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