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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 report 8 cases of hereditary spastic paraplegia type 35 (SPG35) in Chinese mainland, summarize the clinical and genetic features of this disease.Methods:Eight probands with SPG35, admitted in Shanghai Jiao Tong University Affiliated Sixth People′s Hospital and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from September 2006 to June 2021, were collected in detail. Physical examination, cranial imaging examination and whole exome sequencing were conducted, followed by Sanger sequencing and family co-segregation. In addition, the recent advances in clinical, genetic and pathogenesis studies of the disease were also reviewed.Results:Among all of the 8 patients, 7 had juvenile-onset and 1 was adult-onset. The clinical phenotype of 2 cases was pure spastic paraplegia. The other 6 cases presented with complicated form, which was characterized by not only motor dysfunction, but also cognitive impairment and dysphagia, etc. Genetic testing revealed a total of 13 fatty acid 2-hydroxylase (FA2H) gene (NM_024306) mutations, of which 6 were reported and 7 were newly reported in this study.Conclusions:SPG35 is an autosomal recessive neurodegenerative disease with highly phenotypic heterogeneity, with the causative gene as FA2H. The genotype-phenotype correlations in SPG35 are not clear.
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Objective:To investigate the clinical and genetic characteristics of patients with late-onset subtypes (adolescent or adult) of Krabbe disease.Methods:The clinical data of 7 patients with Krabbe disease admitted to Shanghai Jiao Tong University Affiliated Sixth People′s Hospital and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from September 2006 to June 2021 were analyzed and Sanger sequencing of the galactosylceramidase (GALC) gene (NM_000153) and detection of the activity of GALC were conducted. A total of 61 cases of Krabbe disease reported in domestic literature were reviewed and summarized.Results:Among the 7 patients with Krabbe disease, there were 4 males and 3 females. All of them had lower limb weakness or walking difficulty as the initial symptoms, and presented as spastic paraplegia. The symptoms were relatively mild in patients with late onset. There were 4 out of 5 patients undergoing magnetic resonance imaging examination, who showed abnormal signals: 2 had brain atrophy and the remaining 2 had white matter lesions. A total of 5 GALC gene mutations were detected by genetic analysis. Among these, c.1901T>C (p.L634S), c.908C>T(p.S303F) and c.461C>A(p.P154H) are known variants, while c.50_51insTT (p.M17Ifs) and c.1130delT(p.L337X) are novel variants reported for the first time in this paper.Conclusions:Krabbe disease is a rare neurodegenerative disease with phenotypic heterogeneity, which is inherited in an autosomal recessive mode. The severity of clinical manifestations of Krabbe disease is correlated with the age of onset.
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Objective:To summarize and analyze the clinical data of Chinese patients with colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy, and clarify the phenotypic and genetic characteristics of Chinese patients.Methods:Medical history of patients with CSF1R-related leukoencephalopathy diagnosed from April 1, 2018 to January 31, 2021 in the department of neurology of 22 hospitals in China was collected, and scores of Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment Scale (MoCA), magnetic resonance severity scale were evaluated. Group comparison was performed between male and female patients.Results:A total of 62 patients were included, and the male-female ratio was 1∶1.95. The age of onset was (40.35±8.42) years. Cognitive impairment (82.3%, 51/62) and motor symptoms (77.4%,48/62) were the most common symptoms. The MMSE and MoCA scores were 18.79±7.16 and 13.96±7.23, respectively, and the scores of two scales in male patients (22.06±5.31 and 18.08±5.60) were significantly higher than those in females (15.53±7.41 , t=2.954, P=0.006; 10.15±6.26, t=3.328 , P=0.003). The most common radiographic feature was bilateral asymmetric white matter changes (100.0%), and the magnetic resonance imaging severity scale score was 27.42±11.40, while the white matter lesion score of females (22.94±8.39) was significantly higher than that of males (17.62±8.74 , t=-2.221, P<0.05). A total of 36 CSF1R gene mutations were found in this study, among which c.2381T>C/p.I794T was the hotspot mutation that carried by 17.9% (10/56) of the probands. Conclusions:The core phenotypic characteristics of CSF1R-related leukoencephalopathy in China are progressive motor and cognitive impairment, with bilateral asymmetrical white matter changes. In addition, there exist gender differences clinically, with severer cognitive impairment and imaging changes in female patients. Thirty-six CSF1R gene mutations were found in this study, and c.2381T>C/p. I794T was the hotspot mutation.
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Objective To discuss the genotype and phenotype features of 187 patients with spinocerebellar ataxia type 3 (SCA3) and analyze their genotype-phenotype relationship.Methods A total of 187 patients genetically diagnosed as having SCA3 from 160 families were enrolled from our hospital from 2005 to 2015.Detailed medical histories were collected.SPSS 22.0 was conducted to statistically analyze the genotypes and pathogenic CAG expansions of A TXN3 gene in the patients.Results One hundred males and 87 females suffered SCA3.Mean age at onset was 35.43±11.17 years.The ranges of pathogenic CAG expansion were 65-86 repeats,with mean pathogenic CAG expansion of 74.11±3.56 repeats.A negative correlation was found between number of CAG repeats and age of onset (r=-0.815,P=0.000).Frequencies of the patients with tendon hyporeflexia were 28.9％ and 6.0％,respectively,in the smaller pathogenic CAG expansion group (≤74) and larger pathogenic CAG expansion group (＞74),with significant difference (P＜0.05).Frequencies of patients with rigidity were 27.8％ and 49.4％,respectively,in the smaller pathogenic CAG expansion group and larger pathogenic CAG expansion group,with significant difference (P＜0.05).Conclusions SCA3 is neurodegenerative disorder with high clinical and genetical heterogeneity.There are distinct correlations between number of pathogenic CAG expansion and age of onset,frequency ofhyporeflexia and rigidity.
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Objective· To study the clinical and genetic features of familial paroxysmal exercise-induced dyskinesia (PED) in a Chinese mainland family,and review the advances of clinical and genetic studies on PED.Methods· The clinical information of 7 family members in one Chinese pedigree,including 5 patients and 2 healthy people,was analyzed and the patients' response to treatment and prediction were followed up.The SLC2A1 gene in all 7 members of this family was sequenced.The clinical and genetic characteristics of 5 patients were analyzed.Advances of recent clinical and genetic studies related with PED were further reviewed.Results · Among the total 5 patients (male:female=1:4),four patients had pure form of PED,and one patient had PED plus epilepsy.Attacks of the proband and his daughter could not be well controlled by carbamazepine or sodium valproate.In addition,three patients showed a remission trend with age advancing.In this family,the SLC2A1 c.C284T (p.S95L) was identified in all 5 patients,but not in 2healthy members.According to the American College of Medical Genetics and Genomics (ACMG) criteria and guideline,the variant SLC2A1 c.C284T (p.S95L) was classified as pathogenic variant.Conclusion · PED is a rare paroxysmal movement disorder with highly phenorypic heterogeneity as well as a remission trend with age advancing.This paper reviews advances in clinical and genetic studies on PED recently,in order to contribute to the clinical diagnosis and appropriate treatment of PED.