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Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous diseases caused by mutations affecting neuromuscular transmission. Even if the first symptoms mainly occur during childhood, adult neurologists must confront this challenging diagnosis and manage these patients throughout their adulthood. However, long-term follow-up data from large cohorts of CMS patients are lacking, and the long-term prognosis of these patients is largely unknown. We report the clinical features, diagnostic difficulties, and long-term prognosis of a French nationwide cohort of 235 adult patients with genetically confirmed CMS followed in 23 specialized neuromuscular centres. Data were retrospectively analysed. Of the 235 patients, 123 were female (52.3%). The diagnosis was made in adulthood in 139 patients, 110 of whom presented their first symptoms before the age of 18. Mean follow-up time between first symptoms and last visit was 34 years [standard deviation (SD) = 15.1]. Pathogenic variants were found in 19 disease-related genes. CHRNE -low expressor variants were the most common (23.8%), followed by variants in DOK7 (18.7%) and RAPSN (14%). Genotypes were clustered into four groups according to the initial presentation: ocular group (CHRNE -LE, CHRND , FCCMS), distal group (SCCMS), limb-girdle group (RAPSN , COLQ , DOK7 , GMPPB , GFPT1), and a variable-phenotype group (MUSK , AGRN). The phenotypical features of CMS did not change throughout life. Only four genotypes had a proportion of patients requiring intensive care unit admission that exceeded 20%: RAPSN (54.8%), MUSK (50%), DOK7 (38.6%) and AGRN (25.0%). In RAPSN and MUSK patients most ICU admissions occurred before age 18 years and in DOK7 and AGRN patients at or after 18 years of age. Different patterns of disease course (stability, improvement and progressive worsening) may succeed one another in the same patient throughout life, particularly in AGRN, DOK7 and COLQ. At the last visit, 55% of SCCMS and 36.3% of DOK7 patients required ventilation; 36.3% of DOK7 patients, 25% of GMPPB patients and 20% of GFPT1 patients were wheelchair-bound; most of the patients who were both wheelchair-bound and ventilated were DOK7 patients. Six patients died in this cohort. The positive impact of therapy was striking, even in severely affected patients. In conclusion, even if motor and/or respiratory deterioration could occur in patients with initially moderate disease, particularly in DOK7 , SCCMS and GFPT1 patients, the long-term prognosis for most CMS patients was favourable, with neither ventilation nor wheelchair needed at last visit. CHRNE -LE patients did not worsen during adulthood and RAPSN patients, often severely affected in early childhood, subsequently improved. [ABSTRACT FROM AUTHOR]

Background and Aims: Pathogenic variants in the NARS1 gene, which encodes for the asparaginyl‐tRNA synthetase1 (NARS1) enzyme, were associated with complex central and peripheral nervous system phenotypes. Recently, Charcot–Marie–Tooth (CMT) disease has been linked to heterozygous pathogenic variants in NARS1 in nine patients. Here, we report two brothers and their mother from a French family with distal hereditary motor neuropathy (dHMN) carrying a previously unreported NARS1 variant. Methods: The NARS1 variant (c.1555G>C; p.(Gly519Arg)) was identified through whole‐genome sequencing (WGS) performed on the family members. Clinical findings, nerve conduction studies (NCS), needle electromyography (EMG), and functional assays in yeast complementation assays are reported here. Results: The family members showed symptoms of dHMN, including distal weakness and osteoarticular deformities. They also exhibited brisk reflexes suggestive of upper motor neuron involvement. All patients were able to walk independently at the last follow‐up. NCS and EMG confirmed pure motor neuropathy. Functional assays in yeast confirmed a loss‐of‐function effect of the variant on NARS1 activity. Interpretation: Our findings expand the clinical spectrum of NARS1‐associated neuropathies, highlighting the association of NARS1 mutations with dHMN. The benign disease course observed in our patients suggests a slowly progressive phenotype. Further reports could contribute to a more comprehensive understanding of the spectrum of NARS1‐associated neuropathies. [ABSTRACT FROM AUTHOR]

