Myasthenic syndrome caused by plectinopathy

Area of Science:

• Genetics
• Cell Biology
• Neuromuscular Disorders

Background:

• Plectin (PLEC1) is crucial for intermediate filament organization and cellular integrity.
• Defects in plectin cause epidermolysis bullosa simplex (EBS), muscular dystrophy (MD), and pyloric atresia.
• A rare association between EBS and myasthenic syndrome (MyS) was previously reported in one patient.

Observation:

• A fatal case of EBS with progressive muscular weakness and myasthenic symptoms was analyzed.
• Histochemical, immunocytochemical, and electron microscopy revealed muscle fiber and neuromuscular junction abnormalities.
• Genetic analysis identified novel mutations in the PLEC1 gene.

Findings:

• The patient exhibited severe myopathy with dislocated organelles, abnormal nuclei, and sarcolemmal defects, alongside neuromuscular junction destruction.
• Two novel PLEC1 mutations, c.12043dupG and p.Gln2057X, were identified in the fatal case and the previously reported patient.
• These mutations were absent in control populations, confirming their pathogenic role.

Implications:

• The study elucidates the molecular mechanisms underlying myasthenic syndrome in plectinopathies, attributing it to junctional fold destruction.
• Defective anchoring of muscle fiber organelles and compromised sarcolemmal integrity contribute to the associated myopathy.
• This research expands the understanding of PLEC1 mutations and their severe clinical manifestations.