myasthenic syndrome (congenital myasthenic syndrome, CMS)

Introduction

group of inherited disorders of neuromuscular transmission

Etiology

• caused by kinetic abnormalities of the nicotinic receptor

Pathology

• small, simplified neuromuscular junctions
• normal acetylcholine receptor & acetylcholinesterase function (DOK7 type)
• prolonged endplate currents & prolonged AChR channel opening episodes (slow-type)
• decreased activity of the AChR (fast type) by:
  • slowing the rate of opening of the receptor channel
  • speeding the rate of closure of the channel
  • decreasing the number of openings of the channel during ACh occupancy
• failure to achieve threshold depolarization of the endplate & consequent failure to fire an action potential

Genetics

• associated with defects in DOK7 gene (autosomal recessive)
• associated with defects in CHRNA1
  • slow-channel type
  • fast-channel type
• associated with defects in CHRNB1
  • slow-channel type
  • nicotinic receptor deficiency
• associated with defects in CHRND
  • slow-channel type
  • fast-channel type
• 4) associated with defects in CHRNE
  • slow-channel type
  • fast-channel type
• associated with defects in MUSK (autosomal recessive)
• associated with defects in SCNA4

Clinical manifestations

• fatigable muscle weakness
• muscle weakness affecting the axial & limb muscles
  • proximal muscles effected more than distal muscles
  • characteristic 'limb girdle' pattern of muscle weakness
  • onset characterized by difficulty walking after normal motor milestones
  • hypotonia in early-onset forms
• weakness of ocular muscles leads to ptosis & ophthalmoplegia
  • ptosis often present at early age
  • eye movements rarely involved in DOK7 form
• weakness in facial & bulbar musculatur affects sucking & swallowing, & leads to dysphonia
• symptoms fluctuate & worsen with physical effort

Differential diagnosis

limb-girdle muscular dystrophy

Management

• ephedrine may be helpful
• acetylcholinesterase inhibitors without long-term benefit#

# distinguishing feature from limb-girdle muscular dystrophy

More general terms

• genetic syndrome (multisystem disorder)
• muscular disease; myopathy

More specific terms

• congenital myasthenic syndrome with acetylcholine receptor (nAChR) deficiency (ACHRDCMS)
• end-plate acetylcholinesterase deficiency (congenital myasthenic syndrome type 1C)

Additional terms

• myasthenia gravis

Database

• OMIM: https://mirror.omim.org/entry/601462
• OMIM: https://mirror.omim.org/entry/608930
• OMIM: https://mirror.omim.org/entry/608931
• OMIM: https://mirror.omim.org/entry/603967