Familial dystroglycanopathy: same mutation, different phenotypes

Area of Science:

• Genetics
• Neurology
• Biochemistry

Background:

• Limb-girdle weakness with elevated creatine kinase (CK) typically suggests muscular dystrophy.
• However, treatable neuromuscular junction disorders can mimic these symptoms.
• Mutations in GDP-mannose pyrophosphorylase B (GMPPB) disrupt glycosylation, affecting both dystroglycan stability and acetylcholine receptor assembly, bridging dystroglycanopathies and congenital myasthenic syndromes.

Purpose of the Study:

• To describe the diverse clinical and therapeutic phenotypes in siblings with the same homozygous GMPPB pathogenic variant.
• To illustrate the diagnostic challenge posed by overlapping muscular and neuromuscular junction disorders.
• To emphasize the importance of considering neuromuscular transmission defects in limb-girdle weakness with hyperCKaemia.

Main Methods:

• Clinical case description of two siblings with a homozygous GMPPB pathogenic variant.
• Assessment of clinical presentation, including fatigable weakness, myopathic features, and CK levels.
• Evaluation of response to therapeutic agents (pyridostigmine, β-adrenergic agents).
• Electrophysiological studies, including repetitive nerve stimulation.

Main Results:

• Siblings shared the same homozygous GMPPB variant but exhibited distinct phenotypes.
• Brother: Fatigable proximal weakness improved with pyridostigmine.
• Sister: Myopathic features, elevated CK, minimal response to pyridostigmine, but improved with β-adrenergic agents.
• Both showed significant decrements on repetitive nerve stimulation.

Conclusions:

• The GMPPB gene mutation can lead to a wide spectrum of clinical presentations, from myopathic features to treatable neuromuscular junction defects.
• Contrasting phenotypes in siblings underscore the genetic and possibly epigenetic factors influencing disease expression.
• Limb-girdle weakness and hyperCKaemia warrant investigation for treatable neuromuscular transmission disorders, not solely muscular dystrophies.