Search

Congenital myasthenic syndromes (CMS) are a group of heterogeneous diseases of the neuromuscular junction. We report electrodiagnostic testing (EDX) and genetic findings in a series of 120 CMS patients tested with a simple non-invasive EDX workup with surface recording of CMAPs and 3Hz repetitive nerve stimulation of accessory, radial and deep fibular nerves. Five ENMG phenotypes were retrieved based on the presence or not of R-CMAPs and the distribution pattern of decremental CMAP responses which significantly correlated with genetic findings (p0.00001). R-CMAPs were found in all COLQ-mutated patients (CMS1A) and Slow Channel CMS (SCCMS) (CMS1B). CMS1A exhibited greater decrements in accessory nerve RNS than CMS1B. Patients without R-CMAPs were classified into CMS2A (DOK7-, MUSK-, GFPT1-, GMPPB-, TOR1AIP-mutated) when exhibiting predominant accessory nerve RNS decrements, CMS2B (CHRNE, CHRND, RAPSN) with predominant radial nerve RNS decrements, or CMS2C (AGRN) if there were predominant fibular decrements. Our algorithm may have a major impact on diagnostic and therapeutic monitoring in CMS patients, as well as for validation of the pathogenicity of genetic variants. It should also be part of the evaluation of unexplained muscle weakness or complex neuromuscular phenotypes.

We report three siblings from a non-consanguineous family presenting with contractural limb-girdle phenotype with intrafamilial variability. Muscle MRI showed posterior thigh and quadriceps involvement with a sandwich-like sign. Whole-exome sequencing identified two compound heterozygous missense TTN variants and one heterozygous LAMA2 variant. Brain MRI performed because of concentration difficulties in one of the siblings evidenced white-matter abnormalities, subsequently found in the others. The genetic analysis was re-oriented, revealing a novel pathogenic intronic LAMA2 variant which confirmed the LAMA2-RD diagnosis. This work highlights the importance of a thorough clinical phenotyping and the importance of brain imaging, in order to orientate and interpret the genetic analysis.

International audience; Background: The latest practice guidelines from the American College of Cardiology/American Heart Association recommend the prescription of an ACE-i for patients presenting with non-ischemic cardiomyopathy when left ventricular ejection fraction (LVEF) falls below 40%. Objective: To determine if the initiation of treatment with an angiotensin-converting enzyme inhibitor (ACE-i) earlier than recommended by practice guidelines issued by professional societies improves the long-term cardiac outcomes of patients presenting with Becker muscular dystrophy (MD) cardiomyopathy. Methods: From a multicenter registry of Becker MD, we selected retrospectively patients presenting between January 1990 and April 2019 with a LVEF ≥40 and ≤49%. We used a propensity score analysis to compare the risk of a) hospitalization for management of heart failure (HF), and b) a decrease in LVEF to

BACKGROUND AND PURPOSE Preparations for clinical trials of unfolded protein response (UPR) inhibitors (such as Sephin1) that target the upregulated UPR in patients with Charcot-Marie-Tooth disease (CMT) carrying MPZ mutations are currently underway. The inclusion criteria for these trials are still being formulated. Our objective was to characterize the relation between genotypes and phenotypes in patients with CMT caused by MPZ mutations, and to refine the inclusion criteria for future trials. METHODS Clinical and neurophysiological data of CMT patients with MPZ mutations were retrospectively collected at 11 French reference centers. RESULTS Forty-four mutations in MPZ were identified in 91 patients from 61 families. There was considerable heterogeneity. The same mutation was found to cause either axonal or demyelinating neuropathy. Three groups were identified according to the age at disease onset. CMT Examination Score (CMTES) tended to be higher in the early (≤22 years) and adult (23-47 years) onset groups (mean CMTESv2 = 10.4 and 10.0, respectively) than in the late onset group (>47 years, mean CMTESv2 = 8.6, p = 0.47). There was a significant positive correlation between CMTESv2 and the age of patients in Groups I (p = 0.027) and II (p = 0.023), indicating that clinical severity progressed with age in these patients. CONCLUSIONS To optimize the selection of CMT patients carrying MPZ mutations for the upcoming trials, inclusion criteria should take into account the pathophysiology of the disease (upregulated UPR). Recruited patients should have a mild to moderate disease severity and a disease onset at between 18 and 50 years, as these patients exhibit significant disease progression over time.

Eight patients from five families with undiagnosed dominant distal myopathy underwent clinical, neurophysiological and muscle biopsy examinations. Molecular genetic studies were performed using targeted sequencing of all known myopathy genes followed by segregation of the identified mutations in the affected families using Sanger sequencing. Two novel mutations in DNAJB6 J domain, c.149C>T (p.A50V) and c.161A>C (p.E54A), were identified as the cause of disease. The muscle involvement with p.A50V was distal calf-predominant, and the p.E54A was more proximo-distal. Histological findings were similar to those previously reported in DNAJB6 myopathy. In line with reported pathogenic mutations in the glycine/phenylalanine (G/F) domain of DNAJB6, both the novel mutations showed reduced anti-aggregation capacity by filter trap assay and TDP-43 disaggregation assays. Modeling of the protein showed close proximity of the mutated residues with the G/F domain. Myopathy-causing mutations in DNAJB6 are not only located in the G/F domain, but also in the J domain. The identified mutations in the J domain cause dominant distal and proximo-distal myopathy, confirming that mutations in DNAJB6 should be considered in distal myopathy cases.

