BackgroundCharcot-Marie-Tooth disease type 2 (CMT2) is a clinically and genetically heterogeneous group of inherited axonal neuropathies. The aim of this study was to extensively investigate the mutational spectrum of CMT2 in a cohort of patients of Han Chinese.Methodology and Principal FindingsGenomic DNA from 36 unrelated Taiwanese CMT2 patients of Han Chinese descent was screened for mutations in the coding regions of the MFN2, RAB7, TRPV4, GARS, NEFL, HSPB1, MPZ, GDAP1, HSPB8, DNM2, AARS and YARS genes. Ten disparate mutations were identified in 14 patients (38.9% of the cohort), including p.N71Y in AARS (2.8%), p.T164A in HSPB1 (2.8%), and p.[H256R]+[R282H] in GDAP1 (2.8%) in one patient each, three NEFL mutations in six patients (16.7%) and four MFN2 mutations in five patients (13.9%). The following six mutations were novel: the individual AARS, HSPB1 and GDAP1 mutations and c.475-1G>T, p.L233V and p.E744M mutations in MFN2. An in vitro splicing assay revealed that the MFN2 c.475-1G>T mutation causes a 4 amino acid deletion (p.T159_Q162del). Despite an extensive survey, the genetic causes of CMT2 remained elusive in the remaining 22 CMT2 patients (61.1%).Conclusions and SignificanceThis study illustrates the spectrum of CMT2 mutations in a Taiwanese CMT2 cohort and expands the number of CMT2-associated mutations. The relevance of the AARS and HSPB1 mutations in the pathogenesis of CMT2 is further highlighted. Moreover, the frequency of the NEFL mutations in this study cohort was unexpectedly high. Genetic testing for NEFL and MFN2 mutations should, therefore, be the first step in the molecular diagnosis of CMT2 in ethnic Chinese.

Background Hereditary transthyretin (ATTRv) amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We aimed to assess the efficacy and safety of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with ATTRv amyloidosis with polyneuropathy. MethodsThis multi-country, multi-centre, open-label extension (OLE) trial enrolled patients at 43 sites in 19 countries as of 24 September 2018. Patients were eligible if they had completed the phase 3 APOLLO (randomised, double-blind, placebo-controlled [2:1], 18-month study) or phase 2 OLE (single-arm, 24-month study) parent studies and tolerated the study drug. Eligible patients from APOLLO (APOLLO-patisiran [received patisiran during APOLLO] and APOLLO-placebo [received placebo during APOLLO] groups) and the phase 2 OLE (phase 2 OLE patisiran group) studies enrolled in this Global OLE trial and receive patisiran 0•3 mg/kg by intravenous infusion every 3 weeks for up to 5 years. Efficacy assessments include measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress. Patients included in the current efficacy analyses are those who had completed 12-month efficacy assessments as of the data cut-off. Safety analyses included all patients who received ≥1 dose of patisiran up to the data cut-off. The Global OLE is ongoing with no new enrolment, and current findings are based on the 12-month interim analysis. The study is registered with ClinicalTrials.gov, NCT02510261.

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Sympathetic skin response (SSR) and R-R interval variation (RRIV) were studied in 36 chronic, nondiabetic uremics to compare with their nerve conduction studies (NCS) and clinical dysautonomia. Abnormal SSR was noted in 5 (13.9%) patients, abnormal RRIV in 14 (38.9%), and abnormal NCS in 26 (72.2%). The patients were classified into three groups: group (GP) 1: "normal," n = 21 (58.3%), normal RRIV and SSR; GP 2: "isolated parasympathetic dysfunction," n = 10 (27.8%), abnormal RRIV and normal SSR; and GP 3: "sympathetic sudomotor dysfunction," n = 5 (13.9%), abnormal SSR. A significant difference in age was found among the three groups (GP 3 > GP 2 > GP 1; P < 0.0001, ANOVA). After controlling the age factor, we still noted a tendency toward increasing NCS disturbances (distal latency and nerve conduction velocity of peroneal nerve; P < 0.05, multiple regression analysis) and frequencies of clinical autonomic symptoms (postural dizziness and impotence; P < 0.05, Mantel-Hanszel test) from GP 1 to GP 3. Patients with abnormal SSR (GP 3) displayed significantly higher frequencies of postural dizziness and impotence, indicating the relationship between an absence of SSR and clinical dysautonomia.

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From July 1988 to June 1989, the etiology was registered of 520 patients with generalized neuropathy in 5 neurological centers in Taiwan. The neuropathy was diabetic in 256 cases (49.23%), alcoholic in 45 (8.65%), inflammatory in 34 (6.53%; including 21 with acute inflammatory demyelinating polyneuropathy, 12 with chronic inflammatory demyelinating polyneuropathy, and 1 with chronic relapsing polyneuropathy), 12 with associated malignancy (2.31%), 9 with dysproteinemia (1.73%), uremic in 22 (4.23%), hereditary motor and sensory in 22 (4.23%), toxic in 14 (2.69%), ischemic in 12 (2.31%), hypothyroidism in 10 (1.92%), nutritional deficiency and malabsorption in 6 (1.15%), chronic liver disease in 4 (0.77%), other diseases in 11 (2.12%) and unclassified in 63 (12.12%). This survey provided a crude etiological picture of generalized neuropathy on this island.

ObjectiveCharcot–Marie–Tooth disease type X1 (CMTX1), which is caused by mutations in the gap junction (GJ) protein beta‐1 gene (GJB1), is the second most common form of Charcot–Marie–Tooth disease (CMT). GJB1 encodes the GJ beta‐1 protein (GJB1), which forms GJs within the myelin sheaths of peripheral nerves. The process by which GJB1 mutants cause neuropathy has not been fully elucidated. This study evaluated the biophysical characteristics of GJB1 mutants and their correlations with the clinical features of CMTX1 patients.MethodsAll patients with a validated GJB1 mutation were assessed using the Charcot–Marie–Tooth disease neuropathy score version 2 (CMTNS). The impacts of the mutations on the biophysical functions of GJB1 were characterized by assessing intracellular localization, expression patterns, and GJ Ca2+ permeability.ResultNineteen GJB1 mutations were identified in 24 patients with a clinical diagnosis of CMT. Six are novel mutations: p.L6S, p.I20F, p.I101Rfs*8, p.F153L, p.R215P, and p.D278V. Diverse pathological effects of the mutations were demonstrated, including reduced GJB1 expression, intracellular mislocalization, and altered GJ functions. GJB1 mutations that caused a complete loss of GJ Ca2+ permeability appeared to be associated with an earlier disease onset, whereas those resulting in preservation of GJ permeability and with predominant cell membrane expression tended to have a later onset and a milder phenotype.InterpretationThis study demonstrated that the degree of loss of GJ function caused by the GJB1 mutations might contribute to the onset and severity of neuropathic symptoms in CMTX1.