Congenital myasthenic syndrome (CMS) is a rare heterogeneous group of genetic disorders that affect neuromuscular transmission. CMS can present at birth or in early infancy with symptoms like ptosis, external ophthalmoplegia, proximal limb weakness, and respiratory difficulties. Diagnosis involves neurophysiology testing showing a decremental response on repetitive nerve stimulation and increased jitter on single fiber EMG. Genetic testing and muscle biopsy can help identify the underlying cause, which may include defects in presynaptic, synaptic, or postsynaptic proteins. Treatment involves cholinesterase inhibitors, potassium channel blockers, beta-2 agonists, or open channel blockers depending on the CMS subtype. Supportive care like respiratory

1. Congenital myasthenic
syndrome
DR BHAVIN J PATEL
SR NEUROLOGY
GMC KOTA

2. Introduction
Rare, heterogeneous group of genetically determined, disorders of
neuromuscular transmission
No reliable data available on incidence and prevalence
The earliest report of Congenital myasthenic syndrome(CMS) was by Rothbart
in 1937 while the term “congenital myasthenia” was coined by Bowman in 1948.
Most patients with CMS present at birth or early infancy with exception of
some subtypes.

3. Neuroanatomy
SNAP 25
SYT-2
B2 laminin
Multiple site action:-
GFPT1
DPAGT1
ALG2,ALG14
PREPL

4. Classification

5. Prevalence of CMS subtypes

6. Pathophysiology

7. Pathophysiology

8. Pathophysiology

9. Clinical features
Presynaptic:-
1) Choline acetyl transferase (ChAT) deficiency:-
Manifest during infancy and early childhood with some patient
apneic and hypotonic at birth.
Sudden episode of apnea provoked by stress or without apparent
cause.
Some patient develop ventilator failure after acute attack and
required ventilator support.

10. Clinical features
1) Choline acetyl transferase (ChAT) deficiency:-
Prolonged hypoxemia can cause cerebral palsy.
Some patient have variable ptosis and fatigable weakness.
Extraocular muscles are usually spared.
Weakness is worsened by exposure of cold.

11. Clinical features
2) SNAP25B mutation:-
Single patient reported with severe CMS.
Associated with cortical hyperexcitability, ataxia and intellectual
disability.
3)Synaptotagmin 2 deficiency:-
Cause generalized muscle weakness with loss of DTR

12. Clinical features
Synaptic basal lamina associated syndrome:-
1) Acetyl cholinesterase deficiency:-
Severely affected patient present in infancy with apnea and generalized
weakness.
Less severely affected patient develop progressive limb girdle myasthenia
during childhood.
Respiratory involvement is common.
Opthalmoplegia and ptosis are common but variably present.

13. Clinical features
2) β 2 laminin deficiency:-
Component of basal lamina of different tissue and expressed in eye kidney and
muscle.
Pierson syndrome:- combination of malformation of kidney and eyes associated
with myasthenic syndrome.
Patient required early renal transplantation.

14. Clinical features
Defect in AChR:-
1) primary AChR deficiency:-
AChR composed of 5 subunit:
 α2βδγ (fetal)
 α2βδɛ (adult)
CMS result from missense, nonsense, or splice site and promoter region
mutations in each AChR subunit
Most common in ɛ subunit.

15. Clinical features
1) primary AChR deficiency:-
Mostly manifest in infancy with feeding problem and ptosis.
Nearly all patient have opthalmoparesis and moderate to severe limb weakness.
Severely affected patient may required respiratory support since infancy.
Intercurrent infection can worsen weakness but do not experience acute crisis.
Null mutation in allele of α2βδ subunit can result in embryonic death.

16. Clinical features
2)kinetic defect in AChR:- slow channel syndrome
Only autosomal dominant mutation in CMS
Usually manifest in first decade but severely affected patient may present in
neonate period.
Selectively involve cervical, scapular and dorsal forearm muscles.
Acute crisis is unusual.
Leads to excitotoxic EP myopathy.

17. Clinical features
3)kinetic defect in AChR:- fast channel syndrome
Most severe form of CMS
Manifest since birth as feeding difficulties, hypotonia and respiratory failure.
Ptosis and opthalmoplegia are common and severe.
Feeding difficulties persist and required NG tube or PEG.
Episodic apneas and chronic hypoventilation can occur.

18. Clinical features
Defects in EP development and maintenance:-
Mutation in genes of proteins responsible for EP development and maintenance
like agrin, LRP 4, MuSK, DOK 7 an Rapsyn.
1)MuSK deficiency:-
Disease present at birth or in early life.
Present as ptosis and gradually progress to involve ocular, facial and proximal
limb muscle.

19. Clinical features
2) DOK 7 deficiency:-
Present in childhood with deterioration of walking.
Weakness is typically limb girdle distribution.
Subtle facial involvement can occur occasionally.
Few patients have tongue wasting also.
3)Agrin deficiency:-
Only 2 case report with 3 patients
Eyelid ptosis with mild facial and limb weakness.

20. Clinical features
4) Rapsyn Deficiency:-
Onset at birth with respiratory weakness, feeding difficulties with hypotonia
Arthrogryposis is common with facial dysmorphism including high arch palate.
Acute life threatening crisis with respiratory failure is common.
Opthalmoplegia is rare.

21. Clinical features
Defect in glycosylation:-
Glycosylation increases solubility, folding, stability, assembly, and intracellular transport of
nascent peptides.
Four enzymes are identified causing CMS:-
GFPT1
DPAGT1
 ALG2 & ALG14
Patient can have arthrogryposis at birth.
Multisystem involvement like vacuolar myopathy and intellectual disability.