Fatigue is one of the most disabling symptoms in Multiple Sclerosis (MS) patients and is associated with a low quality of life. Fingolimod (Fg), a sphingosine 1-phosphate receptor modulator, is the first oral MS disease modifying treatment. Little is known about its effect on fatigue. To assess the impact of Fg on fatigue within the first 6 months of treatment in MS patients, we conducted a prospective, open label study, in real life setting.Change of Modified Fatigue Impact Scale (MFIS) between Fg treatment start and at 6 months was used as a first outcome. Secondary outcomes were changes of MFIS subscales, Fatigue severity scale (FSS) and Visual Analogic Scale of Fatigue (VAS-F) scores, RESULTS: 54 completed the study at M6. No significant change was noted in global MFIS (and neither in sub analysis of MFIS), FSS or VAS-F at M6. Patients with high level of fatigue (MFIS or ≥38) had a higher EDSS score than patients with lower level of fatigue (MFIS38), (mean 3.3, [SD 1.6] versus 1.6 [SD1.1], p=0.0002) but showed no significant difference in MFIS evolution at M6. There was no significant statistical difference in fatigue parameters evolution at M6 within patients Nz+ or Nz-.There is no significant impact of Fg on fatigue after 6 months of treatment.

PIEZO2 mutations have been described in dominant arthrogryposis, but homozygous mutations of PIEZO2 may also be responsible for more complex clinical patterns, associating distal arthrogryposis, neonatal respiratory insufficiency, scoliosis and proprioceptive impairment. We report here two sisters presenting with these clinical and genetic features. They had a similar phenotype, with severe hypotonia and respiratory distress at birth, delayed acquisition of motor milestones and need of scoliosis surgery. Hypotonia and alteration of proprioception were at the forefront of clinical examination for both, along with areflexia, hyperlaxity, cutis laxa, and discrete facial dysmorphy. Electrophysiological studies, including electroneuromyography and sensory evoked potentials, showed a mild sensory axonopathy without any myopathic features, but revealed a peripheral proximal lemniscal defect. Creatine kinase, muscular MRI and biopsy were normal, as well as cerebral MRI and neurometabolic biological explorations. They had a moderate restrictive syndrome on respiratory function tests and cardiac function was normal. Molecular studies performed on a panel of genes involved in distal arthrogryposis disclosed a nonsense homozygous c.3241C > T (p.Arg1051*) mutation in the PIEZO2 gene, which was also present at the heterozygous state in their mother's DNA. This new PIEZO2 mutation was in accordance with the phenotype combining arthrogryposis, scoliosis, hyperlaxity and proprioceptive impairment.

To describe the phenotype and the response to folinic acid supplementation of cerebral folate deficiency (CFD) in adults, a disorder diagnosed on low 5-methyltetrahydro-folate (5MTHF) in cerebrospinal fluid (CSF), which can correspond to a inherited disorder of folate metabolism (IDFM) or to a metabolic consequence of various neurological diseases.We conducted a retrospective study on 224 adult patients with neurological symptoms who had a 5MTHF CSF dosage, collecting their neurologic and neuroimaging data.69 patients had CFD (CSF 5MTHF level 41 nmol/L), 25 of them had severe CFD (sCFD; ≤25 nmol/L) with adult onset neurological symptoms in 41%. 56% of sCFD patients had an underlying identified neurologic disorder, mainly mitochondrial diseases, hepatic encephalopathy and primary brain calcifications (no identified IDFM), the others were classified as undiagnosed. sCFD patients presented most frequently pyramidal syndrome (75%), movement disorders (56%), cerebellar syndrome (50%) and intellectual disability (46%). MRI findings mostly showed white matter abnormalities (WMA; 32%) and calcifications (12%), and were normal in 23%. The clinico-radiological phenotype of sCFD patients was not clearly different from non CFD patients in terms of manifestations frequency. However, their neurological picture was more complex with a higher number of combined neurological symptoms (4.7±1.6 vs 3.4±1.7, p = .01). In Magnetic Resonance Spectroscopy (MRS), Choline/Creatine (Cho/Cr) ratio was lower in sCFD patients (n = 7) compared to non-CFD patients (n = 73) (p = .005), with good sensitivity (71%) and excellent specificity (92%). Among twenty-one CFD patients treated with folinic acid, nine had a sustained improvement, all with sCFD but one (50% of sCFD patients improved). In two undiagnosed patients with extremely low 5MTHF CSF values, MRI WMA and low Cho/Cr ratios, folinic acid treatment leaded to a dramatic clinical and radiological improvement.CSF 5MTHF dosage should be considered in patients with mitochondrial diseases, primary brain calcifications and unexplained complex neurological disorders especially if associated with WMA, since folinic acid supplementation in patients with sCFD is frequently efficient.

