Myasthenic Syndrome, Congenital, 2a, Slow-Channel

A number sign (#) is used with this entry because of evidence that slow-channel congenital myasthenic syndrome-2A (CMS2A) is caused by heterozygous mutation in the CHRNB1 gene (100710) on chromosome 17p13.

Mutation in the CHRNB1 gene can also cause congenital myasthenic syndrome-2C associated with acetylcholine receptor (AChR) deficiency (CMS2C; 616314).

Description

Slow-channel congenital myasthenic syndrome (SCCMS) is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the acetylcholine receptor channel, specifically from prolonged opening and activity of the channel, which causes prolonged synaptic currents resulting in a depolarization block. This is associated with calcium overload, which may contribute to subsequent degeneration of the endplate and postsynaptic membrane. Treatment with quinine, quinidine, or fluoxetine may be helpful; cholinesterase inhibitors and amifampridine should be avoided (summary by Engel et al., 2015).

For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).

Clinical Features

Engel et al. (1996) reported a 19-year-old girl who had myasthenic symptoms since birth involving ocular and other cranial and limb muscles. Electrophysiologic studies showed prolonged endplate currents and prolonged AChR channel-opening episodes, and ultrastructural studies of muscle biopsies showed an endplate myopathy with loss of AChR from degenerating junctional folds.

Gomez et al. (1996) reported a 32-year-old man with SCCMS. He had presented with poor head control and a weak suck after a normal birth. He sat at 30 months and walked at 5 years of age. Ophthalmoparesis was noted at 8 years, and he developed fatigability at age 10 years. By age 13, he had knee and hip contractures and was wheelchair-bound. Edrophonium test was positive. Prednisone produced subjective improvement at age 14. From age 15 to 16 he was treated with pyridostigmine, guanidine, and thymectomy without improvement. The patient was a thin male with short stature, a long, thin face, high-arched palate, and high-pitched voice. He had nearly complete ophthalmoparesis, fatigable ptosis, and severe atrophy and weakness of all limb muscles. Electrophysiologic studies showed a repetitive compound muscle action potential (CMAP) response to single nerve stimulus and a decremental response to repetitive stimulation. The duration of the endplate potential was increased and prolonged, and miniature endplate potential (MEPP) amplitudes were decreased, consistent with impaired kinetics. Muscle biopsy showed a severe endplate myopathy with degeneration of the junctional folds and extensive remodeling of the postsynaptic membrane.

Molecular Genetics

In a 19-year-old girl with CMS2A, Engel et al. (1996) identified a heterozygous missense mutation in the CHRNB1 gene (V266M; 100710.0001),

In a 32-year-old male with CMS2A, Gomez et al. (1996) identified a heterozygous missense mutation in the CHRNB1 gene (L263M; 100710.0002). Functional expression studies showed that the L263M mutation interrupted the leucine ring of the AChR channel gate, causing an 8-fold increase in channel open time and resulting in severe endplate myopathy as well as extensive remodeling of the postsynaptic membrane. The pronounced abnormalities in neuromuscular synaptic architecture and function and the muscle fiber damage and weakness resulting from a single point mutation were a dramatic example of a mutation having a dominant gain of function and of hereditary excitotoxicity.