Clinical features of the myasthenic syndrome arising from mutations in GMPPB

Abstract

Patients with GMPPB-CMS have phenotypic features aligned with CMS subtypes harbouring mutations within the early stages of the glycosylation pathway. Additional features shared with the dystroglycanopathies include myopathic features, raised CK levels and variable mild cognitive delay. This syndrome underlines that CMS can occur in the absence of classic myasthenic manifestations such as ptosis and ophthalmoplegia or facial weakness, and links myasthenic disorders with dystroglycanopathies. This report should facilitate the recognition of this disorder, which is likely to be underdiagnosed and can benefit from symptomatic treatment.

Untangling the complexity of limb‐girdle muscular dystrophies

“…Patients with congenital myasthenic syndromes typically have normal or mildly elevated CK levels; a markedly elevated CK value in these patients would point toward GMPPB mutations, thus allelic to LGMD2T . Not all patients with GMPPB mutations have neuromuscular transmission defects, but those with abnormal decrements on repetitive nerve stimulations responded favorably to pyridostigmine or a combination of pyridostigmine and albuterol . To our knowledge, neuromuscular transmission defects have not been reported in other forms of α‐dystroglycanopathy LGMD2.…”

“…Recently, a group of congenital myasthenic syndromes secondary to hypoglycosylation of neuromuscular junction proteins has been identified as resulting from mutations in ALG2, ALG4, DPGAT, GFPT1 , and GMPPB . This subset of congenital myasthenic syndromes share a common phenotype characterized by fatigable limb‐girdle weakness, sparing of the extraocular and facial muscles, and variable involvement of eyelid elevators (also called limb‐girdle congenital myasthenic syndrome) .…”

Is the serum creatine kinase level elevated in congenital myasthenic syndrome?

“…In contrast to dystroglycanopathies, however, limb-girdle type CMS-associated molecules are not directly relevant to glycosylation of α-dystroglycan except for GMPPB. Involvement of GMPPB in glycosylation of α-dystroglycan makes GMPPB-CMS different from the other forms of CMS 1. First, serum CK levels are on average ∼10 times higher than normal.…”

“…In their JNNP paper, Rodriguez Cruz et al 1 report clinical features of eight patients with CMS carrying mutations in GMPPB. GMPPB encodes a glycosynthetic enzyme, GDP-mannose pyrophosphorylase B, that catalyses the conversion of mannose-1-phosphate and GTP to GDP-mannose.…”

“…Legacy disease names and MDDG annotations sometimes but not always have one-to-one correspondence. Interestingly, recessive mutations in GMPBB cause dystroglycanopathy (MDDGA14, MDDGB14, and MDDGC14),3 in addition to CMS with elevated CK and mild cognitive delay 1 2. Limb-girdle type CMS are also caused by defects in glycosylation pathways.…”