Background and Aims Methods Results Interpretation Porphyrias are inherited metabolic disorders caused by mutations in genes encoding enzymes involved in the heme biosynthetic pathway, leading to the accumulation of heme precursors. Acute hepatic porphyrias (AHP), including acute intermittent porphyria (AIP), can present with predominant peripheral neurological manifestations, often leading to a misdiagnosis as Guillain‐Barré syndrome.We report a case of AIP initially presenting as a peripheral neuropathy mimicking Parsonage‐Turner syndrome (neuralgic amyotrophy, NA). Clinical and electrophysiological evaluations were conducted, including nerve conduction studies and needle electromyography (EMG).A 41‐year‐old woman presented with burning pain and electric shock‐like sensations in the shoulders and trunk, alongside asymmetrical motor weakness in the upper limbs affecting arm abduction and finger extension. Electrophysiological evaluation revealed involvement of the superior trunk of the brachial plexus and the posterior interosseous nerve. Initially diagnosed with NA, she showed significant improvement in proximal strength over nine months but relapsed at fourteen months with severe finger extension weakness. Concurrent severe abdominal pain with constipation led to the identification of elevated urinary porphobilinogen (PBG) and delta‐aminolevulinic acid (ALA) levels, confirming AHP and specifically AIP via genetic and biochemical testing. The patient received hemin and givosiran infusions, resulting in decreased ALA levels, improvement of motor weakness, and no further attacks.This case underscores the need to consider AIP in the differential diagnosis of acute neuropathies like NA, especially when accompanied by abdominal pain and severe constipation. Early recognition and appropriate testing for PBG and ALA can prevent misdiagnosis and enable targeted treatment. [ABSTRACT FROM AUTHOR]

Distal hereditary motor neuropathy represents a group of motor inherited neuropathies leading to distal weakness. We report a family of two brothers and a sister affected by distal hereditary motor neuropathy in whom a homozygous variant c.3G > T (p.1Met? ) was identified in the COQ7 gene. This gene encodes a protein required for Coenzyme Q10 biosynthesis, a component of the respiratory chain in mitochondria. Mutations of COQ7 were previously associated with severe multi-organ disorders characterized by early childhood onset and developmental delay. Using patient blood sample and fibroblasts derived from a skin biopsy, we investigated the pathogenicity of the variant of unknown significance c.3G > T (p.1Met? ) in the COQ7 gene and the effect of Coenzyme Q10 supplementation in vitro. We showed that this variation leads to a severe decrease in COQ7 protein levels in the patient's fibroblasts, resulting in a decrease in Coenzyme Q10 production, and in the accumulation of 6-demethoxycoenzyme Q10, the COQ7 substrate. Interestingly, such accumulation was also found in the patient's plasma. Normal Coenzyme Q10 and 6-demethoxycoenzyme Q10 levels were restored in vitro by using the Coenzyme Q10 precursor 2,4-dihydroxybenzoic acid, thus bypassing COQ7 requirement. Coenzyme Q10 biosynthesis deficiency is known to impair mitochondrial respiratory chain. Seahorse experiments showed that the patient's cells mainly rely on glycolysis to maintain sufficient ATP production. Consistently, the replacement of glucose by galactose in the culture medium of these cells reduced their proliferation rate. Interestingly, normal proliferation was restored by Coenzyme Q10 supplementation in the culture medium, suggesting a therapeutic avenue for these patients. Altogether, we have identified the first example of recessive distal hereditary motor neuropathy caused by a homozygous variation in the COQ7 gene, which should thus be included in the gene panels used to diagnose peripheral inherited neuropathies. Furthermore, 6-demethoxycoenzyme Q10 accumulation in the blood can be used to confirm the pathogenic nature of the mutation. Finally, supplementation with Coenzyme Q10 or derivatives should be considered to prevent the progression of COQ7-related peripheral inherited neuropathy in diagnosed patients. [ABSTRACT FROM AUTHOR]