A Case Report And Systematic Review Of CMTX1 Patients With Episodic Neurological Dysfunction

Objective: X-linked Charcot-Marie-Tooth type 1(CMTX1)is an inherited peripheral neuropathy caused by mutations in the gap junction beta 1(GJB1)gene,which encodes the connexin32 protein.A small number of patients with GJB1 mutations present with episodic neurological dysfunction and reversible white matter lesions,which has not been adequately reported.We aim to enable clinicians to further understand this particular situation through systematically reviewing all published relevant cases.Methods: We reported a female patient with CMTX1 who had recurrent episodes of neurological dysfunction in the puerperium.Gene sequencing showed that the pathogenic mutation of GJB1 gene was c.622G>A(p.Glu208Lys).We comprehensively searched the medical literature related to patients with CMTX1 episodic neurological dysfunction in Pub Med electronic database,then collected the general information of related cases and analyzed the pathogenicity of all mutations using Gnom AD database,Revel score and Clin Var database,and made a statistical analysis of clinical manifestations,and characteristics of magnetic resonance imaging(MRI),cerebrospinal fluid(CSF)analysis,and nerve conduction study(NCS).Results: We identified 47 cases of CMTX1 associated with episodic central nervous system(CNS)dysfunction.All mutations in CMTX1 patients with episodic neurological deficits are pathogenic or likely to be pathogenic according to ACMG criteria.CMTX1 patients experienced episodic CNS deficits at a young age,ranging from infancy to 26 years,and 45(95.7%)of them were male.The CNS symptoms manifested as facial,lingual,or limb weakness in 44(93.6%),dysarthria or dysphagia in 39(83.0%),facial or limb numbness in 15(31.9%),and ataxia in 10(21.3%)patients.The duration of episodic symptoms ranged from 3 minutes to 6 months.Thirty(63.8%)CMTX1 cases have reported obvious predisposing factors,among which the most common factors were infection or fever(27.7%),travel to high altitude(12.8%),and intensive exercise(8.5%).As for brain MRI,most abnormal signals were found in bilateral deep white matter(88.9%)and corpus callosum(80.0%).In addition,most of the NCS results were abnormal,including prolonged latency,reduced amplitude,and slowed conduction velocity.The motor nerve conduction velocity(MNCV)of median nerve was the most detectable and valuable,ranging from 25 to 45 m/s.Interpretation: We present the most comprehensive summary of the demographic and clinical profiles of CMTX1 patients with episodic CNS dysfunction and provide new insights into the phenotypic spectrum of CMTX1.In clinical practice,the diagnosis of CMTX1 should be considered in patients with episodic CNS dysfunction and abnormal white matter signals on MRI.In addition,detailed neurological examination and NCS will provide key clues for the correct diagnosis of CMTX1.