Clinical and genetic characterization of NEFL-related neuropathy in Taiwan.

BACKGROUND: Mutations in the neurofilament light polypeptide gene (NEFL) are an uncommon cause of Charcot-Marie-Tooth disease (CMT). The aim of this study is to elucidate the clinical characteristics and genetic spectrum of NEFL-related neuropathy in a Taiwanese CMT cohort. METHODS: Mutational analysis of the coding regions of NEFL was performed by Sanger sequencing or targeted resequencing. Twenty-one patients from nine CMT pedigrees, identified from a cohort of 508 unrelated CMT patients, were found to have a NEFL mutation. Genetic, clinical and electrophysiological features were analyzed. RESULTS: Six NEFL mutations were identified, including two novel ones (p.P8S, p.N98Y). NEFL p.E396K was the most common mutation, accounting for 33.3% of the patients in our cohort. All patients manifested sensorimotor polyneuropathy with a mean age of disease onset of 13.5 ± 9.6 (1-40) years. Their motor nerve conduction velocities (MNCVs) of the ulnar nerve ranged from 22.1 to 48.7 m/s. Seventy percent of the patients could be classified as intermediate CMT with ulnar MNCVs between 25 and 45 m/s. Six of the 21 patients (28.6%) had additional features of central nervous system (CNS) involvement, including motor developmental delay, spasticity, cerebellar signs, neuropathic pain and scoliosis. CONCLUSION: NEFL mutations account for 1.8% (9/508) of the CMT patients in Taiwan. The present study delineates the clinical and genetic characteristics of NEFL-related neuropathy in Taiwan, and highlights that ulnar MNCV above 25 m/s and CNS involvement may serve as diagnostic clues for NEFL-related neuropathy.

Investigating ZFYVE26 mutations in a Taiwanese cohort with hereditary spastic paraplegia.

BACKGROUND/PURPOSE: Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited neurodegenerative disorders characterized by slowly progressive lower limbs spasticity and weakness. HSP type 15 (SPG15) is an autosomal recessive subtype caused by ZFYVE26 mutations. The aim of this study was to investigate the frequency and clinical and genetic features of ZFYVE26 mutations in a Taiwanese HSP cohort. METHODS: Mutational analysis of the coding regions of ZFYVE26 was performed by targeted resequencing in the 195 unrelated Taiwanese patients with HSP. All of the patients were of Han Chinese ethnicity. Clinical, neuropsychological, electrophysiological evaluations and imaging studies were collected. RESULTS: Among the 195 patients, only one SPG15 patient was identified. The patient had a novel recessive ZFYVE26 frameshift truncating mutation, p.R1806Gfs∗36 (c.5415delC), and presented with insidious onset spastic weakness of lower-extremities and cognitive impairment. Neuropsychological assessment revealed deficits in executive function, visual naming, category verbal fluency, and manual dexterity. Brain MRI showed thin corpus callosum and the "ears of lynx" sign. CONCLUSION: SPG15 accounts for approximately 0.5% (1/195) of the Taiwanese HSP cohort. This study identified the first Taiwanese SPG15 case and delineated the clinical, genetic, neuropsychological, and neuroimaging features. These findings expand the mutational spectrum of ZFYVE26 and also broaden the knowledge of clinical and neuropsychological characteristics of SPG15.

A missense mutation in human INSC causes peripheral neuropathy.

PAR3/INSC/LGN form an evolutionarily conserved complex required for asymmetric cell division in the developing brain, but its post-developmental function and disease relevance in the peripheral nervous system (PNS) remains unknown. We mapped a new locus for axonal Charcot-Marie-Tooth disease (CMT2) and identified a missense mutation c.209 T > G (p.Met70Arg) in the INSC gene. Modeling the INSCM70R variant in Drosophila, we showed that it caused proprioceptive defects in adult flies, leading to gait defects resembling those in CMT2 patients. Cellularly, PAR3/INSC/LGN dysfunction caused tubulin aggregation and necrotic neurodegeneration, with microtubule-stabilizing agents rescuing both morphological and functional defects of the INSCM70R mutation in the PNS. Our findings underscore the critical role of the PAR3/INSC/LGN machinery in the adult PNS and highlight a potential therapeutic target for INSC-associated CMT2.

Clinical and genetic profiles of hereditary transthyretin amyloidosis in Taiwan.

OBJECTIVE: The clinical and genetic profiles of hereditary transthyretin amyloidosis (ATTR) in Chinese populations remain elusive. We aim to characterize the features of ATTR in a Taiwanese cohort of Han Chinese descent. METHODS: Seventy-nine patients with molecularly confirmed ATTR from 57 Taiwanese families were identified by sequencing the transthyretin gene (TTR). The clinical and electrophysiological data were scrutinized. Cardiac involvement of ATTR was evaluated by echocardiography and cardiac scintigraphy. Four microsatellite and seven single-nucleotide polymorphism markers flanking TTR were genotyped to investigate the founder effect of the TTR Ala97Ser mutation. RESULTS: Most of the patients had a peripheral neuropathy with variable autonomic symptoms. The average age at disease onset (AO) was 58.2 ± 7.2 years, and the male patients had an earlier AO than female patients (56.6 ± 5.7 years vs. 61.8 ± 8.9 years, P = 0.013). Electrophysiological studies revealed a generalized axonal sensorimotor polyneuropathy and isolated median neuropathy in 84.5% and 15.5% of the patients, respectively. Up to 80% of the patients with ATTR had symptomatic or subclinical cardiac involvement. Six TTR mutations were identified in the participants including one novel mutation Glu89Asp. Among them, Ala97Ser was the most common mutation, accounting for 91.2% of the ATTR pedigrees. Detailed haplotype analyses demonstrated a shared haplotype in the 47 patients with the Ala97Ser mutation, suggesting a founder effect. INTERPRETATION: The present study delineates the distinct features of ATTR in Taiwan and provides useful information for the diagnosis and management of ATTR, especially in patients of Chinese descent.

Coexistence of Charcot Marie Tooth disease type 1A and diabetes in Taiwan: A clinicopathological study.

BACKGROUND: Charcot Marie Tooth disease type 1A (CMT1A) is the most commonly inherited demyelinating polyneuropathy with variable phenotypes, affected by several comorbidities, especially diabetes mellitus (DM). Previous studies showed that DM exacerbates the clinical manifestations of CMT1A. PATIENTS AND METHODS: We retrospectively evaluated patients with CMT1A in our hospital, and identified three groups among 12 cases, which comprised four patients with CMT1A, four with CMT1A+DM, and four with DM. We reviewed the CMT neuropathy score (CMTNS), electrophysiological data, and histomorphological parameters of the sural nerve, including fiber density, myelin thickness, axon diameter, g-ratio, regenerative clusters, and regeneration ratio. RESULTS: The CMTNS was significantly higher in patients with CMT1A+DM (21.5±2.52) than in those with CMT1A only (10.8±4.4; p=0.03). Pathological findings in patients with CMT1A+DM included a significant decrease of myelinated fiber density (p=0.02) and reduction in the regenerative ratio (p=0.01), indicating severe degeneration with impaired regeneration. In non-parametric analyses, DM was found to play a more important role than CMT1A in influencing nerve degeneration and regeneration. CONCLUSIONS: In patients with CMT1A, DM exacerbated clinical and pathological manifestations including increased loss of myelinated fibers, abnormal axon-myelin interaction, and impaired nerve regeneration.