT11 locus hasbeen excluded in some families with M-D (Orthet al., 2007) and at least three unrelated families havebeen linked to a different locus (DYT 15). A family

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with M-D carrying a missense mutation in the DRD2gene on chromosome 11 was described (Klein et al.,1999). Years later, mutations in the SGCE weredetected in this family, raising doubts about the patho-genetic role of the genetic alteration at the DRD2 gene(Klein et al., 2002).

Secondly, it has been demonstrated that large geno-mic deletions of the SGCE, undetectable with conven-tional mutational screening (polymerase chain reactionand direct sequencing of exons and intron/exon bound-aries) can be responsible for M-D (Asmus et al., 2005;Han et al., 2008). As more patients are screened forgenomic deletions of the SGCE gene, it is reasonable toexpect that a higher frequency of DYT11 mutationsamong patients with clinically defined M-D will bedetected.

Myoclonus-dystonia at locus 18p11(DYT 15 M-D)

Grimes et al. (2002) described a large Canadian familywith M-D in whom linkage analysis identified a novellocus, named DYT15, on chromosome 18p11. Two otherfamilies with M-D reported 2 years later showed possiblelinkage to this locus (Schule et al., 2004). The clinical fea-tures described in these families are totally in accordancewith the M-D phenotype: autosomal-dominant inheri-tance with reduced penetrance compatible with maternalimprinting, early onset with predominant myoclonus,alcohol-responsiveness. The 18p11 locus was recently nar-rowed and all the known and predicted genes sequenced,but no mutation was disclosed (Han et al., 2007).

Neurophysiological studies

The first descriptions of polymyographic findings inM-D syndrome, including patients with unspecifiedand probably heterogeneous genetic backgrounds,revealed electromyographic (EMG) irregular bursts ofvariable duration (from 50 to 200 ms) superimposedupon dystonic contractions in the same or distant mus-cles, the presence of negative myoclonus and longrepetitive jerks defined as myorhythmia (Obeso et al.,1983; Quinn, 1996).

Recent studies in M-D patients describe morehomogeneous polymyographic features, includingisolated jerks with EMG bursts lasting from 60 to500 ms (Nardocci et al., 2008; Roze et al., 2008). Themyoclonic jerks may be evident at rest, occurring ona silent background, and during voluntary muscle acti-vation. Short and long bursts may occur in the samepatients: they occur synchronously and asynchronouslyin antagonist muscles. Most patients show polymyo-graphic features consistent with dystonia characterizedby co-contraction of agonist and antagonist muscles

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during voluntary movements; in these patients themyoclonic jerks are superimposed to the abnormal pro-longed tonic activity (Fig. 41.1). No differences have beenreported between SGCE-positive and -negative M-Dpatients (Nardocci et al., 2008). Isolated negative myoclo-nus and stimulus-sensitive myoclonus in response tounexpected stimuli have also been described (Marelliet al., 2008).DYT11M-D patients do not showmyoclonicbursts of short duration (<40 ms) or enlarged somato-sensory evoked potentials, and enhanced long-loopreflexes typical of cortical myoclonus (Shibasaki, 2000),and jerk locked back-averaging studies consistently failto demonstrate associated EEG transients (Obeso et al.,1983; Quinn, 1996; Li et al., 2008; Marelli et al., 2008;Roze et al., 2008). These features support a subcorticalorigin of the myoclonus, but do not indicate any specificgenerator and do not exclude a possible cortical partici-pation in the pathophysiology of myoclonus in M-D.

