[Charcot-Marie-Tooth disease].

Charcot-Marie-Tooth disease (CMT), also called hereditary motor and sensory neuropathy (HMSN), is the most common inherited peripheral neuropathy, comprised by a group of genetically heterogeneous disorders that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, and depressed tendon reflexes. It can be categorized according to its electrophysiological or pathological features, transmission patterns, age of disease onset, and molecular pathology. CMT type 1 (CMT1; MIM 118200) is a group of autosomal dominant-inherited demyelinating neuropathies with a disease onset at or after childhood. Five different subtypes have been identified based on different causative genes. Among them, CMT1A (MIM #118220) is most common and is usually associated with a duplication of a 1.5-Mb region on chromosome 17p11.2, which includes peripheral myelin protein 22 gene (PMP22; MIM *601097). Currently, there is no cure or obviously effective disease-modifying treatment for CMT. Two potential effective therapeutic agents for CMT1A were investigated recently. One is ascorbic acid and another is neurotrophin-3 (NT-3), an important component of the Schwann cell autocrine survival loop. Early diagnosis can facilitate CMT patients to modify their life styles timely for minimizing nerve injury to delay or avoid disability. Molecular diagnosis of CMT can provide the basis for appropriate genetic counseling and further CMT research.

Common mitochondrial DNA and POLG1 mutations are rare in the Chinese patients with adult-onset ataxia on Taiwan.

BACKGROUND AND PURPOSE: Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative disorders with common features of adult-onset cerebellar ataxia. Many patients with clinically suspected SCA are subsequently diagnosed with common SCA gene mutations. Previous reports suggest some common mitochondrial DNA (mtDNA) point mutations and mitochondrial DNA polymerase gene (POLG1) mutations might be additional underlying genetic causes of cerebellar ataxia. We tested whether mtDNA point mutations A3243G, A8344G, T8993G, and T8993C, or POLG1 mutations W748S and A467T are found in patients with adult-onset ataxia who did not have common SCA mutations. METHODS: Four hundred seventy-six unrelated patients with suspected SCA underwent genetic testing for SCA 1, 2, 3, 6, 7, 8, 10, 12, 17, and DRPLA gene mutations. After excluding these SCA mutations and patients with paternal transmission history, 265 patients were tested for mtDNA mutations A3243G, A8344G, T8993G, T8993C, and POLG1 W748S and A467T mutations. RESULTS: No mtDNA A3243G, A8344G, T8993G, T8993C, or POLG1 W748S and A467T mutation was detected in any of the 265 ataxia patients, suggesting that the upper limit of the 95% confidence interval for the prevalence of these mitochondrial mutations in Chinese patients with adult-onset non-SCA ataxia is no higher than 1.1%. CONCLUSIONS: The mtDNA mutations A3243G, A8344G, T8993G, T8993C, or POLG1 W748S and A467T are very rare causes of adult-onset ataxia in Taiwan. Routine screening for these mutations in ataxia patients with Chinese origin is of limited clinical value.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: two novel mutations in the NOTCH3 gene in Chinese.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disorder caused by NOTCH3 mutations, usually localized to exons 3 and 4, and characterized by recurrent subcortical infarctions, dementia and leukoencephalopathy. So far, there has been only limited information about CADASIL in Chinese population. OBJECTIVES: To analyze the NOTCH3 mutations in ethnic Chinese in Taiwan with clinically suspected CADASIL and to characterize their clinical and molecular features. METHODS: Mutation analysis of NOTCH3 by direct nucleotide sequencing was performed in eight unrelated Chinese patients with clinically suspected CADASIL. Skin biopsy with ultrastructural studies by electronic microscopy was performed in four patients. RESULTS: Five NOTCH3 mutations, S118C, R141C, R332C, R544C and C977S, respectively, were identified from five patients, of which S118C and C977S are novel. None of these nucleotide sequence variations could be found among 50 healthy controls. Among the five mutations, two were in exon 4, and the other three were in exons 6, 11 and 18, respectively. Skin biopsy showed the presence of characteristic granular osmiophilic material only in the patient with the NOTCH3 mutation of R332C. CONCLUSION: Our study demonstrated the clinical and molecular features of CADASIL in Chinese patients and broadened the spectrum of NOTCH3 mutations. Lack of evidence of a strong clustering of mutations in a particular exon tentatively suggests that a comprehensive screening of NOTCH3 mutation is still necessary for molecular diagnosis of CADASIL in Chinese population.