Mutations inGMPPBcause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies

Abstract

Congenital myasthenic syndromes are associated with impairments in neuromuscular transmission. Belaya et al. show that mutations of the glycosylation pathway enzyme GMPPB, which has previously been implicated in muscular dystrophy dystroglycanopathy, also cause a congenital myasthenic syndrome. This differential diagnosis is important to ensure that affected individuals receive appropriate medication.

Clinical Reasoning: A 14-year-old boy with fatigue and episodic worsening of weakness

“…[3][4][5][6][7][8] Dok-7 interacts with MuSK, which is important for the clustering of acetylcholine receptors on the postsynaptic cleft. Dok-7 deficiency presents with limb-girdle weakness with relatively lesser degree of facial and cervical muscle involvement.…”

“…Higher CK level and dystrophic features on muscle biopsy are usually present. 8 Finally, late-onset Rapsyn deficiency can also present with limb-girdle muscle weakness, with no ocular involvement, but these patients typically have substantial foot drop. 9 Considering all these differentials, Dok-7 deficiency appeared to be the best fit for this patient, given the presence of stridor, recurrent episodic severe weakness, and absence of TA on muscle biopsy.…”

Clinical and genetic basis of congenital myasthenic syndromes

“…Cases present with a notably exclusive appendicular (mainly proximal) weakness phenotype without facial and eye muscle involvement. They also present with typical myopathic changes in different laboratory evaluations, including high serum creatine kinase levels and unspecific myopathic changes in muscle biopsy and muscle MRI studies 39 . Mutations in this same gene also give rise to a broad clinical spectrum with congenital muscular dystrophies from the dystroglycanopathy family, including allelic conditions such as autosomal recessive congenital muscular dystrophies from the dystroglycanopathy group (types A, B and C).…”

“…Mutations in this same gene also give rise to a broad clinical spectrum with congenital muscular dystrophies from the dystroglycanopathy family, including allelic conditions such as autosomal recessive congenital muscular dystrophies from the dystroglycanopathy group (types A, B and C). Despite its rarity, GMPPB-related myasthenic syndromes should be considered in the setting of a nearly proximal appendicular myopathic patient in whom therapeutic strategies have failed or clinical outcomes have unexpectedly worsened 39 .…”

Limb girdle myasthenia with digenic RAPSN and a novel disease gene AK9 mutations

“…CMS is caused by mutations of genes encoding proteins located in the presynaptic, synaptic and postsynaptic regions of NMJ. To date, more than 20 disease genes of CMS have been identified, 1 that is, ALG2, 2 ALG14, 2 AGRN, 3 CHAT, 4 CHRNA1, 5 CHRNB1, 5 CHRND, 6 20 Four of the genes, GFPT1, DPAG1, ALG14 and ALG2 are recently known to cause limb-girdle type CMS by affecting N-glycosylation pathway. 21 The product of GFPT1 is N-acetylglucosamine and is the substrate for DPAG1 for the production of UDP-N-acetylglucosamine and the reaction requires UTP.…”