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Background@#and Purpose X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is characterized by peripheral neuropathy with or without episodic neurological dysfunction. We performed clinical, neuropathological, and genetic investigations of a series of patients with mutations of the gap-junction beta-1 gene (GJB1) to extend the phenotypic and genetic description of CMTX1. @*Methods@#Detailed clinical evaluations, sural nerve biopsy, and genetic analysis were applied to patients with CMTX1. @*Results@#We collected 27 patients with CMTX1 with GJB1 mutations from 14 unrelated families. The age at onset (AAO) was 20.9±12.2 years (mean±standard deviation; range, 2–45 years). Walking difficulties, weakness in the legs, and pes cavus were common initial symptoms. Compared with female patients, males tended to have a younger AAO (males vs. females=15.4±9.6 vs. 32.0±8.8 years, p=0.002), a longer disease course (16.8±16.1 vs. 5.5±3.8 years, p=0.034), and more-severe electrophysiological results. Besides peripheral neuropathy, six of the patients had special episodic central nervous system (CNS) evidence from symptoms, signs, and/or reversible white-matter lesions. Neuropathology revealed the loss of large myelinated fibers, increased number of regenerated axon clusters with abnormally thin myelin sheaths, and excessively folded myelin. Genetic analysis identified 14 GJB1 variants, 6 of which were novel. @*Conclusions@#These findings expand the phenotypic and genetic spectrum of CMTX1. Although CMTX1 was found to have high phenotypic and CNS involvement variabilities, detailed neurological examinations and nerve conduction studies will provide critical clues for accurate diagnoses. Further exploration of the underlying mechanisms of connexin 32 involvement in neuropathy or CNS dysfunction is warranted to develop promising therapies.
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Objective:To summarize and analyze the clinical and genetic characteristics of Chinese patients with adrenomyeloneuropathy (AMN).Methods:Clinical data were collected and analyzed retrospectively on AMN patients who were diagnosed by genetic testing in Shanghai Sixth People′s Hospital, Shanghai Jiao Tong University School of Medicine from May 2008 to August 2022. Clinical characteristics of AMN patients with different types of gene mutations were compared. Loe score was used to evaluate the severity of white matter demyelinating, and the serum levels of very long-chain fatty acids (VLCFA) in patients with or without white matter demyelinating were compared. The motor function of the AMN patients was assessed using the Expanded Disability Status Scale (EDSS), and the association between EDSS scores and the course of disease was analyzed.Results:A total of 23 male patients with onset age of (29.52±9.91) years were included in this study. The first symptom of all patients was abnormal lower extremities, of which 17 patients showed stiffness and weakness in their lower limbs (73.9%, 17/23), and 6 patients showed numbness and pain in both lower limbs (26.1%, 6/23). The occurrence of symptoms was not related to the type of gene mutation. White matter demyelination occurred in 33.3% (7/21) of patients over a disease duration of (7.67±4.46) years. There was no statistically significant difference in serum VLCFA level between the white-matter demyelination group and the non-demyelination group. The EDSS score was positively correlated with the disease duration ( r=0.57, P=0.006). Sixteen ABCD1 gene mutations were found in this study, among which c.5_19delinsTCTCCAGG (p.P2Lfs *12) was reported for the first time. Four probands belonging to different families carried the c.1415_1416del (p.Q472Rfs *83) variant. Conclusions:Lower limb movement disorders and sensory dysfunction are the prominent clinical manifestations in AMN patients, with deterioration of motor function associated with the course of disease. AMN may be converted to cerebral type and VLCFA concentration is not associated with the phenotypic changes. The c.1415_1416del (p.Q472Rfs *83) mutation is a hot spot mutation of the disease.