O.21 Congenital Myasthenic Syndrome (CMS), autophagic myopathy, and cognitive dysfunction caused by mutations in DPAGT1

Abstract

We recently identified two CMS patients with CNS involvement. Patient 1 is a16-year-old mentally retarded girl with severe generalized CMS since infancy. One of her siblings is also affected and has autistic features. Patient 2 is a 14-year-old girl with mild cognitive deficits and progressive limb-girdle CMS since infancy. Both respond poorly to anti-AChE therapy. Intercostal muscle specimens in both show small tubular aggregates in type 2 fibers, type1 fiber atrophy, and a vacuolar myopathy with autophagic features. Endplate studies reveal that quantal release, postsynaptic response to acetylcholine, and endplate AChR content are reduced to ∼50% of normal. Quantitative EM of 65 endplate regions shows hypoplastic endplates, very small nerve terminals, and poorly differentiated postsynaptic regions. Neither patient harbors mutations in currently recognized CMS disease genes but exome sequencing in each identified two heteroallelic mutations in DPAGT1 coding for dolichyl-phosphate N-acetylglucosamine phosphotransferase, an enzyme subserving protein N-glycosylation. Immunoblots of muscle extracts probed by two different antibodies demonstrates reduced to absent glycosylation of ∼70 kDa proteins in Patient 1 but not in Patient 2. We conclude that DPAGT1 mutations result in both pre- and postsynaptic structural and electrophysiologic abnormalities. We hypothesize that hypoglycosylation of synapse-specific proteins causes defects in motor as well as central synapses. We recently identified two CMS patients with CNS involvement. Patient 1 is a16-year-old mentally retarded girl with severe generalized CMS since infancy. One of her siblings is also affected and has autistic features. Patient 2 is a 14-year-old girl with mild cognitive deficits and progressive limb-girdle CMS since infancy. Both respond poorly to anti-AChE therapy. Intercostal muscle specimens in both show small tubular aggregates in type 2 fibers, type1 fiber atrophy, and a vacuolar myopathy with autophagic features. Endplate studies reveal that quantal release, postsynaptic response to acetylcholine, and endplate AChR content are reduced to ∼50% of normal. Quantitative EM of 65 endplate regions shows hypoplastic endplates, very small nerve terminals, and poorly differentiated postsynaptic regions. Neither patient harbors mutations in currently recognized CMS disease genes but exome sequencing in each identified two heteroallelic mutations in DPAGT1 coding for dolichyl-phosphate N-acetylglucosamine phosphotransferase, an enzyme subserving protein N-glycosylation. Immunoblots of muscle extracts probed by two different antibodies demonstrates reduced to absent glycosylation of ∼70 kDa proteins in Patient 1 but not in Patient 2. We conclude that DPAGT1 mutations result in both pre- and postsynaptic structural and electrophysiologic abnormalities. We hypothesize that hypoglycosylation of synapse-specific proteins causes defects in motor as well as central synapses.