Cortical motor functions have been evaluated bytranscranical magnetic stimulation (TMS) and by theevent-related synchronization and event-related desyn-chronization patterns associated with voluntary move-ments with contrasting results. Paired-pulse TMSrevealed the presence of a subtle short intracorticalinhibition (SICI) impairment in a series of DYT11M-D patients (Marelli et al., 2008), but was normal inother series (Li et al., 2008; Meunier et al., 2008). SICIimpairment has been demonstrated in patients withcortical myoclonus (Brown et al., 1996; Hanajimaet al., 1996; Manganotti et al., 2001), in patients withfocal or generalized dystonia (Ridding et al., 1995;Gilio et al., 2000; Edwards et al., 2003), and in parox-ysmal kinesigenic dyskinesia (Mir et al., 2005). Theimpaired SICI observed in dystonic patients has beenattributed to a reduction in the power of gamma-ami-nobutyric acid receptor type a (GABA-a) circuitry inthe motor cortex due to primary dysregulation of thestriatopallidothalamocortical loop. A similar functionalabnormality may play a role in the pathophysiologicalmechanism of DYT11 M-D (Berardelli et al., 1998).

Enhanced recovery of the mean R2 component ofthe blink reflex has been demonstrated in DYT11M-Dpatients, suggesting the presence of a hyperexcitablebrainstem interneuronal pool (Nakashima et al., 1989;Marelli et al., 2008). Enhanced recovery of the blinkreflex has also been reported in dystonia of differentetiologies, including primary dystonia, and thought tobe the result of defective suprasegmental control mech-anisms (Berardelli et al., 1985; Nakashima et al., 1989).A similar mechanism should also be considered inDYT11M-D patients.

The neurophysiological features of myoclonus inDYT11 M-D patients suggest the involvement of morethan one system in the generation of the movement

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Fig. 41.1. Electromyogram (EMG) activity from DYT11 myoclonus-dystonia patients recorded with surface electrodes from

upper right limb. Muscles are from top downwards: wrist flexors (WF), wrist extensors (WE), brachial biceps (BB), brachial

triceps (BT). (A) At rest on distal muscles isolated burst lasting 150 ms. (B) Prolonged tonic activity with superimposed repet-

itive EMG bursts lasting 200–400 ms during voluntary movements. (C) Synchronous bursts lasting 300 ms at rest on distal

muscles. (D) Brief bursts (60–80 ms) on distal muscles during postural maintenance. (Reproduced from Nardocci N, Zorzi

G, Barzaghi C, et al (2008). Myoclonus-dystonia syndrome: clinical presentation, disease course, and genetic features in 11

families. Mov Disord 23: 28-34.)

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disorder. The prominent myoclonic feature of DYT11M-D patients is thought to be the result of a multiplebrain-level dysfunction due to the genetic defect.SGCE protein is widely localized in various brainregions, including the cortex and brainstem (Nishiyamaet al., 2004), and has a subcellular localization in neu-ronal membranes, possibly leading to an interneuronalsystem imbalance sustaining physiological inhibition inmultiple brain areas (Nishiyama et al., 2004; Esapaet al., 2007).

Genetic

The first M-D locus was mapped on chromosome 7q21in a large family from North America in 1999 (Nygaardet al., 1999) and confirmed in other families (Kleinet al., 2000; Asmus et al., 2001; Vidailhet et al.,2001), indicating DYT11 as a major locus for this disor-der. In 2001, five heterozygous mutations in the genecoding for epsilon-sarcoglycan (SGCE) were identifiedin six German families with M-D (Zimprich et al.,2001). Since then more than 40 different mutations in

the SGCE have been described, including several re-current mutations (Grunewald et al., 2008). Variousmutations have been described: nonsense, missense,deletions, and insertions. One patient, carrying two het-erozygous mutations located at the same allele, wasreported (Ritz et al., 2009). The vast majority of muta-tions cause premature termination of translation, butthere is evidence that missense mutations lead to proteindegradation and are “loss of function” mutations(Esapa et al., 2007).

