To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular and/or bulbar motor weakness, in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurological symptoms. Main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia) (n=45, 100%), motor weakness (n=18, 40%), ophthalmoplegia (n=20, 45%) and bulbar symptoms (n=6, 13%). Forty five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiological studies showed a demyelinating or axonal pattern in respectively 60 and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40). Overt hematologic malignancies were diagnosed in 16 patients (36%), most frequently Waldenström macroglobulinemia (n=9, 20%). Forty-one patients (91%) required treatment for CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with respectively 53 and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line and rituximab-based regimens for second-line treatment. These compiling data argue for CANOMAD to be included in neurological monoclonal gammopathy of clinical significance.

Patients with antibodies to clustered AChR account for a significant proportion of SNMG patients and resemble patients with AChR antibodies detected by standard radio-immunoprecipitation.

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Pinnatoxins (PnTXs) are a group of emerging marine biotoxins produced by the benthic dinoflagellate Vulcanodinium rugosum, currently not regulated in Europe or in any other country in the world. In France, PnTXs were detected for the first time in 2011, in mussels from the Ingril lagoon (South of France, Mediterranean coast). Since then, analyses carried out in mussels from this lagoon have shown high concentrations of PnTXs for several months each year. PnTXs have also been detected, to a lesser extent, in mussels from other Mediterranean lagoons and on the Atlantic and Corsican coasts. In the French data, the main analog is PnTX G (low levels of PnTX A are also present in some samples). No cases of PnTXs poisoning in humans have been reported so far in France or anywhere else in the world. In mice, PnTXs induce acute neurotoxic effects, within a few minutes after oral administration. Clinical signs of toxicity include decreased mobility, paralysis of the hind legs, tremors, jumps and breathing difficulties leading to death by respiratory arrest at high doses. The French agency for food safety (ANSES) recently conducted a review of the state of knowledge related to PnTXs and V. rugosum. Based on (i) the clinical signs of toxicity in mice, (ii) the mode of action of PnTXs as nicotinic acetylcholine receptor competitive antagonists and (iii) knowledge on drugs and natural toxins with PnTX-related pharmacology, potential human symptoms have been extrapolated and proposed. In this work, a provisional acute benchmark value for PnTX G of 0.13 μg/kg bw per day has been derived from an oral Please note that this is an author-produced PDF of an article accepted for publication following peer review. The definitive publisher-authenticated version is available on the publisher Web site.acute toxicity study in mice. Based on this value and a large shellfish meat portion size of 400g, a concentration lower than 23 μg PnTX G/kg shellfish meat is not expected to result in adverse effects in humans. ANSES recommends taking into account PnTXs in the French official monitoring program for shellfish production and identified data gaps to refine health risk assessment. Highlights► A state of knowledge of PnTXs and Vulcanodinium rugosum is proposed. ► A provisional acute healthbased guidance value for PnTX G of 0.13 μg/kg bw per day has been derived. ► PnTXs in shellfish should not exceed 23 μg PnTX G/kg. ► PnTXs should be included in national official monitoring programs for shellfish production. ► This work is a major step forward in taking into account this emerging hazard.

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The cyanotoxin β-methylamino-L-alanine (BMAA) has received renewed attention as an environmental risk factor for sporadic cases of amyotrophic lateral sclerosis (ALS) (Nunn et al., Brain Res 410:375-379, 1987). The aim of the present study was to develop and to validate an analytical procedure that allows the quantification of native BMAA and of its natural isomer, 2,4 diaminobutyric acid (DAB), in brain tissues. An analytical procedure was previously reported by our group for the determination of underivatized BMAA in environmental samples. It included a step of sample clean-up by solid phase extraction (SPE) with a mixed-mode sorbent and the analyses were performed by LC/MS-MS using hydrophilic interaction chromatography and multiple reactions monitoring scan mode. As brain tissues have a higher lipid content, the crucial step of sample clean-up had been optimized by evaluating the efficiency of the addition of a liquid/liquid extraction step prior to the SPE procedure or alternatively, of washing steps to the SPE extraction procedure. The efficiency was checked by visualizing the complexity of the resulting chromatograms in LC/MS and their performance by using spiked brain samples. The optimized analytical procedure, including a washing step with cyclohexane to the SPE with a recovery yield close to 100%, was validated using the total error approach and allowed the quantification of BMAA in a concentration level ranging from 20 to 1,500 ng/g in brain samples. Finally, the feasibility of implementation of this procedure was verified in human brain samples from two patients who died of ALS.

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