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Congenital Myasthenic Syndromes, CMS - CHRNE, CHRNA1, CHRNB1, CHRND, RAPSN, DOK7, COLQ, CHAT, GFPT1, SCN4A

Clinical Features

Clinically and pathogenically speaking, Congenital Myasthenic Syndrome (CMS) represents a heterogeneous group of disease whose common defect is a disruption of neuromuscular conduction in the region of the motor end plate. The symptoms of CMS normally begin in early childhood, most often in the first 24 months. The progression and severity of the disease vary greatly and range from severe "floppy infant" syndrome at birth to minimal symptoms with ptosis and light muscle weakness. Feeding difficulties, a weak cry, and general muscle hypotonia with or without ptosis can be observed in infancy. In many cases, respiratory infections may lead to critical decline, resulting in respiratory failure and cot death. In adults, abnormal muscle fatigue is prominent, commonly accompanied by ptosis (dependant on time of day) with or without problems of the external eye musculature. In some cases, the course of the disease is progressive and may lead to severe handicaps and death in the first decades of life. Some patients can be satisfactorily treated with acetylcholinesterase inhibitors. However, this therapy often results in only temporary success, if any. In contrast to the autoimmune disease Myasthenia gravis, no serum antibodies against acetylcholine receptors or MuSK (muscle-specific receptor tyrosine kinase) can be detected and patients are thus unresponsive to immunosuppressive therapy.

Genetic Information

Disease-causing mutations were identified in a number of genes coding for proteins participating in signal conduction in the region of the neuromuscular synapse:

• pre-synaptic
  CHAT, 10q11.2, Choline-Acetyltransferase
  

• synaptic
  COLQ, 3p25.1, Collagenic-like tail subunit of AChE

• the various subunits of the post-synaptic nicotine acetylcholine receptors
  CHRNA1, 2q31.1
  CHRNB1, 17p13.1
  CHRND, 2q37.1
  CHRNE, 17p13.2

• post-synaptic
  RAPSN, 11p11.2, Rapsyn
  DOK7, 4p16.3, Dok7
  GFPT1, 2p13, GFAT (Glutamine-fruktose-6-phosphat-amidotransferase)

In some cases, mutations in the muscle-specific Thyrosin-Kinase MuSK (MUSK) and post-synaptic Natrium channel (SCN4A), AGRN (Agrin) and LAMB2 (Lamin beta 2 have been described.

Prevalence

The exact incidence of CMS in not known. CMS represent approx. 10% of all myasthenias and an even larger percentage of childhood myasthenias.

Diagnostic