In 2005 the first two patients with M-D due to exondeletions were reported (Asmus et al., 2005). Exonrearrangements are not detectable with the usualtechnique of polymerase chain reaction and directsequencing accounts for a variable proportion ofmutation-negative cases (Grunewald et al., 2008; Hanet al., 2008; Ritz et al., 2009). No definitive correlationbetween genotype and phenotype has been established.Exceptions are those few patients presenting myoclo-nus and dystonia in addition to developmental delayand various dysmorphic and malformative featuresdue to genomic deletions in the 7q21 (DeBerardinis

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et al., 2003; Bonnet et al., 2008). All deletions containthe SGCE gene plus additional neighboring genes,and the clinical phenotype is determined by exten-sion of the deletions (Asmus et al., 2007a). A patientwith M-D-plus features typical of Silver–Russell syn-drome has been reported; in this case a new geneticalteration – maternal chromosome 7 disomy – wasfound (Guettard et al., 2008).

The SGCE gene consists of 12 exons (exon 1–11,plus an alternatively spliced exon 9) and encodes fora 438-amino acid protein with a single transmembranedomain. The SGCE is a member of a gene family thatalso includes alpha-, beta-, delta-, epsilon-, and zeta-sarcoglycans that compose a complex that is an essen-tial structure of dystrophin-associated glycoproteinassembly in striated muscle. This assembly links thecytoskeleton to the extracellular matrix. Alpha anddelta sarcoglycans are expressed predominantly inskeletal muscle; recessive mutations in gene codingfor these sarcoglycan family members result in varioustypes of limb girdle muscular dystrophies. Epsilon-sarcoglycan is 68% homologous to a-sarcoglycansand is widely expressed in many tissues of the body,including various regions of the brain – cerebral cor-tex, basal ganglia, hippocampus, cerebellum and theolfactory bulb (Ettinger et al., 1997; McNally et al.,1998; Zimprich et al., 2001; Xiao and Le Doux, 2003;Nishiyama et al., 2004; Chan et al., 2005). It has beenpostulated that epsilon-sarcoglycan participates in thedevelopment of various organs and tissues, includingbrain, as demonstrated in animals (Xiao and Le Doux,2003). Currently the exact function of sarcoglycans inbrain and in the pathogenesis of M-D is unknown. Incellular models expressing the mutant SGCE protein,the abnormal protein is retained intracellularly andrapidly degraded, indicating impaired trafficking tothe plasma membrane (Esapa et al., 2007).

The SGCE gene is imprinted. Initially, M-D wasregarded as an autosomal-dominant disease withreduced penetrance, but reinvestigation of pedigreessuggested maternal imprinting: mutation carriers man-ifest symptoms when the mutated gene is inheritedfrom the father with almost complete penetrance(Grabowski et al., 2002; Muller et al., 2002). There areseveral other human genes that are imprinted, includinggenes located on chromosome 7, and many of themare involved in human diseases. Usually, the mecha-nism of imprinting is a methylation of cytosine resi-dues at the promoter region that inactivates the gene.This mechanism has been confirmed for the SGCEgene by showing a differential pattern of methylationof the parental allele in patients with M-D (Grabowskiet al., 2002). Some families have been described inwhich the affected individual inherited the SGCE

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mutation from the mother whereas other family mem-bers were asymptomatic carriers who inherited themutation from the father (Grabowski et al., 2002;Muller et al., 2002; Raymond et al., 2008). In someof these patients a loss of imprinting with subsequentbilallelic expression of the SGCE gene has beendemonstrated (Muller et al., 2002).

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Treatment

Due to lack of knowledge about the pathogenesis,treatment in M-D is symptomatic and largely basedon case reports, case series, and personal experience,with few controlled studies.

M-D is usually benign, but can cause significant dis-ability due to myoclonus rather than dystonia. Myoclo-nus may be refractory to medical treatment. M-D mayalso be associated with some psychiatric conditions,including obsessive-compulsive disorders, anxiety, anddepression, that may require specific treatment.

Medication for treating myoclonus includes anti-convulsants that reduce neuronal excitability with aGABAergic mechanism. Benzodiazepines, particularlyclonazepam, valproic acid, and topiramate, have beenreported to ameliorate myoclonus (Kyllerman et al.,1990; Nygaard et al., 1999; Goetz and Horn, 2001).Improvement with L-5-hydroxytryptophan has beendescribed (Frucht, 2000; Scheidtmann et al., 2000).

