Familial dystroglycanopathy: same mutation, different phenotypes

Patients presenting with limb-girdle weakness and elevated creatine kinase (CK) are usually assumed to have a primary muscular dystrophy. Occasionally, however, a treatable neuromuscular junction disorder may be hidden within this presentation. Mutations in GMPPB (GDP-mannose pyrophosphorylase B) disrupt glycosylation pathways required both for α-dystroglycan stability and acetylcholine receptor assembly, creating such an unusual overlap between dystroglycanopathy and congenital myasthenic syndrome. We describe two siblings who carry the same homozygous GMPPB pathogenic variant but presented with markedly different clinical and therapeutic profiles. The brother developed fatigable proximal weakness that showed a striking and sustained improvement with pyridostigmine. His sister, however, presented with prominent myopathic features and markedly elevated CK, minimal response to cholinergic therapy but improvement with β-adrenergic agents. Both siblings showed a significant decrement in repetitive nerve stimulation. These contrasting phenotypes illustrate the remarkable clinical diversity resulting from the same mutation and emphasise an important diagnostic lesson: patients presenting with limb-girdle weakness and hyperCKaemia may still harbour a treatable defect of neuromuscular transmission.