Novel variants and cellular studies on patients' primary fibroblasts support a role for NEK1 missense variants in ALS pathogenesis.

In the last few years, NEK1 has been identified as a new gene related to amyotrophic lateral sclerosis (ALS). Loss-of-function variants have been mostly described, although several missense variants exist, which pathogenic relevance remains to be established. We attempted to determine the contribution of NEK1 gene in an Italian cohort of 531 sporadic and familial amyotrophic lateral sclerosis (ALS) patients applying massive parallel sequencing technologies. We filtered results of NEK1 gene and identified 20 NEK1 rare variants (MAF < 0.01) in 22 patients. In particular, we found two novel frameshift variants (p.Glu929Asnfs*12 and p.Val1030Ilefs*23), 18 missense variants, including the p.Arg261His in three patients, and a novel variant in the start codon, the p.Met1?, which most likely impairs translation initiation. To clarify the role of NEK1 missense variants we investigated NEK1 expression in primary fibroblast cultures. We obtained skin biopsies from four patients with NEK1 variants and we assessed NEK1 expression by western blot and immunofluorescence. We detected a decrease in NEK1 expression in fibroblasts from patients with NEK1 variants, suggesting that missense variants in NEK1 gene may have a pathogenic role. Moreover, we observed additional variants in ALS related genes in seven patients with NEK1 variants (32%), further supporting an oligogenic ALS model.

Evaluating the contribution of the gene TARDBP in Italian patients with amyotrophic lateral sclerosis.

BACKGROUND AND OBJECTIVES: Genetic variants in the gene TARDBP, encoding TDP-43 protein, are associated with amyotrophic lateral sclerosis (ALS) in familial (fALS) and sporadic (sALS) cases. Objectives of this study were to assess the contribution of TARDBP in a large cohort of Italian ALS patients, to determine the TARDBP-associated clinical features and to look for genotype-phenotype correlation and penetrance of the mutations. METHODS: A total of 1992 Italian ALS patients (193 fALS and 1799 sALS) were enrolled in this study. Sanger sequencing of TARDBP gene was performed in patients and, when available, in patients' relatives. RESULTS: In total, 13 different rare variants were identified in 43 index cases (10 fALS and 33 sALS) with a cumulative mutational frequency of 2.2% (5.2% of fALS, 1.8% of sALS). The most prevalent variant was the p.A382T followed by the p.G294V. Cognitive impairment was detected in almost 30% of patients. While some variants, including the p.G294V and the p.G376D, were associated with restricted phenotypes, the p.A382T showed a marked clinical heterogeneity regarding age of onset, survival and association with cognitive impairment. Investigations in parents, when possible, showed that the variants were inherited from healthy carriers and never occurred de novo. CONCLUSIONS: In our cohort, TARDBP variants have a relevant frequency in Italian ALS patients and they are significantly associated with cognitive impairment. Clinical presentation is heterogeneous. Consistent genotype-phenotype correlations are limited to some mutations. A marked phenotypic variability characterizes the p.A382T variant, suggesting a multifactorial/oligogenic pathogenic mechanism.

Effect of RNS60 in amyotrophic lateral sclerosis: a phase II multicentre, randomized, double-blind, placebo-controlled trial.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. RNS60 is an immunomodulatory and neuroprotective investigational product that has shown efficacy in animal models of ALS and other neurodegenerative diseases. Its administration has been safe and well tolerated in ALS subjects in previous early phase trials. METHODS: This was a phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial. Participants diagnosed with definite, probable or probable laboratory-supported ALS were assigned to receive RNS60 or placebo administered for 24 weeks intravenously (375 ml) once a week and via nebulization (4 ml/day) on non-infusion days, followed by an additional 24 weeks off-treatment. The primary objective was to measure the effects of RNS60 treatment on selected biomarkers of inflammation and neurodegeneration in peripheral blood. Secondary objectives were to measure the effect of RNS60 on functional impairment (ALS Functional Rating Scale-Revised), a measure of self-sufficiency, respiratory function (forced vital capacity, FVC), quality of life (ALS Assessment Questionnaire-40, ALSAQ-40) and survival. Tolerability and safety were assessed. RESULTS: Seventy-four participants were assigned to RNS60 and 73 to placebo. Assessed biomarkers did not differ between arms. The mean rate of decline in FVC and the eating and drinking domain of ALSAQ-40 was slower in the RNS60 arm (FVC, difference 0.41 per week, standard error 0.16, p = 0.0101; ALSAQ-40, difference -0.19 per week, standard error 0.10, p = 0.0319). Adverse events were similar in the two arms. In a post hoc analysis, neurofilament light chain increased over time in bulbar onset placebo participants whilst remaining stable in those treated with RNS60. CONCLUSIONS: The positive effects of RNS60 on selected measures of respiratory and bulbar function warrant further investigation.

