Dados do Trabalho

Título

Phenotypic variability in 3 siblings with CLCN1 associated Becker’s myotonia congenita

RESUMO

Case presentation: Three affected siblings whose parents and grandparents were consanguineous. The parents had 3 affected and 7 non-affected children. Case 1: A 40-year-old woman presented with a history of muscle cramps, difficulty standing-up after being seated for a long period, stiffness in legs while walking, dysphonia and sporadic transfer dysphagia. She exhibited pronounced muscular hypertrophy and generalized myotonic phenomenon (GMP) at examination, was able to walk unassisted and did not need medication for myotonic phenomenon. Electroneuromyography (EMG) showed diffuse myotonic discharges. Case 2: A 48-year-old male presented with GMP and complaints of dysphagia for liquids, difficulty climbing stairs and brushing his teeth. He reported weakness since childhood and had frequent falls and needed intermittent assistance when walking. Myotonic phenomenon did not respond well to carbamazepine or phenytoin. EMG demonstrated non-dystrophic myotonic syndrome. Case 3: A 51-year-old male with a history of muscle cramps, dysphagia and dysphonia, muscle stiffness with difficulty running and standing-up after being seated for a long period. Examination showed GMP, hyporeflexia and myoclonus in upper and lower limbs. Myotonic phenomenon was well controlled with phenytoin 200mg/day. None of the siblings reported exacerbation of myotonic phenomenon by cold. The 3 siblings were submitted to a genetic panel for neuromuscular disorders which revealed a CLCN1 c.1886T>C variant in homozygosity.
Discussion: Myotonia Congenita is an inherited disorder caused by biallelic pathogenic variants in CLCN1, which encodes chloride channel ClC-1 expressed predominantly in skeletal muscles. These variants cause muscle hyperexcitability and delayed muscle relaxation. The disease usually presents in childhood but has a highly variable phenotype even in patients with the same variants, such as in this family, where one patient had muscle hypertrophy and mild myotonic phenomenon without disability while her brother had intense, drug-resistant myotonic phenomenon leading to falls, difficulty walking and quality of life impairment.
Final comments: Our study reports three patients with the same pathogenic variant presenting with different phenotypes. There’s still a lack of description on the multitude of repercussions related to chloride channel alterations. We therefore encourage more research regarding this topic in order to unveil the potential repercussions of this condition.

Palavras Chave

Myotonia Congenita. Phenotype viriability. CLCN1. ClC-1. Myotonic Phenomenon. Becker's myotonia.

Área

Neurogenética