Background and Objective:The GGC repeat expansion in the 5’ untranslated region of NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease (NIID), which may manifest with peripheral neuropathy. The aim of this study is to investigate its contribution to inherited neuropathy.Methods:This cohort study screened patients with molecularly undiagnosed Charcot-Marie-Tooth disease (CMT) and healthy control individuals for the GGC repeat expansion in NOTCH2NLC using repeat-primed PCR and fragment analysis. The clinical and electrophysiological features of the patients harboring the GGC repeat expansion were scrutinized. Skin biopsy with immunohistochemistry staining and electric microscopic imaging were performed.Results:One hundred and twenty-seven unrelated patients with CMT, including 66 cases with axonal CMT (CMT2), and 200 healthy control individuals were included.Among them, seven CMT patients carried a mutant NOTCH2NLC allele with GGC repeat expansion, but it was absent in controls. The sizes of the expanded GGC repeats ranged from 80 to 104 repeats. All seven patients developed sensory predominant neuropathy with an average age at disease onset of 37.1 years (range 21-55). The electrophysiological studies revealed mild axonal sensorimotor polyneuropathy. Leukoencephalopathy was absent in the five patients who received a brain MRI. Skin biopsy from two patients showed eosinophilic, ubiquitin- and p62-positive intranuclear inclusions in the sweat gland cells and dermal fibroblasts. Two of the seven patients had a family history of NIID.Discussion:The NOTCH2NLC GGC repeat expansions are an underdiagnosed and important cause of inherited neuropathy. The expansion accounts for 10.6% (7/66) of molecularly unassigned CMT2 cases in the Taiwanese CMT cohort.Classification of Evidence:This study provides Class III evidence that in Taiwanese patients with genetically undiagnosed CMT, 10.6% of the CMT2 cases have the GGC repeat expansion in NOTCH2NLC.

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ObjectiveThe NEK1 gene has been recently implicated in amyotrophic lateral sclerosis (ALS). This study aims to assess the influence of NEK1 variants on the occurrence of ALS and investigate the spectrum and clinical features of NEK1 loss‐of‐function (LOF) variants in a Taiwanese ALS cohort.MethodsWe screened 325 unrelated ALS patients for coding variants in NEK1 by targeted resequencing and queried the Taiwan Biobank database for NEK1 coding variants in 1000 Taiwanese healthy individuals. The clinical features of the patients with a NEK1 LOF variant were analyzed.ResultsSix patients and two healthy individuals carried NEK1 LOF variants. The rare missense variants with minor allele frequencies <0.1% in Taiwanese population were present in 2.8% of the ALS patients and 1.6% of the healthy subjects. NEK1 LOF variants, but not rare missense variants, are significantly enriched in the ALS patients (P = 0.0037 and 0.24, Fisher’s exact test). The odds ratio of an individual carrying a NEK1 LOF variant to develop ALS is 9.39 (95% confidence interval: 1.88–46.7). All the six patients carrying a NEK1 LOF variant had a hand‐onset ALS with an onset age from 52 to 64 years. Comparing with ALS patients without a NEK1 LOF variant, patients with a NEK1 LOF variant tend to have a hand‐onset disease (P = 0.0008, Fisher’s exact test).InterpretationOur study supports the pathogenic role of NEK1 LOF variants and demonstrates their spectrum and clinical features in a Taiwanese cohort with ALS.

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Recently, DNAJC7 was found to be associated with amyotrophic lateral sclerosis (ALS) in a single large-scale exome sequencing study. 1 Multiple protein-truncating variants were detected in individuals with ALS that were absent in control subjects. 1 DNAJC7 encodes a member of the DnaJ heat-shock protein family (HspP40), which functions in protein homeostasis, including protein folding and degradation. 2 To validate the pathogenic role of DNAJC7 in ALS and further understand the relevant clinical features, we screened a Taiwanese ALS cohort for DNAJC7 mutations.

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Background and ObjectivesTo investigate the frequency, spectrum, and molecular functional effect of glycosyltransferase 8 domain-containing protein 1 (GLT8D1) variations in Taiwanese patients with amyotrophic lateral sclerosis (ALS).MethodsWe performed genetic analyses of GLT8D1 in 410 unrelated patients with ALS by Sanger sequencing. The 410 patients were selected from a cohort of 477 unrelated patients with ALS after excluding variations in common ALS disease genes. Functional effects of the GLT8D1 variation were investigated by in vitro functional analysis.ResultsWe identified a novel heterozygous missense variation in GLT8D1, p.I290M (c.870C>G), in 1 single patient with familial ALS. The patient with the p.I290M variation had a spinal-onset ALS with disease onset at age 60 years and a survival of 6 years. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity.DiscussionGLT8D1 variations account for 0.2% (1/477) of the patients with ALS in Taiwan. These findings expand the spectrum of GLT8D1 variation and support the pathogenic role of GLT8D1 variations in ALS.