Generalized Epilepsy in a Patient with GBJ1 X-Linked Charcot-Marie-Tooth Disease

Abstract

Charcot-Marie-Tooth (CMT) disease is an inherited neuropathy known for its genetic and phenotypic heterogeneity. Although unusual, the involvement of the central nervous system (CNS) has also been reported, including epilepsy.A 23-year-old man who at the age of 8 started to develop a gait disturbance. His neurological examination revealed distal weakness, muscular atrophy of the four limbs and decreased deep tendon reflexes. The electromyogram and nerve conduction study revealed a chronic symmetric axonal sensorimotor polyneuropathy. Next generation gene panel sequencing identified a hemizygous variant on GJB1 gene (c.547C>T, p.R183C) consistent with X-linked CMT. At the age of 21, he developed recurrent unprovoked tonic-clonic seizures. An electroencephalogram was consistent with a generalized epilepsy.The association of CMT disease with epilepsy is rare. GJB1 encodes the gap junction protein connexin32, which is expressed primarily in Schwann cells of peripheral nerves but also in oligodendrocytes and certain neuronal populations, possibly explaining the CNS manifestations. ResumoA doença de Charcot-Marie-Tooth (CMT) é uma neuropatia hereditária reconhecida por sua heterogeneidade genética e fenotípica. Embora incomum, também há relatos do envolvimento do sistema nervoso central (SNC), incluindo epilepsia.Homem de 23 anos que aos 8 anos se apresenta com alterações da marcha. Ao exame neurológico apresentava fraqueza muscular distal, atrofia dos quatro membros e hiporreflexia generalizada. O eletromiograma e estudo de condução nervosa revelaram sinais de polineuropatia sensitivo-motora axonal simétrica crónica. O estudo genético identificou uma variante hemizigótica no gene GJB1 (c.547C>T, p.R183C) consistente com CMT ligada ao X. Aos 21 anos, desenvolveu crises tónico--clónicas recorrentes, não provocadas. O eletroencefalograma foi compatível com epilepsia generalizada.A associação da doença CMT com epilepsia é rara. O gene GJB1 codifica a proteína conexina32, que é expressa principalmente nas células de Schwann dos nervos periféricos, mas também nos oligodendrócitos e determinadas populações neuronais, possivelmente explicando as manifestações do SNC.

Brain Gene Co-Expression Network Analysis Identifies 22q13 Region Genes Associated with Autism, Intellectual Disability, Seizures, Language Impairment, and Hypotonia

“…SBF1 is a target gene commonly associated with a neurological disorder, Charcot Marie Tooth disease (CMT) [52], and is highly expressed in the brain region "https://www.proteinatlas.org/ENSG00000100241-SBF1/tissue (accessed on 20 October 2022)". The clinical evidence of epilepsy in patients with CMT [53][54][55][56] and hypermethylation of SBF1 in patients with Drug-resistant Temporal Lobe Epilepsy [57] highlights the role of the SBF1 gene in epilepsy. The other gene identified in our study, BRD1, is associated with neuropsychiatric disorders such as schizophrenia and bipolar disorder along with its impact on neurodevelopmental disorders [58,59].…”