Sural nerve biopsy in peripheral neuropathies: 30-year experience from a single center.

INTRODUCTION: Nerve biopsy has been widely used to investigate patients with peripheral neuropathy, and in many centers, it is still a useful diagnostic tool in this setting. In this study, we reviewed the histopathological spectrum of the nerve biopsies performed in our center in a 30-year period and we analyzed their relevance in the clinical setting. MATERIALS AND METHODS: Retrospective analysis of the retrieved data was done for cases of nerve biopsies performed in our institute between 1988 and 2018. Surgical technique and histopathological analysis were done accordingly to standard protocol. RESULTS: Complete clinical and pathological data were available only for 717 cases. The procedure was generally safe, with only 0.3% superimposed infection. Main pathological results were "unspecific" axonal polyneuropathy (49.8%), vasculitis neuropathy (9.3%), acquired demyelinating neuropathy (8.9%), and Charcot-Marie-Tooth (8.2%). Considering clinical-neurophysiological suspicion of vasculitis, nerve biopsy confirmed the diagnosis in 60.9% of cases. DISCUSSION: In conclusion, for inherited neuropathies, we do not recommend this invasive procedure, but we strongly suggest a genetic test. Conversely, in vasculitic neuropathies or in dysimmune neuropathies not clearly confirmed by neurophysiological examination, nerve biopsy continues to represent a useful and irreplaceable tool.

Elevated Levels of Selenium Species in Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients with Disease-Associated Gene Mutations.

BACKGROUND: Although an increasing role of genetic susceptibility has been recognized, the role of environmental risk factors in amyotrophic lateral sclerosis (ALS) etiology is largely uncertain; among neurotoxic chemicals, epidemiological and biological plausibility has been provided for pesticides, the heavy metal lead, the metalloid selenium, and other persistent organic pollutants. Selenium involvement in ALS has been suggested on the basis of epidemiological studies, in vitro investigations, and veterinary studies in which selenium induced a selective toxicity against motor neurons. OBJECTIVE: Hypothesizing a multistep pathogenic mechanism (genetic susceptibility and environmental exposure), we aimed to study selenium species in ALS patients carrying disease-associated gene mutations as compared to a series of hospital controls. METHODS: Using advanced analytical techniques, we determined selenium species in cerebrospinal fluid sampled at diagnosis in 9 ALS patients carrying different gene mutations (C9ORF72, SOD1, FUS, TARDBP, ATXN2, and TUBA4A) compared to 42 controls. RESULTS: In a patient with the tubulin-related TUBA4A mutation, we found highly elevated levels (in µg/L) of glutathione-peroxidase-bound selenium (32.8 vs. 1.0) as well as increased levels of selenoprotein-P-bound selenium (2.4 vs. 0.8), selenite (1.8 vs. 0.1), and selenate (0.9 vs. 0.1). In the remaining ALS patients, we detected elevated selenomethionine-bound selenium levels (0.38 vs. 0.06). CONCLUSIONS: Selenium compounds can impair tubulin synthesis and the cytoskeleton structure, as do tubulin-related gene mutations. The elevated selenium species levels in the TUBA4A patient may have a genetic etiology and/or represent a pathogenic pathway through which this mutation favors disease onset, though unmeasured confounding cannot be excluded. The elevated selenomethionine levels in the other patients are also of interest due to the toxicity of this nonphysiological selenium species. Our study is the first to assess selenium exposure in genetic ALS, suggesting an interaction between this environmental factor and genetics in triggering disease onset.

Mutations in the 3' untranslated region of FUS causing FUS overexpression are associated with amyotrophic lateral sclerosis.