An intriguing feature of M-D is the response toethanol. Adult patients frequently report that alcoholimproves myoclonus, often resulting in alcohol abuse.The pathophysiological basis of the alcohol action isunknown. The information on the effect of ethanolon the central nervous system originates from studieson essential tremor and from the knock-out mice ofGABA-a. They suggest that ethanol produces an inhib-itory effect on central nervous system motor pathwaysby an agonistic effect on GABA-a a1 subunit andglycine receptors and by modulating glutamatergicand adenosinergic transmission (Mihic et al., 1997;Kralic et al., 2005).

Promising results with gamma-hydroxybutyric acid(GHB), used for the treatment of alcohol withdrawaland for maintaining abstinence from alcohol, and itssodium salt form, sodium oxybate, have been reportedin open-label studies including a few patient with M-D(Priori et al., 2000; Frucht et al., 2005). Tolerability wassatisfactory but further studies of these drugs areneeded since risks of overdose and abuse exist. Themechanism of action of sodium oxybate is unknown.GHB is synthesized in the brain from its precursorGABA and some of its actions are mediated by spe-cific receptors distinct from the GABA-b receptors(Tunnicliff, 1997; Wu et al., 2004).

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The treatment of dystonia includes various options,including drug treatment and chemodenervation withbotulinum toxin injections. The selection of a particulartreatment is based on the age of the patient, the distri-bution of dystonia, and the severity of motor disability(Jankovic, 2006). In children or adolescents, a trial withlevodopa should be the initial choice. If ineffective,anticholinergic treatment may be considered. In themajority of M-D patients dystonia has a focal or seg-mental distribution, mainly involving cervical muscles.Many clinical studies have provided evidence that bot-ulinum toxin is the treatment of choice for patientswith cervical dystonia (Jankovic, 2006).

Deep-brain stimulation (DBS) has been recognizedas an effective therapeutic option for patients withdrug-resistant dystonia of various etiologies, in partic-ular for primary generalized dystonia linked to theDYT1 mutation (Coubes et al., 2000; Zorzi et al.,2005; Ostrem and Starr, 2008). This surgical techniquehas been tested in a few patients with M-D. Improve-ment of both myoclonus and dystonia after bilateralDBS of the globus pallidus internus (GPi) has beenreported in three patients, one of whom had a confirmedSCGE mutation. The age at surgery ranged between8 and 28 years (Liu et al., 2002; Cif et al., 2004;Magarinos-Ascone et al., 2005). Myoclonus improvedearlier than dystonic movements and postures, andthe benefit persisted during 24 months of follow-up.The ventral intermediate nucleus of the thalamus hasalso been used as a target of a unilateral and subse-quently bilateral stimulation in one patient aged 60.Postoperatively myoclonus improved without any sig-nificant change in dystonic symptoms (Trottenberget al., 2001). The mechanism of the effect of DBS onthese structures remains unexplained. Some hypoth-eses emerge from intraoperative recordings in dystonicpatients that demonstrate abnormal patterns of dis-charges in the external and internal portions of the glo-bus pallidus (Sanghera et al., 2003). High-frequencystimulation of GPi could restore the discharge patternin the GPi, reducing the cortical overactivation typicalof dystonia. The marked improvement of myoclonussuggests that GPi is also involved in the generation ofthe myoclonic activity in patients with M-D.

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PRIMARY DYSTONIASWITHMYOCLONUS (MYOCLONIC DYSTONIA)

Primary dystonia is a progressive disorder character-ized by dystonia as the only neurological abnormality,except for tremor and occasionally myoclonus, and isclinically and genetically heterogeneous (Bressman,2004; Tarsky and Simon, 2006). Early-onset primarydystonia is the most severe form of primary dystonia

and is linked to several genetic loci. Many cases areinherited with an autosomal-dominant pattern withreduced penetrance; the disease is caused by the GAGdeletion in the DYT1 gene on chromosome 9. The geneencodes for the protein TorsinA with particular homol-ogy to heat shock protein. It is expressed in severaltissues, in particular in the basal ganglia (substantianigra, thalamus, and globus pallidus) and cerebral cor-tex (Ozelius et al., 1997). DYT1 gene mutation accountsfor 53% of early-onset primary dystonia in non-Jewsand 80–90% of patients in Ashkenazi Jews (Bressmanet al., 1994; Valente et al., 1998; Zorzi et al., 2002).

