Congenital Myasthenic Syndromes
Dr Pinki Munot
Paediatric Neurologist
Dubowitz Neuromuscular Centre
Great Ormond Street Hospital for Children Institute of Child Health, UCL
One case was fatal and diagnosed at post-mortem
2011
2016
Courtesy for family tree: Jackie Pitchforth
Outline
• Background and ‘barriers’
• Understanding Pathogenesis to guide Rx
• Drug therapy
• Supportive therapy – Respiratory/feeding
• Genetic counselling
• Prognosis with current treatments
• Challenges in treatment
• Therapies on the horizon
• Genetic disorders with abnormal neuromuscular
transmission • Barriers: Rare -estimated 600 patients in the UK Diagnosis frequently delayed by years Often misdiagnosed as congenital myopathies or seronegative MG
Background and Barriers to Diagnosis and Treatment
Fatigue is a key symptom
Clustered AChR
MuSK
CMS-associated genes
AChE
COLQ
LAMB2
CHRNA
CHRNB
CHRND
CHRNE
CHRNG
RAPSN
MUSK
DOK-7
CHAT
SCN4A
AGRN
GFPT1 DPAGT1 ALG2&14 GMPPB
LRP4
PREPL
Gene % of CMS
CHAT 4%-5%
CHRNE 50%
COLQ 10%-15%
DOK7 10%-15%
RAPSN 15%-20%
>30 genes
Understanding Pathophysiology
Courtesy Dr Pedro Cruz
UK Genetic subtypes 2017-2018
Courtesy Dr Pedro Cruz, Oxford
Phenotypes
Presentation
Birth: Hypotonia Weakness: ocular, bulbar, poor suck Respiratory Stridor Arthrogryposis Infancy: Hypotonia and fatigable weakness Weak cry, feeding difficulties Ptosis, ophthalmoplegia Delayed motor milestones Recurrent chest infections (IPPV) Episodic apnoea Childhood or Adults : Fatigable limb girdle weakness
• 14m • Recurrent respiratory crises • 24 hour ventilation • Progressive fluctuating weakness
• Abnormal rep stim and SSFEMG • Muscle biopsy mild myopathy
A trial of Pyridostigmine, resulted in worsening with constant weakness, head drop and pronounced ptosis
RAPSYN, CHAT DOK7 and CHRNE negative
• Started on oral Salbutamol 1mg BD
• After 3months reduced to nocturnal NIV
Now 5 years old
• Ongoing fatigue, neck weakness, chest infections
AChR Deficiency (CHRNE)
• Onset: infancy • autosomal recessive
• Symptoms: ptosis, ophthalmoplegia, bulbar, motor problems • Responded to pyridostigmine
• Prognosis: stable
CMS with episodic apnoea – CHAT
• Onset in infancy • Autosomal recessive
• Fluctuating weakness • Severe apnoeic attacks induced by infection, fever, excitement, overexertion •May respond to pyridostigmine resuscitation measures
CMS Episodic apnoeas – RAPSN N88K example
• 6 year old • Recurrent rapid respiratory crises • Developed ptosis and fatigue • Responded to pyridostigmine and add-on 3,4 DAP • BIPAP for emergency use • Improved with age • EMG no decrement but limited
CMS: Fast Channel Syndromes
• Symptoms from birth
• Hypotonia • Weakness • Arthrogryposis • opthalmoplegia • Respiratory problems • Stridor (vocal cord palsy) • Feeding difficulties
• Respiratory crises: • Frequent, severe, rapid onset
• Respond to pyridostigmine
Normal motor milestones Waddling gait Limb girdle weakness Ptosis variable Rare ophthalmoparesis Birth: stridor, VCP, poor feeding May need tracheostomy Can develop Respiratory crises Progressive, may need NIV Do not respond long term to pyridostigmine
Good response to Salbutamol
CMS: DOK-7
Slow channel Syndromes
Open Channel Blockers Fluoxetine
Quinidine No Pyridostigmine
Establishing the diagnosis
• Clinical history and examination
• EMG : RNS decrement
• StimSFEMG abnormal jitter
• Absence of AChR/MuSK abs
• Molecular genetic analysis
(clues from phenotype)
• Response to acetyl cholinesterase
inhibitors
• Muscle biopsy and Muscle MRI to exclude
congenital myopathies
Fast channel CHRNE RAPSYN CHAT
Slow channel DOK7 COLQ LRP4
MUSK Agrin
Cholinergic Agonists
MUSCLE
NERVE
Na+ Na+ Na+ Na+
PYRIDOSTIGMINE
→ stops breakdown of ACh
MUSCLE
NERVE
ACh
3,4-DAP Prolongs the nerve firing
Adrenergic drugs
Nerve Terminal
ACh
Excess entry of cations
Destabilised
postsynaptic structure
Agrin
MuSK
Dok-7
b2AR
Salbutamol
Ephedrine
Compensation 2nd messenger
Rapsyn
Empirically found to be effective Mechanism not fully understood Stabilizes the NMJ Gradual reversal of myopathy over months
Motor ability pre and post Salbutamol
10y ambulant girl pre and 6m post 13y non-ambulant boy pre, 4 and 16 m post
Courtesy for video : Dr Andrea Klein
CMS Comparison of clinical features
CHAT COLQ RAPSN CHRNE DOK7 FCS SCS
Arthrogryposis - - + - - + -
Episodic crises +++ ++ +++ - - + -
Ophthalmoplegia - + - +++ + +++ +
Improvement + - + +/- - +/- -
Treatment P,D E,S P,D P,D,E,S E,S P,D Q,F
Medications: P=pyridostgimine, D=3,4-diaminopyridine, E=ephedrine, S=salbutamol, Q=quinidine, F=fluoxetine
• Treatment is life long • Drugs that benefit one type can be ineffective or harmful in another type • Example: Acetylcholinesterase inhibitors (pyridostigmine) worsen some types • Establish genetic diagnosis ideally to inform choice • Therapeutic trial without genetic diagnosis should only be done in hospital • Trial of treatment: Pyridostigmine / 3,4-DAP exert effect as soon as the medication is absorbed But Salbutamol/ephedrine and the AChR channel blockers act more slowly over days, weeks, or months.
