Myasthenic Syndrome, Congenital, 8

A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-8 (CMS8) is caused by homozygous or compound heterozygous mutation in the AGRN gene (103320) on chromosome 1p36.

Description

Congenital myasthenic syndromes are genetic disorders of the neuromuscular junction (NMJ) that are classified by the site of the transmission defect: presynaptic, synaptic, and postsynaptic. CMS8 is an autosomal recessive disorder characterized by prominent defects of both the pre- and postsynaptic regions. Affected individuals have onset of muscle weakness in early childhood; the severity of the weakness and muscles affected is variable (summary by Maselli et al., 2012).

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

Clinical Features

Huze et al. (2009) reported a brother and sister, born of distantly related Swiss parents, with congenital myasthenic syndrome. The proband was a 42-year-old woman who reported inability to run and ptosis from early childhood. Physical examination showed mild facial weakness and slight muscle weakness. Her 36-year-old brother presented with similar manifestations: he had had difficulty running since early childhood and presented with mild right ptosis, normal ocular pursuit, and intermittent mild masticatory difficulties. Both patients had a thin thorax and flat feet. Diplopia, bulbar symptoms, and dyspnea were never reported. Cholinesterase inhibitors were ineffective. Repetitive stimulation of certain muscles at 3 Hz resulted in a clear decrement of the compound muscle action potentials (CMAPs). Skeletal muscle biopsy showed type 2 fiber atrophy and disruption of the global architecture of the neuromuscular junction (NMJ). There were both pre- and postsynaptic alterations, including perturbation of the presynaptic compartment with absence of axon profiles or small axon terminals, suggesting denervation, and fragmentation of synaptic gutters into discontinued postsynaptic gutters. There was also evidence of remodeling of the NMJ. Both patients showed remarkable clinical improvement after treatment with ephedrine.

Maselli et al. (2012) reported a 39-year-old man with a relatively severe form of congenital myasthenic syndrome. In childhood, he had ptosis, was easily fatigued, and had numerous episodes of respiratory insufficiency requiring tracheotomy. An older brother with similar symptoms died in childhood. As an adult, the proband had ptosis, facial weakness, high-arched palate, mild weakness of some extraocular muscles, proximal and distal upper limb weakness, and proximal lower limb weakness. He required respiratory support for large parts of the day. Cognition was normal. He responded moderately to an AChE inhibitor (see 100740), but not to ephedrine. Repetitive muscle stimulation caused a decremental CMAP response, and electrode studies showed features consistent with presynaptic failure of neuromuscular transmission. Muscle biopsy showed occasional small angular fibers and type I fiber predominance. Electron microscopy showed pre- and postsynaptic abnormalities at the neuromuscular junction. There was simplification and distortion of the postsynaptic membrane, small presynaptic axon terminals, and widened synaptic clefts containing extracellular matrix material or globular debris. There was also a reduction in the endplate area and a decrease in agrin staining at the neuromuscular junction compared to controls.

Inheritance

The transmission pattern of congenital myasthenic syndrome in the family reported by Huze et al. (2009) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a Swiss brother and sister with CMS, Huze et al. (2009) identified a homozygous mutation in the AGRN gene (G1709R; 103320.0001). Mutant agrin was expressed and localized correctly in patient muscle, but the overall organization of the neuromuscular junction was perturbed, affecting both the pre- and postsynaptic regions.

In a man with congenital myasthenic syndrome, Maselli et al. (2012) identified compound heterozygosity for a missense and a nonsense mutation in the AGRN gene (V1727F, 103320.0002 and Q353X, 103320.0003).

Animal Model

Lin et al. (2001) analyzed early stages of postsynaptic differentiation in muscles of mutant mice lacking agrin, MuSK (601296), rapsyn (601592), and/or motor nerves. Lin et al. (2001) found that the defect in MuSK mutants is due to an absence of initiation of postsynaptic differentiation, whereas the impairment in agrin mutants is caused by loss of agrin-dependent maintenance of the postsynaptic apparatus. On the basis of these and previous studies, Lin et al. (2001) proposed the existence of 3 early overlapping steps in the formation of the postsynaptic apparatus at the neuromuscular junction. First, a muscle-intrinsic, nerve/agrin-independent and MuSK-dependent mechanism initiates formation of postsynaptic specialization in an endplate band. Second, nerve-derived agrin acts through MuSK to promote apposition of nerve terminals to these nerve-independent acetylcholine receptor clusters and/or to induce new postsynaptic sites. Agrin is also required for the growth and maintenance of most, if not all, synaptic sites. Third, motor axons, or Schwann cells that accompany them, provide an agrin-independent signal that destabilizes or disperses postsynaptic apparatuses that have not been stabilized by agrin.