Congenital myasthenic syndrome

Dr. Parag MoonSR1, Dept. of Neurology

GMC Kota.

Congenital myasthenic syndromes (CMSs) form a heterogeneous group of genetic diseases characterized by a dysfunction of neuromuscular transmission.

Incidence-one in 500 000

Presynaptic (generally caused by an anomaly of choline acetyltransferase ChAT),

Synaptic (corresponding to an anomaly of the acetylcholinesterase collagen tail)

Postsynaptic (secondary to an anomaly of acetylcholine receptor or rapsyn).

Classification

Congenital myasthenic syndromes caused by ChAT mutations

Manifest at birth or in the neonatal period with bulbar disorders and respiratory insufficiency with apnoea or even sudden death.

Triggered by fever, fatigue and overexertion.

Apart from these bouts, the myasthenic signs are often modest or not present.

Presynaptic congenital myasthenic syndromes

CHAT gene encoding ChAT, located on 10q11.2.

ChAT is a presynaptic protein localized in the nerve terminals, where it catalyses acetylcholine production.

Mutations lead to a reduction or even abolition of the catalytic capacity of the enzyme

14 mutations reported

Microelectrophysiology-after prolonged10 Hz repetitive stimulation, a reduction in amplitude of the miniature endplate potentials.

Ultrastructural examination-when muscle is at rest, the synaptic vesicles are of reduced size

Cholinesterase inhibitors are effective.

1. Lambert–Eaton-like CMS Diminished action potentials markedly

potentiated by tetanic stimulation Good response to guanidine No mutation found in calcium channel2. Sporadic myasthenic syndrome with

associated signs of cerebellar ataxia Marked reduction in the spontaneous or

nerve stimulation-induced release of acetylcholine quanta.

Other presynaptic myasthenic syndromes

Acetylcholinesterase deficiency Autosomal recessive Symptoms usually arise in the neonatal

period Slowed but inconstant pupil responses to

light. Repetitive compound muscle action

potential (CMAP) after single stimulation Absence of response to cholinesterase

inhibitors

Synaptic congenital myasthenic syndrome:

Genetics- Mutations in the COLQ gene coding for the collagenic tail of acetylcholinesterase

Twenty-four recessive mutations No effective treatment

Broadly categorised in 2 category1. CMS in connection with a kinetic anomaly

of the acetylcholine receptor2. CMS with a decreased number of

acetylcholine receptors at the neuromuscular junction

Postsynaptic congenital myasthenic syndromes

1. Slow channel syndrome Autosomal dominant Characterized by a prolonged opening time

of the acetylcholine receptor. Fifteen missense point mutations causing a

gain of function of the acetylcholine receptor

M1 for mutations of the a and b subunits M2 more frequent, affecting the a, b, d and

e subunits.

CMS caused by acetylcholine receptor kinetic anomalies

Clinical expression may vary from early onset and severe to late onset and moderate

Prevalent atrophic deficit of the finger extensors and cervical muscles is highly suggestive

Repetitive CMAP after a single stimulation No response to cholinesterase inhibitors Treatment- Quinidine can normalize

prolonged opening time of channel Fluoxetine

2) Fast channel syndromes Autosomal recessive although a case of

autosomal dominant transmission reported Microelectrophysiology –shortening of the

acetylcholine receptor opening time Clinical severity is variable. Responsive to the combination of 3,4-

diaminopyridine and cholinesterase inhibitors.

Genetics-Eight mutations were identified affecting a, d and e subunits

Located either in the extracellular domain, in the M3 transmembrane domain or in the cytoplasmic loop between the M3 and M4 domains (e mutations only).

Half of all CMS Autosomal recessive Cholinesterase inhibitors are effective 3,4-diaminopyridine can provide additional

benefit.

CMS with predominant acetylcholine receptor deficiency (with absent or only slight kinetic anomalies)

Genetics- 60 + mutations identified Mutations are located on the whole gene

encoding the acetylcholine receptor e subunit

Rapsyn is postsynaptic cytoplasmic protein Participates in acetylcholine receptor

assembly at the neuromuscular junction and allows its anchoring to the cytoskeleton by b-dystroglycan

Autosomal recessive

CMS with mutations of the rapsyngene (RAPSN)

Two phenotypes: (1) a neonatal form,even antenatal (with

arthrogryposis multiplex congenita),with major respiratory disorders and severe progression of the disease

(2) mild forms beginning during childhood or in adulthood

Both responds well to cholinesterase inhibitors or combination of cholinesterase inhibitors and 3,4-diaminopyridine

Plectin is structural protein of the cytoskeleton expressed in several cell types, including skeletal muscle and the postsynaptic membrane.