Introduction Le fingolimod est reserve aux formes actives de scleroses en plaques remittentes. Certains patients alleguent une fatigue plus marquee sous traitement. Or peu de donnees existent concernant son impact sur ce symptome. Objectifs Nous avons voulu mesurer l’evolution de la fatigue ressentie chez des patients suivis pour une SEP remittente avant et pendant le traitement par fingolimod. Methodes Cette etude monocentrique prospective observationnelle a inclus consecutivement 38 patients SEP hospitalises pour initiation d’un traitement par fingolimod. Deux auto-questionnaires valides (MFIS et FSS) et une echelle visuelle (VAS) mesurant leur fatigue etaient completes le jour de l’initiation et a 6 mois. Les caracteristiques cliniques et demographiques ainsi que les donnees radiologiques ont ete detaillees. L’impact du traitement sur la fatigue est mesure par le taux de variation de la MFIS entre M0 et M6. Resultats L’âge moyen etait de 35 ans. A M0, le score moyen de l’EDSS etait a 3, de la MFIS a 43, de la FFS a 42 et de la VAS a 6. A M6, les 15 premiers patients avaient un EDSS moyen a 3, une MFIS a 44, une FSS a 39 et une VAS a 7. Bien que les scores ne different pas de M0 a M6 le score MFIS pour chaque patient etait augmente en moyenne de 62 %, variation plus marquee sur les items physique (73 %) et cognitif (86 %) que psychosocial (14 %). Quatre patients avaient presente au moins 1 poussee et deux avaient progresse sur l’IRM. Discussion La fatigue est une plainte frequente au cours de la SEP (pour plus de 70 % des patients), et peut jouer un role majeur dans le handicap. Au vu de ces resultats preliminaires, le fingolimod semble majorer ce symptome, en particulier sur les plans physique et cognitif, independamment de l’activite clinique ou radiologique de la maladie. Les resultats sur l’ensemble de la cohorte seront presentes au congres (objectif de 40 patients). Conclusion Les resultats de cette etude reveleront si la fatigue alleguee par certains patients est en rapport avec le traitement par fingolimod. Il se discutera alors de prendre en compte ce symptome lors sa prescription.

Introduction Nous rapportons le cas d’un syndrome de la queue de cheval d’aggravation progressive, aboutissant au diagnostic de lymphome B de la zone marginale, lie a une arachnoidite chronique avec infiltration des racines lombosacrees. Observation Une patiente de 73 ans fut hospitalisee en 2014 pour des troubles de la marche avec lombo-radiculalgies, et incontinence urinaire et fecale, s’aggravant progressivement depuis 3 ans. Plusieurs bilans exhaustifs avaient ete pratiques (dont 2 biopsies meningees) sans diagnostic etabli. La corticotherapie debutee depuis plusieurs mois avait permis une amelioration transitoire. A l’examen, on notait une paraparesie, une ataxie proprioceptive, sans autre signe general qu’un syndrome sec. Les IRM du nevraxe montrerent un aspect d’arachnoidite lombosacree avec prise de contraste des meninges et des racines de la queue de cheval tres epaissies, et une hydrocephalie communicante tetraventriculaire. L’analyse du LCR ramenait une meningite lymphocytaire (496/mm 3 ) avec 22 % de lymphocytes B actives monotypiques, une proteinorachie a 13 g/L et une elevation des IL6 et 10. On retrouvait un pic monocolonal IgM serique, une sialadenite grade 4 et a l’EMG une neuropathie axonale avec radiculopathie L4-L5. Le bilan systemique (TDM-TAP, BOM, FOGD) etait negatif. Une nouvelle biopsie radiculaire conclut a un lymphome B de la zone marginale (MALT), infiltrant directement les racines nerveuses. Un traitement par rituximab et chloraminophene fut debute. Discussion Les lymphomes du MALT du systeme nerveux sont rares. Ils se developpent volontiers dans les zones d’agregation meningotheliales, se presentant comme une masse durale intracrânienne mimant un meningiome. Nous n’avons pas trouve de cas similaire se revelant par une atteinte meningoradiculaire isolee. Cette observation interroge sur l’origine primitivement peripherique (neurolymphomatose) du MALT et sur son lien avec un syndrome de Sjogren. Conclusion Ce cas decrit une presentation exceptionnelle de lymphome du MALT sous une forme meningo-radiculaire isolee, qui elargit le spectre clinique de la maladie. Informations complementaires Remerciements : Dr Fouad Skandrani, Dr Frederic Charlotte, Dr Delphine Larrieu-Ciron.