Mutations in the gene encoding fused-in-sarcoma (FUS) have been identified in a subset of patients with sporadic and familial amyotrophic lateral sclerosis (ALS). Variants in the 3' untranslated region (3'UTR) of FUS have also been reported in ALS patients, but their pathogenic role has not been assessed. We sequenced the whole 3'UTR of FUS in 420 ALS patients who were negative for mutations in the currently known ALS genes and in 480 ethnically matched controls. We detected four 3'UTR variants (c.*48 G>A, c.*59 G>A, c.*108 C>T and c.*110 G>A) in four sporadic and in one familial ALS patients compared with none in controls (P = 0.02).We investigated whether these variants impaired FUS expression in primary fibroblast cultures from three patients harbouring the c.*59 G>A, c.*108 C>T and c.*110 G>A variants, respectively. The pattern of FUS expression was also investigated in fibroblasts from one ALS patient with FUS R521C mutation, in two ALS patients without mutations in the known ALS genes and in four control individuals. By immunostaining and immunoblotting, large amounts of FUS were observed in both the cytoplasm and nuclei of mutant 3'UTR FUS fibroblasts. In FUS R521C mutant fibroblasts, we observed a slight increase of FUS in the cytoplasm associated with a remarkable loss of detection in nuclei. Our findings show that mutations in 3'UTR of FUS are overrepresented in ALS patients and result into translation de-regulation of FUS. Overexpression and mislocalization of wild-type FUS likely contribute to ALS pathogenesis in these cases.

Primary multifocal lymphoma of peripheral nervous system: case report and review of the literature.

INTRODUCTION: Primary lymphomas of peripheral nerves are extremely rare, and only a few cases have been reported. METHODS: We describe the clinical, neurophysiological, radiological, and pathological findings in a 61-year-old woman affected by primary multifocal lymphoma of the peripheral nervous system without systemic involvement. RESULTS: Fascicular left femoral nerve biopsy was decisive for the diagnosis of diffuse large B-cell non-Hodgkin lymphoma. Magnetic resonance imaging, fluorine-18 fluorodeoxyglucose positron emission tomography computed tomography, and nerve ultrasound contributed to the diagnosis. CONCLUSIONS: Primary lymphoma of peripheral nerves (PLPNs) is a rare but potentially treatable condition, which is frequently misdiagnosed. In the literature, there are very few descriptions of PLPNs, most of which are mononeuropathies. The possibility of a neuropathy associated with lymphoma should be considered in patients with poor response to treatment and severe pain symptoms.

Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients.

BACKGROUND: In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant. METHODS: In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48 weeks (median period of 84 weeks, range 48-108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1 year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients. RESULTS: Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p = 0.023 and p = 0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60% of patients. Such alterations were clinically asymptomatic in all but two patients who showed an acute pure motor radiculitis, which responded to steroid therapy. CONCLUSIONS: Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients.

Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72.

A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for ~40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis-frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis-frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6-7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7-2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for ~60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis.

TTR-related amyloid neuropathy: clinical, electrophysiological and pathological findings in 15 unrelated patients.

Familial amyloid polyneuropathy (FAP) is a rare condition caused by mutations of the transthyretin (TTR) gene and it is generally characterized by a length-dependent polyneuropathy affecting prevalently the small fibers. We reviewed clinical, electrophysiological and pathological findings of 15 unrelated patients with genetically confirmed TTR-FAP. All patients presented a progressive sensory-motor polyneuropathy. Pathological findings were negative for amyloid deposits in about half of the cases. Sequence analysis of TTR gene revealed the presence of three different mutations (p.Val30Met, p.Phe64Leu, and p.Ala120Ser). The p.Val30Met was the most frequently identified mutation and it often occurred in apparently sporadic cases. Conversely, the p.Phe64Leu generally presented in a high percentage of familial cases in patients coming from Southern Italy. Clinicians should consider, to avoid misdiagnosis, the screening for TTR mutations in patients presenting with progressive axonal polyneuropathy of undetermined etiology, including apparently sporadic cases with pathological examinations negative for amyloid deposition.

Characterization of SOD1-DT, a Divergent Long Non-Coding RNA in the Locus of the SOD1 Human Gene.