DYT1 dystonia begins in childhood or adolescencewith a focal action dystonia involving one limb (writingdystonia, walking dystonia with foot inversion or ever-sion); dystonia subsequently spreads to involve otherbody regions and generalization is frequent. Dystoniamay also start in the neck or in the cranial muscles;in these patients the disease course is more variableand dystonia may remain focal or segmental. Overall,up to 65% of patients with DYT1 dystonia have ageneralized dystonia, with the limbs being the most fre-quent sites involved (Bressman et al., 2000). A malepatient of Ashkenazi origin with typical M-D and alco-hol-responsiveness carrying the DYT1 mutation wasreported (Tezenas du Montcel et al., 2006).

Many early-onset primary dystonia patients do nothave the DYT1 mutation and are designated non-DYT1primary dystonia. The clinical features of non-DYT1 pri-mary dystonia patients overlap with those ofDYT1 cases,except for familial cases that frequently show morefocal involvement of cranial or cervical muscles anda relatively benign course with rare generalization(Fasano et al., 2006).

Patients with primary dystonia may show irregular,arrhythmic “jerky” movements associated with dysto-nia, which led to the definition of “jerky” idiopathicdystonia (Mahloudji and Pickienly, 1967; Obeso et al.,1983) and more recently to “jerky” primary dystoniaor myoclonic dystonia (Asmus and Gasser, 2004;Valente et al., 2005). In most of these patients thesame muscles are involved in both the myoclonus anddystonia. Polymyographic features are typical of sub-cortical myoclonus with irregular jerks of brief dura-tion (50–200 ms) often superimposed on prolongedtonic contractions involving cervical and upper-limbmuscles, and indistinguishable from the EMG patternseen in M-D patients (Canavese et al., 2008). Clinicaldifferentiation between myoclonic dystonia and M-Dmay be difficult in individual patients; however, thefrequent absence of a family history, the predominanceof dystonia, and the occurrence of the jerks in the samemuscles involved by dystonia are important clues forthe correct diagnosis.

NIA SYNDROME 569

570 N. NARD

AUTOSOMAL-DOMINANTGTPCHDEFICIENCY (DYT5 DYSTONIA)

Autosomal-dominant guanosine triphosphate cyclohy-drolase I (GTP-CH) deficiency, also called DYT5dystonia, is the most frequent form of the so-calleddopa-responsive syndromes which constitute a seriesof inherited neurological conditions characterizedby different types of movement disorders and L-doparesponsiveness, sometimes with signs and symptomsof a more diffuse central nervous system involvement.These disorders are a result of defects in one of theenzymes involved in the synthesis of dopamine andserotonin, and are sometimes referred to as neuro-transmitter disorders (Swoboda and Hyland, 2002).GTP-CH is the first and rate-limiting enzyme in thesynthesis of tetrahydrobyopterin, which is the essentialcofactor for tyrosine hydroxylase and dopamine syn-thesis (Ichinose et al., 1994). A family withh GTP-CHdeficiency with phenotypic presentation of M-D hasbeen reported (Leuzzi et al., 2002). From the age of3 years, the proband had jerky movements of the upperlimbs that progressively worsened, spreading to lowerlimbs, trunk, and face. On examination at age 15, hehad continuous, rhythmic (1.5–2 Hz), synchronousjerks involving proximal muscles of upper and lowerlimbs during action, and arrhythmic erratic myoclonicjerks affecting trunk and face. The involuntary move-ments disappeared at rest and during sleep. He alsoexhibited mild dystonic postures of upper limbs andneck, mild bradykinesia, and lack of facial expression.No diurnal fluctuation of symptoms was observed andmental capacity was normal. Myoclonus, dystonia, restand postural tremor of the limbs or other body parts,without diurnal fluctuation, were reported in relatives.