Drug Doses
• Pyridostigmine 4-7mg/kg/day given up to 3hrly • 3,4 Diaminopyridine caution in young children 0.5mg/kg/day up to 1mg/kg/day given TDS • Salbutamol 100 microgram/kg BD – 4mg slow release BD Or Ephedrine 1-3mg/kg/day in three divided doses • Quinidine 15-60mg/kg/day in 4 to 6 divided doses or
fluoxetine (dose in children not yet established; suicidal ideation risk
Respiratory complications –types?
• Episodic apnoea/crises CHAT
RAPSN
Fast Channel
• Nocturnal hypoventilation AChE deficiency
SCS
COLQ
• Stridor and vocal cord palsy DOK7
• Increased weakness with
intercurrent infections All
Respiratory interventions – How can we help?
Specialist referral for all CMS children with respiratory symptoms or at risk mutations • Fast track care pathway locally • Flu & pneumococcal vaccination • Antibiotic supply at home • Regular clinical review & sleep studies • CPR training for parents • AMBU Bag (CHAT, RAPSN)
• Nocturnal NIV for respiratory
insufficiency • NIV when unwell or for assisted cough • Adenotonsillectomy for OSA • Tracheostomy rarely
Feeding Interventions
• Specialist SLT assessment
• VFSS - weak and delayed swallow
• Eat when strong (30-60 min post pyridostigmine)
• Texture modification
• Supplementation during illness, crises and faltering growth
• Risk of choking/aspiration when weak or unwell
• Tube feeding/ gastrostomy/ Nissen fundoplication
Genetic Counselling
• Risk of recurrence
• Carrier testing
• Undiagnosed siblings and Parents !!!!!
Prognosis
• Variation in severity
• Progressive deterioration eg SCS, COLQ, DOK7
• May require NIV, gastrostomy, spinal fusion
• May remain mild eg CHRNE
• Some improve eg RAPSN
Challenges to Treatment
• Highly heterogeneous - no one drug for all
• Time frame for rapid genetic testing
• Difficulty with no validated outcome measures
• New emerging phenotypes overlapping with muscular dystrophies, brain involvement and peripheral neuropathies
Upcoming therapies ………
• DOK7 gene therapy in mice aimed at enlarging neuromuscular junctions with promising results
Summary
• Rare but recognition is key to minimise M&M
• Genetic diagnosis ideally before drug therapy
• Some subtypes (COLQ, SCS, DOK7) may be worsened by Pyridostigmine
• Salbutamol/ephedrine may time to show effect
• Think how you will measure response in empirical trials
• Anticipatory management of respiratory symptoms is critical
Nationally commissioned HSS for CMS in UK
CMS HSS service April 2017- March 2018
CLINIC APPOINTMENTS
Acknowledgements
HSS Rare Neuromuscular Disorders Diagnostic and
Advisory Services for Congenital Myasthenia and Congenital Myopathies and Dystrophies
Oxford Radcliffe Hospitals and Weatherall Institute of Molecular Medicine, Oxford and Dubowitz Neuromuscular Centre GOSH, ICH and ION, London
GOSH Matthew Pitt Stephanie Robb Pinki Munot Francesco Muntoni Adnan Manzur Anna Sarkozy Rahul Phadke
Oxford David Beeson Jackie Palace Sandeep Jayawant Pedro Cruz Ravi Knight Marzena Hilarowicz Sithara Ramdas Mike Oldfield
Patients, Families and referrers