Researchers studying Amyotrophic Lateral Sclerosis (ALS) have made significant efforts to find a unique mechanism to explain the etiopathology of the different forms of the disease. However, despite several mutations associated with ALS having been discovered in recent years, the link between the mutated genes and its onset has not yet been fully elucidated. Among the genes associated with ALS, superoxide dismutase 1 (SOD1) was the first to be identified, but its role in the etiopathogenesis of the disease is still unclear. In recent years, research has been focused on the non-coding part of the genome to fully understand the mechanisms underlying gene regulation. Non-coding RNAs are conserved molecules and are not usually translated in protein. A total of 98% of the human genome is composed of non-protein coding sequences with roles in the transcriptional and post-transcriptional regulation of gene expression. In this study, we characterized a divergent nuclear lncRNA (SOD1-DT) transcribed in the antisense direction from the 5' region of the SOD1 coding gene in both the SH-SY5Y cell line and fibroblasts derived from ALS patients. Interestingly, this lncRNA seems to regulate gene expression, since its inhibition leads to the upregulation of surrounding genes including SOD1. SOD1-DT represents a very complex molecule, displaying allelic and transcriptional variability concerning transposable elements (TEs) included in its sequence, widening the scenario of gene expression regulation in ALS disease.

Analysis of STMN2 CA repeats in italian ALS patients shows no association.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease caused by a complex interaction of genetic and environmental factors. Recently, a polymorphic intronic CA repeat in STMN2 gene has been proposed as risk factor for ALS. The presence of long/long CA genotype, especially if one allele had 24 CA, was reported to be significantly associated with the disease in a cohort of sporadic ALS patients. We tested an Italian cohort of 366 ALS patients and 353 healthy controls and we found no association between CA length and ALS risk.

Oral anticoagulants in fragile patients with percutaneous endoscopic gastrostomy and atrial fibrillation: the ORIGAMI pilot investigation.

BACKGROUND: Extensive data support the superior safety without any trade-off in efficacy of direct oral anticoagulants (DOACs) compared to vitamin K antagonists (VKA) in patients with nonvalvular atrial fibrillation, deep venous thrombosis or pulmonary embolism. Whether DOACs may be successfully used to treat complex and fragile patients with percutaneous endoscopic gastrostomy (PEG) remains to be proven. The purpose of this pilot study was to evaluate the feasibility, anticoagulant effect, and preliminary safety/efficacy profile of edoxaban administered via PEG in patients with an indication for long-term oral anticoagulation. METHODS: In this prospective, single-arm, pilot study, 12 patients with PEG and guideline-recommended indication for anticoagulation for nonvalvular atrial fibrillation were prospectively enrolled. Crushed edoxaban at approved doses was administered via PEG. Quantitative measures of edoxaban's antifactor Xa activity were performed at steady state. Thromboembolic and bleeding events were assessed at one-month follow-up. RESULTS: Steady state edoxaban plasma levels were at therapeutic range in all patients; mean plasma concentration was 208.5 (±78.6) ng/mL. At one month follow-up, none had suffered a thromboembolic event; one developed minor bleeding, and one died from non-cardiovascular death, owing to sudden worsening of a pre-existing underlying severe condition. CONCLUSIONS: In this pilot investigation, we report for the first time that crushed edoxaban, administered at approved doses through PEG in fragile and complex patients, is feasible, results in therapeutic edoxaban concentrations, and is apparently effective and safe.

Classification of familial amyotrophic lateral sclerosis by family history: effects on frequency of genes mutation.

OBJECTIVE: To classify familial amyotrophic lateral sclerosis (FALS) on the base of family history, and to determine whether frequency of mutations in major amyotrophic lateral sclerosis (ALS) genes varies in different FALS categories. METHODS: Included in the study are 53 FALS families. Patients were classified as definite, probable and possible FALS, according to recently proposed criteria. Seven ALS-associated genes, including SOD1, TARDBP, FUS, ANG, ATXN2, OPTN and C9ORF72, were analysed. RESULTS: Thirteen patients (24.5%) were included in the definite group. The great majority of our FALS cases (40/53, 75.5%) were families with only two affected relatives; of these, 31 (58.5%) were included in the probable, and 9 (17%) in the possible FALS categories. The percentage of mutations was 61.5% in definite, 41.9% in probable and 11.1% in possible FALS. With respect to probable FALS, if cases with parent-to-child transmission of the disease were considered separately, the mutational load increased to 61.5%, as observed in definite FALS. CONCLUSIONS: Our findings provide evidence that frequency of mutations in currently known ALS genes varies widely among different FALS categories. Families with only two affected relatives have heterogeneous genetic components, the chance to detect mutations being higher in cases with parent-to-child transmission.