Presents with progressive myopathy, associated with myasthenic syndrome (involving facial, limb and oculomotor muscles), and epidermolysis bullosa

CMS with plectin deficiency

Presents since birth with very short bouts (3–30 min) of respiratory distress and bulbar paralysis.

Electrophysiology of the intercostal Muscle- the impossibility of evoking an action potential after nerve stimulation.

Two mutations of SCN4A were identified.

CMS caused by a mutation in thesodium channel SCN4A

Previously named ‘myasthenic myopathy’ Autosomal recessive Clinically, the absence of oculobulbar signs

is remarkable. Weakness and fatigability involved the

girdles. Tubular aggregates in their muscle biopsy Responds favourably to cholinesterase

inhibitors

Familial limb girdle myasthenia

Tubular aggregates at the histological muscle examination

Presents with slowly progressive myopathy beginning in early childhood associated with cardiomyopathy

Favourable response to cholinesterase inhibitors

CMS with tubular aggregates

Approx. 15% of newborns of myasthenic mother

Passive transfer of antibody directed against fetal AChR

Fetal AChR is structurally different from adult AChR.

Severity of symptoms Correlates with the ratio of fetal to adult AChR antibodies in the mother

Not with the severity or duration of weakness in the mother.

Transitory Neonatal Myasthenia

Hypotonic in utero Arthrogryposis Feeding difficulties Generalized hypotonia Eager to feed, but ability to suck fatigues

quickly Onset within hours of birth but delay until the

3rdDay Weakness of cry and lack of facial expression:

50% Limitation of EOM &Ptosis: 15%

Clinical features

Respiratory insufficiency : Uncommon Weakness becomes progressively worse in

the first few days and then improves. Duration of symptoms is 18 Ds (5D-2 mn) Complete recovery TNM does not develop into MG later in life

Diagnosis High serum concentrations of AChR binding

Ab Temporary reversal of weakness :S/c or I/V

inj. Edrophonium chloride, 0.15 mg/kg

WORKUP AND DIAGNOSTIC STUDIES

Clinical presentation

Suspected in any person presenting with Fatigable ocular Bulbar Limb weakness during infancy or early

childhood With a positive family history(autosomal

recessive except slow channel)

Response to cholinesterase inhibitors (neostigmine test)

Favourable effect of cholinesterase inhibitors seen in all CMS except

1. slow channel syndrome2. acetylcholinesterase deficiency

Decremental response in the CMAP: RNS low frequency (2 Hz) is strongly s/o

impaired NM transmission, but may only be present in a few muscle groups.

SFEMG : abnormal jitter and blocking.  AChR and MuSK antibody : Negative

(essential prerequisite)

Rule out myopathy Predominance of type I fibres and the

marked atrophy of type II fibres is suggestive of CMS

Tubular aggregates NMJ visualized for (acetyl)cholinesterase by

histochemical technique of Koelle, fasciculin or specific antibodies,

for acetylcholine receptor by fluorescent a-bungarotoxin

Role of muscle biopsy

8 genes tested usually Acetylcholine receptor subunits (CHRNE,

CHRNA1,CHRNB1, CHRND) Rapsyn (RAPSN) Collagen tail of acetylcholinesterase (COLQ) Choline acetyltransferase (CHAT) Sodium channel (SCN4A).

Genetic testing

Immediate treatment of respiratory distress Prevention of infections and of malnutrition

as a result of swallowing disorders Orthopaedic surveillance of spinal

complications and retractions

Treatment

Cholinesterase inhibitors are efficient in all CMSs except slow channel syndrome and acetylcholinesterase deficiency

3,4-Diaminopyridine mode of action is presynaptic, is sometimes effective in pre- or postsynaptic CMSs

Quinidine helpful in slow channel

Thank you

Congenital myasthenic syndromes: Daniel Hantaı et al :Current Opinion in Neurology 2004, 17:539–551

Congenital myasthenic syndromes: Seminars in neurology:2004;24(1):111-123

Bradleys principles of neurology

References