Treatment with L-dopa/carbidopa resulted in com-plete disappearance of arm myoclonus, neck dystonia,bradykinesia, and hypomimia. Myoclonus of the lowerlimb was reduced but persisted after 1 year of therapy.

VITAMIN E DEFICIENCY

Isolated vitamin E deficiency is an autosomal-recessivecondition associated with a defect in the alpha-tocopheroltransfer protein. It manifests with progressive ataxia,hyporeflexia, and decreased proprioceptive sensation;dystonia is infrequently reported during the diseasecourse. However, the association of myoclonus anddystonia in one patient affected by isolated vitamin Edeficiency has been reported (Angelini et al., 2002).Myoclonic dystonia was the presenting symptom andremained the only manifestation for 6 years beforethe appearance of typical features of the disease. Fam-ily history was negative and the child’s developmentwas normal. At age 8 years, small-amplitude head jerks

began to occur during emotional stress. Two yearslater, torsion of the head on action and during emo-tional stress appeared. At age 11, the jerks worsenedand were often associated with torsion of the trunk. Neu-rological examination disclosed irregular and arrhythmicmyoclonus involving head and arms, combined with dys-tonic posturing of the head and slight dysarthria. Poly-myography with surface electrodes disclosed featuresconsistent with myoclonic dystonia: irregular bursts ofEMG activity lasting between 100 and 250 ms, superim-posed on prolonged tonic co-contraction of the trapeziusand splenius muscles. Treatment with clonazepam signif-icantly reduced the myoclonus but did not affect thedystonia. Treatment with alpha-tocopherol produced amarked reduction in dystonia, but myoclonus continuedto manifest in stressful situations.

The importance of considering isolated vitamin Edeficiency rests on the fact that it is eminently treatable,particularly if vitamin E supplementation is institutedpromptly (Rayner et al., 1993).

The main neuropathological features of vitamin Edeficiency are degeneration of large-caliber myelinatedsensory axons, particularly in the posterior column,and loss of cerebellar Purkinje cells consistent withthe spinocerebellar signs and symptoms observed inthe condition (Yokota et al., 2000). However, patholog-ical involvement of the nigrostriatal pathways has beendescribed in animal models (Dexter et al., 1994b) and invitamin E deficiency secondary to various causes,including abetalipoprotein (Dexter et al., 1994a). Inthese cases, the neuropathological features includenigral dopaminergic cell loss, axonal swelling in theglobus pallidus and zona reticularis of the substantianigra, reduced pigmentation of the substantia nigra,and lipofuscin-like pigment deposition in the glia ofthe globus pallidus, substantia nigra, and inferiorputamen. These findings may explain the prominentmovement disorder observed in the patient.

OCCI

DIFFERENTIAL DIAGNOSIS

The clinical conditions (Table 41.1) constituting the“myoclonus-dystonia syndrome” are all nonprogressiveneurological disorders, with a positive familial historyand a clinical presentation dominated by the movementdisorder. The “core” of the myoclonus-dystoniasyndrome is represented by inherited M-D that haswell-defined clinical criteria that allow the correctidentification of patients. Dystonia and myoclonus,alone or in combination, can be part of the neuro-logical manifestations seen in a long list of secondaryand heredodegenerative conditions, but these can beoften differentiated on clinical findings. Patients withmyoclonus-dystonia syndrome do not need to undergo

TO

extensive etiological investigations, since the diagnosisis based upon careful familial and personal history andneurological examination.

However, there are two other clinical conditions thatneed to be considered because they pose diagnosticproblems. One, benign hereditary chorea (BHC), wasoften misdiagnosed as myoclonus-dystonia until theresponsible genetic alteration was identified. Thesecond was Unverricht–Lundborg disease (ULD), aprogressive myoclonic epilepsy. Patients with ULDhave no cognitive deterioration, seizures may be spo-radic and the clinical picture, especially in the earlystage of the disease, can be dominated by myoclonus,thus posing some diagnostic problems.

