Dados do Trabalho

Título

Congenital myasthenic syndrome due to GMPPB variants

RESUMO

Case Report:

A 40-year-old Brazilian woman presented with a long-standing slowly progressive clinical course of muscle fatigue and exercise intolerance since age 22 years. After two years of symptom-onset, she also noted eyelid ptosis without diplopia and dysgraphia. There was also worsening of muscle weakness at the end of the day and after physical activity. By the age of 36, weakness worsened, and she could not walk for more than 10 minutes. At that time, serum creatine kinase levels were evaluated and disclosed mild elevation (900; 3 times the upper limit value). One year ago, she started diplopia, dyspnea, and dysphagia. Medical history disclosed dyslipidemia. Parental consanguinity was present. Family history disclosed her sister with similar symptoms. Examination disclosed mild proximal weakness in the upper and lower limbs, mild axial muscle weakness.
Her nerve conduction studies were unremarkable. Needle electromyography disclosed typical chronic myopathic features. Muscle biopsy showed nonspecific myopathic findings. A next-generation sequencing-based multigene panel for inherited neuromuscular disorders disclosed the presence of the pathogenic variant c.95C>T (p.Pro32Leu) and the variant of uncertain significance c.478G>A (p.Val160Met) in compound heterozygosity in the gene GMPPB, thus enabling the diagnosis of GMPPB-related Congenital Myasthenic Syndrome (CMS) associated with myopathic involvement. Oral salbutamol and pyridostigmine were started with clinical stability of symptoms.

Discussion:
GMPPB-related neuromuscular disorders represent Congenital Disorders of Glycosylation and occur due to variable deficiency of mannose-1-phosphate beta-guanylyltransferase, which is involved with GDP-mannose biosynthesis related to multiple glycosylation pathways. It has been previously associated with autosomal recessive limb-girdle muscular dystrophy type 19 (formerly LGMD2T), Congenital Muscular Dystrophy-Dystroglycanopathy type 14 and, more recently, with late-onset CMS phenotypes. Some of the previously described GMPPB-associated myopathies had dysfunction of the neuromuscular junction and mildly raised serum creatine kinase levels.

Final comments:
Clinicians must be aware about the possibility of late-onset presentations of CMS due to GMPPB variants, which should be considered in cases with myopathic findings in neurophysiological studies and raised serum creatine kinase levels.

Palavras Chave

Congenital Myasthenia, Congenital Disorders of Glycosylation, Neuromuscular Junction, Neurogenetic disorders

Área

Doenças Neuromusculares