22. Clinical features
PRPEL deletion syndrome:-
Patient had myasthenic syndrome since birth and growth hormone deficiency.
PEPEL along with SLC3A1 gene deletion causes hypotonia-cystenuria
syndrome.
Na channel myasthenia:-
Only 2 patients has been reported
Abrupt onset of facial, respiratory and bulbar muscle weakness.
SCN4A gene mutation.

23. Clinical features
Plectin deficiency:-
Plectin is concentrated at sites of mechanical stress.
Can present as muscular dystrophy, myasthenic syndrome and epidermolysis
bullosa simplex.
CMS associated with Centronuclear myopathies:-
Eyelid ptosis, exercise intolerance and decremental NCV study found in
centronuclear myopathy.
Caused by mutation in amphiphysin, myotubularin and dynamin 2 gene.

24. Journal of Neurology Received: 8 January 2019 / Accepted: 8 February 2019

25. Diagnosis
Neurophysiology:-
Decremental (>10%) response on RNST
In slow channel syndrome and COLQ congenital myasthenia, the decremental
response is rate-dependent.
Single fiber EMG is more sensitive but less specific
Increased jitter on single fiber EMG.

26. Diagnosis
Neurophysiology:-
In ChAT deficiency subtetanic stimulation reduced the CMAP 50% below the
baseline (normal <30%) followed by slow recovery over 5–10 minutes .
A marked decrease of the CMAP amplitude after subtetanic stimulation also
occurs in other CMS but is followed by recovery in less than 5 minutes

27. Diagnosis
Muscle biopsy:-
Shows mild non specific changes in form of increased fiber size variability, type
2 fiber atrophy, central nuclei with necrosis and regeneration of fibers.
Tubular aggregates of sarcoplasmic reticulum seen in GFPT1, DPAGT1 and
ALG2.
Cytochemical and immunohistochemical localization at the EP of AChE, AChR,
chat, agrin, rapsyn,musk,dok-7.
Quantitative electron microscopy and cytochemistry.

29. Diagnosis
Genetic study:-
Mutation analysis
Linkage analysis
Whole genome sequencing
Microarray based comparative genomic hybridization to detect large scale deletions
or duplications

30. Differential Diagnosis

31. Differential Diagnosis

32. Treatment
Cholinesterase inhibitor
Potassium channel blocker
Beta 2 agonist
Open channel blocker
Other supportive treatment

33. Treatment
Cholinesterase inhibitors:-
Prolong lifetime of Acetycholine at the end plate.
Pyridostigmine is commonly used
Dose:- 7 mg/kg/day
10 mg/kg/day during crisis
Can exacerbate weakness in some type of CMS.

34. Treatment
Potassium channel blocker:-
Act on presynaptic nerve terminal results in increased release of Ach.
3,4 DAP is commonly used drug.
Short duration of action so usually taken 3-4 times a day
Dose depends on severity of disease
Usual adult dose :- 10 mg TDS, max dose is 80 mg per day
Side effect:- short lived tingling sensation in extremity and perioral region.
seizure

35. Treatment
Beta 2 agonist:-
Stimulate beta 2 adrenergic receptor and improve signal transmission by
stabilizing post synaptic architecture.
Ephedrine and salbutamol are commonly used
Dose:- salbutamol--- 4 mg bd or tds, max dose: 16 mg per day
ephedrine--- 15-30 mg BD, max dose; 90 mg /day

36. Treatment
Beta 2 agonist:-
Effect start with in 1 month and continues for 6-9 month.
Side effect:- insomnia
hypertension, palpitation, hypertension
muscle cramp

37. Treatment
Open channel blocker:-
Reduces channel opening time
 exclusively used in slow channel CMS
Fluoxetine > quinidine
Dose :- fluoxetine from 20 to 120 mg
Side effects:- QT prolongation (quinidine)
risk of suicidality (fluoxetine)

38. Treatment
Other supportive treatment:-
Respiratory care
Ptosis surgery
Anesthetic considerations
Genetic counseling

40. Treatment approach

41. References
Bradely’s neurology in clinical practice, 7th edition
Congenital myasthenic syndromes: pathogenesis, diagnosis and treatment, Lancet Neurol.
2015 April ; 14(4): 420–434.
Congenital myasthenic syndromes: an update Finlayson S, et al. Pract Neurol 2013;13:80–
91.
Congenital myasthenic syndromes: Natural history and long-term prognosis , SA jagtap et al,
Annals of Indian Academy of Neurology, July-September 2013, Vol 16, Issue 3
Congenital Myasthenic Syndrome: Spectrum of Mutations in an Indian Cohort, J Clin
Neuromusc Dis 2018;20:14–27
raredisease.org/congenital myasthenia syndrome
UpToDate.com

42. Thank you

43. Summary
Autosomal dominant inheritance Slow channel CMS
CMS refractory to AChE inhibitors DOK 7, MuSK, Agrin, LRP4,plectin,COlQ
Delayed pupillary light response ColQ mutation
Congenital contractures Rapsyn, AChR def., ChAT defi
Episodic apnea induced by stress or infection ChAT defi, Rapsyn, Na channel CMS
Limb girdle and axial weakness DOK 7,defect of glycosylation, occasional
Rapsyn
Stridor and vocal cord palsy in infants DOK 7
Nephrotic syndrome and ocular manifestation Laminin B 2
Asso. with seizure and intellectual disability DPAGT1
Asso. with EBS and muscular dystrophy Plectin