MYOCLONUS-DYS

Benign hereditary chorea

BHC is a rare autosomal-dominant disorder character-ized by early-onset nonprogressive chorea withoutdementia, linked to mutations in the thyroid transcrip-tion factor (TITF-1) (Breedveld et al., 2002b). Prior tothe identification of the causative gene the diagnosiswas based on clinical criteria. Patients were reportedunder the term BHC syndrome, characterized by spe-cific clinical features: age at onset of chorea rangingbetween early infancy and adolescence often withdelayed motor and cognitive development, nonprogres-sive course, and the movement disorder not interferingwith normal life activity, and essentially normal mentalcapacity (Leli et al., 1984; Kleiner-Fisman and Lang,2007). Most patients with TITF-1 mutations share theclinical features described. However, gene-positivepatients may have other neurological features, includ-ing dysarthria and intention tremor (de Vries et al.,2000), diplegia (Breedveld et al., 2002a), spasticity,mental impairment and learning disabilities (do CarmoCosta et al., 2005), developmental delay (Kleiner-Fisman et al., 2003), Babinski signs and increasedreflexes, slow saccadic eye movements, and gait diffi-culties (Breedveld et al., 2002a). Finally, lung, thyroidand neurological abnormalities in variable combinationhave been reported in patients with TITF gene and theterm “brain–thyroid–lung” syndrome has been intro-duced (Krude et al., 2002; Doyle et al., 2004; Willem-sen et al., 2005).

The clinical distinction between chorea and myoclo-nus can be difficult (Schrag et al., 2000). Chorea is char-acterized by irregular rapid abnormal movementsusually involving many different parts of the body.Myoclonus consists of sudden jerks, which are usuallyrepetitive and stereotypic. However, rapid and repeti-tive choreic movements, in particular involving armsand fingers, may resemble myoclonus (Schrag et al.,2000). Furthermore, the distinction between BHC and

inherited M-D may be difficult since the two condi-tions may show phenotypic similarities in terms ofage at onset, pattern of inheritance, and course. Thecombination with dystonia is not a definite criterionsince cervical, axial, and limb dystonia and alcohol-responsiveness have been described in a patient withBHC (Asmus et al., 2007b). Finally, electrophysiologicalinvestigations are unhelpful because a mixture of shortand long bursts with and without co-contraction are theusual polymyographic features observed in both M-Dand chorea (Berardelli et al., 1999). Lightning myo-clonic jerks aggravated by complex intentional tasksinvolving mainly the proximal limbs and comorbiditywith affective disorders have been suggested to bethe main criteria for the clinical differentiation ofM-D from BHC patients (Asmus et al., 2007b).

NIA SYNDROME 571

Unverricht–Lundborg disease

ULD is an autosomal-recessive disorder due to the cista-tin B gene (CSTB) on chromosome 21q22.3 (Lehesjokiet al., 1991). ULD is the most common progressivemyoclonic epilepsy. Age at onset is 6–15 years; multi-focal myoclonus may be the presenting symptom, oftenprecipitated by posture, action, or external stimuli(Lehesjoki, 2002). Generalized tonic-clonic seizuresand absence seizures are frequent and occur in the earlystage of the disease, but rarely may not occur. Neurolog-ical examination at onset is normal and incoordination,intention tremor, and ataxia develop during the courseof the disease, with dementia occurring usually as a latefeature. The EEG during the course of the diseaseshows diffuse slow background activity with typical epi-leptic abnormalities with photosensitivity (Berkovicet al., 1991). However, background activity may be nor-mal during the first years of the disease and the EEGmay mimic that of idiopathic generalized epilepsy.Magnetic resonance imaging of the brain may benormal, even in advanced stages of the disease whenvariable degrees of cerebellar or cerebral atrophy maybe evident (Mascalchi et al., 2002).

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