Myasthenic Syndrome, Congenital, 5

A number sign (#) is used with this entry because congenital myasthenic syndrome-5 (CMS5), also known as endplate acetylcholinesterase deficiency (EAD), is caused by homozygous or compound heterozygous mutation in the COLQ gene (603033) on chromosome 3p25.

Description

Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction. Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Endplate acetylcholinesterase deficiency is an autosomal recessive congenital myasthenic syndrome characterized by a defect within the synapse at the neuromuscular junction (NMJ). Mutations in COLQ result in a deficiency of acetylcholinesterase (AChE), which causes prolonged synaptic currents and action potentials due to extended residence of acetylcholine in the synaptic space. Treatment with ephedrine may be beneficial; AChE 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. (1977) reported a patient with a severely disabling CMS associated with EAD. Symptoms began soon after birth with generalized weakness increased by exertion, fatigability, hyporeflexia, and no response to AChE inhibitors. EMG showed a decremental response to stimulation and a repetitive response to single nerve stimulation. Miniature endplate potentials (MEPPs) had prolonged duration and decreased frequency. Electron microscopy of muscle biopsy showed decreased nerve terminal size, reduced postsynaptic membrane density, and focal degeneration of the postsynaptic folds. Degenerating nuclei were also present. Histochemical analysis did not detect AChE at the endplate. Engel et al. (1977) suggested a congenital defect in the molecular assembly of AChE or its attachment to the postsynaptic membrane.

Hutchinson et al. (1993) reported studies of the patient reported by Engel et al. (1977) and 4 other patients, 2 of whom were sisters. All patients had generalized weakness that was exacerbated by exertion, and mild slowing of the pupillary light reflex; however, ophthalmoparesis was not a constant feature. Electrophysiologic studies revealed a decremental response to stimulation, prolonged endplate currents, and reduced quantal release. All patients had absence of AChE from the NMJ, which explained the lack of clinical benefit from AChE inhibitors. Electron microscopy showed small nerve terminals, abnormal encasement of the presynaptic membrane by Schwann cells, and degeneration of the junctional folds and organelles in the junctional sarcoplasm. Muscle extracts from 3 patients showed absence of the collagen tail of AChE, while kinetic properties of the enzyme were normal. Studies of the AChE catalytic subunit gene (ACHE; 100740) revealed no abnormality in the exons that encode the domain to which the tail subunit binds. Hutchinson et al. (1993) concluded that the molecular defect resided in a faulty tail subunit, preventing assembly of the AChE enzyme.

Jennekens et al. (1992) reported a 6-year-old boy with partial deficiency of both endplate acetylcholinesterase and the acetylcholinesterase receptor (see 608931).

In a study of 5 patients with congenital myasthenia associated with EAD, Camp et al. (1995) found that the ACHE gene had a normal sequence and normal assembly of catalytic subunits. The authors suggested that the defect resided in an altered structure of the collagen-containing tail subunit or, alternatively, in an alteration in a protein involved in promoting the assembly between the catalytic subunit and tail unit.

Donger et al. (1998) reported a large consanguineous Spanish family in which 6 of 11 sibs had CMS with EAD. Age at onset ranged from 6 to 10 years. By the second decade, all patients complained of great fatigability on exertion. One of them presented with permanent neck and upper limb weakness; another had generalized weakness. Electrophysiologic studies performed on 4 patients showed impaired muscle-nerve conduction, with decremental responses at 3 Hz, repetitive responses to single motor nerve stimulation, and abnormal jitter. A discrete ptosis, in the patient who had generalized weakness, was indicative of a mild myopathic syndrome. No anti-ACh receptor (AChR) antibody was detected. Parenteral administration of anticholinesterase drugs had either no benefit or worsening effect.

Molecular Genetics

In 6 patients with AChE deficiency, Ohno et al. (1998) identified 6 recessive mutations in the COLQ gene (603033.0001-603033.0006). Two of the patients had previously been reported by Engel et al. (1977) and Hutchinson et al. (1993).

In affected members of a consanguineous Spanish family with EAD, Donger et al. (1998) identified a homozygous mutation in the COLQ gene (603033.0007).

Shapira et al. (2002) reported 3 novel mutations in the COLQ gene in 8 patients with variable features of EAD: 1 patient was a compound heterozygote; the other 7 patients, 6 Palestinian Arabs and 1 Iraqi Jew, were all homozygous for a gly240-to-ter mutation (G240X; 603033.0010), suggesting a founder effect. The patients with the G240X mutation demonstrated phenotypic variability, including differences in age of onset, disease progression, respiratory and feeding difficulties, severity of weakness, and ophthalmoplegia.