Replication of association of CHRNA4 rare variants with sporadic amyotrophic lateral sclerosis: the Italian multicentre study.

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels widely expressed throughout the mammalian brain, including bulbar and spinal motor neurons. They are involved in neuroprotection and in control of release of many neurotransmitters, including glutamate. Previous data raised the hypothesis that rare variants in the region coding the intracellular loop subunits of nAChRs might represent one of several genetic risk factors for SALS. The aim of present study was to replicate the study in an independent cohort of ALS patients. We analysed 718 sporadic ALS patients from five Italian ALS centres and 1300 ethnically matched controls. We focused primarily on CHRNA4, encoding α4 subunit, since most mutations were previously detected in this gene. We observed a significant association between CHRNA4 mutations and ALS (OR 2.91; 95% CI 1.4080-6.0453; p = 0.0056). Most mutations detected in patients were not present in the dbSNP134 and in 3500 ethnically matched control chromosomes and affected evolutionary conserved amino acid residues. In conclusion, the present data confirm that CHRNA4 variants are overrepresented in SALS strengthening the hypothesis can they act as predisposing genetic factors for SALS.

Sural nerve pathology in ALS patients: a single-centre experience.

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of upper and lower motor neurons. Sensory involvement is thought not to be a feature of ALS. We reviewed 17 cases of sural nerve biopsies performed in a large cohort of ALS patients referred to our centre over a 23-year period. More than two-third of biopsies revealed a variable degree of axonal loss. In one case, pathological findings suggested the concomitant presence of an inherited neuropathy, subsequently confirmed by genetic evaluation. In another case, pathological and neurographic data were similar to those of an inflammatory demyelinating neuropathy, but the clinical course corroborated the diagnosis of ALS. Our data confirm that sensory nerve involvement may be found in ALS patients. This finding should prompt physicians to carefully investigate a possible alternative diagnosis, but does not exclude the possibility that the patient may have ALS.

Generation of an induced pluripotent stem cell line (UCSCi002-A) from a patient with a variant in TARDBP gene associated with familial amyotrophic lateral sclerosis and frontotemporal dementia.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that selectively affects motor neurons. In 20% of cases, ALS appears in comorbidity with frontotemporal dementia (FTD). We generated patient-derived-induced Pluripotent Stem Cells (iPSCs), from an ALS/FTD patient. The patient had a familial form of the disease and a missense variant in TARDBP gene. We used an established protocol based on Sendai virus to reprogram fibroblasts. We confirmed the stemness and the pluripotency of the iPSC clones, thus generating embryoid bodies. We believe that the iPSC line carrying a TARDBP mutation could be a valuable tool to investigate TDP-43 proteinopathy linked to ALS.

Thr124Met myelin protein zero mutation mimicking motor neuron disease.

Mutations in myelin protein zero (MPZ) are associated with heterogeneous manifestations. In this study, we report clinical, electrophysiological, pathological, and muscle MRI findings from two relatives with MPZ Thr124Met variants, disclosing different phenotypes. The proband was a 73-year-old female with a 12-year-story of atrophy, weakness, and fasciculations in her proximal and distal lower limbs. EMG examination showed neurogenic signs with active denervation together with reduced sensory action potentials, without sensory symptoms. The initial diagnosis was of a slowly progressive lower motor neuron disease (MND) with subclinical sensory axonal neuropathy. Two years later, the observation of her 60-year-old nephew, who had a distal sensory-motor neuropathy, prompted the analysis of inherited neuropathies-related genes and revealed a MPZ Thr124Met mutation in both cases. Our findings expand the clinical spectrum of MPZ-related neuropathy and highlight that Thr124Met mutation may cause a syndrome mimicking MND. The challenging issue to detect sensory features in the diagnostic MND work up is discussed.