A Genetic Research Of An X-linked Charcot-marie-tooth Disease Pedigree

Background and ObjectiveX-linked Charcot-Marie-Tooth disease(CMTX)is a hereditary peripheral neuropathy,which is X-dominant.CMTX1 is characterized by progressive distal muscle weakness and atrophy,weakened or disappeared tendon reflexes.Type 1 CMTX(CMTX1)is caused by mutations in gap junction β1 gene(GJB1).In addition to neuromuscular manifestations,a part of patients with CMTX1 also have transient central nervous system symptoms,but the mechanisms are not clearly understood.In this research,the proband presented with the symptom of recurrent "dysphonia and symmetric weakness of four limbs for 20 hours ".We investigated this CMTX1 pedigree and carried out the genetic research to determine the mutation site in GJB1,confirming the genetic and clinical diagnosis,and discussing the mechanisms of CMTX1 was also disscussed.MethodsThe proband presented with "dysphonia and symmetric weakness of four limbs for 20 hours".The detailed medical history was collected and neurological physical examination was carried out on proband.Necessary biochemical,imaging,and neuroelectrophysiological examinations were completed.His family member’s medical history and physical examination were also collected and the pedigree chart was drew.The peripheral blood of the proband and his family members were collected and their DNA was extracted.The next generation sequencing was used to detect neuropathy-related genes of the proband,and the first exon of GJB1 was sequenced with the method of Sanger sequencing technology.After detecting the mutation site of the proband,the corresponding sites of other members in the family were sequenced and analyzed the pedigree transfer.The co-segregation of the mutation in the pedigree found in the proband was further tested.ResultsThe proband presented with the symptoms of "dysphonia and symmetric weakness of four limbs for 20 hours",neurological examination revealed distal muscle weakness,atrophy and disappearance of tendon reflexes.He experienced the same kind of transient "stroke-like" symptoms twice in the past.During the episode,his brain MRI showed bilaterally symmetric T2 FLAIR hyperintensity in the deep white matter and the splenium of the corpus callosum and reduced diffusion.Electroneuromyography in the peripheral nerve indicated both demyelination and axon loss change,meanwhile,he has a transient hyperthyroidism during the "stroke-like" episode.Pedigree analysis of this family suggests that the disease was X-linked dominant inheritated.Female patients showed less severe symptoms than males and they all presented with peripheral neuropathy.But the proband was the only one who presented with "stroke-like" symptoms.The exon 1 of the GJB1 gene of the proband was sequenced by Sanger sequencing,and a new mutation site c.-170T> G was found in the nerve-specific promoter,namely the P2 region.The mutation co-segregated with the phenotypes and not found in 100 normal control DNA samples.So it can be identified as the pathogenic mutation of this family.ConclusionA novel pathogenic mutation c.-170T> G in the nerve-specific promoter P2 region of the non-coding region of the GJB1 gene is the pathogenic mutation of this pedigree.This is the first reported mutation located in non-coding region associated with transient CNS symptoms.Thyroid dysfunction may be associated with the "stroke-like" symptoms.This mutation may reduce the expression of gap junction protein(Cx32),leading to the disease phenotype.