Myasthenic Syndrome, Congenital, 17

A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-17 (CMS17) is caused by compound heterozygous mutation in the LRP4 gene (604270) on chromosome 11p11. One such family has been reported.

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

Clinical Features

Ohkawara et al. (2014) reported a young woman with a congenital myasthenic syndrome who presented soon after birth with respiratory and feeding difficulties. She started to walk at age 18 months, but fatigued easily during childhood and was partially wheelchair-bound. Examination at age 9 and 14 years showed mild ptosis, slight limitation of lateral eye movements, moderately severe proximal greater than distal weakness, and hyporeflexia. Repetitive nerve stimulation showed a decremental response with transient improvement with a fast-acting cholinergic agonist. Skeletal muscle biopsy showed type 1 fiber predominance and irregularly arrayed synaptic contacts that varied in shape and size. Electron microscopy showed that the size of the nerve terminals was reduced to 60% and that of the postsynaptic region to 48%. There was normal expression of the acetylcholine receptor (AChR) and acetylcholinesterase (AChE; 100740), although the total number of AChR per endplate was slightly decreased. There was no family history of a similar disorder.

Molecular Genetics

In a 17-year-old girl with CMS17, Ohkawara et al. (2014) identified compound heterozygous missense mutations in the LRP4 gene (E1233K; 604270.0011 and R1277H; 604270.0012). The mutations were found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that both mutations decreased binding affinity of LRP4 for agrin (AGRN; 103320) and MuSK (601296) and did not enhance downstream activation of the MuSK signaling pathway, thus impairing clustering of AChRs. Neither mutation had an effect on WNT (see 164820) signaling.

Animal Model

Lrp4-null mutant mice die prematurely. Barik et al. (2014) found that conditional knockdown of the Lrp4 gene in adult mouse skeletal muscle resulted in progressive loss of muscle mass and strength, scoliosis, and ultimately death, consistent with a myasthenic phenotype. Skeletal muscle biopsy of mutant mice showed fragmentation of the neuromuscular junction (NMJ) as well as decreased AChR compared to controls. Electron microscopic studies showed decreased junctional folds at the NMJ and decreased electron density of the synaptic basal lamina in the synaptic cleft. There was also a decrease of synaptic vesicles at the axon terminals. Electrophysiologic studies of mutant mice showed a decremental response of the compound muscle action potential (CMAP) upon repetitive nerve stimulation. Miniature endplate potentials (MEPPs) were also decreased, resulting from both postsynaptic decrease of AChR clusters and decreased presynaptic spontaneous release of ACh. Agrin was decreased at the NMJ synapse and found to be irregularly dispersed. The findings indicated that LRP4 is required for maintenance of the NMJ and likely regulates the stability of agrin.