Ovarian failure (OF) at age <40 years occurs in ∼1% of all women. Other than karyotype abnormalities, very few genes are known to be associated with this ovarian dysfunction. We studied eight ...patients who presented with premature OF and white-matter abnormalities on magnetic resonance imaging. Neurological signs may be absent or present after OF. In seven patients, we report for the first time mutations in three of the five
EIF2B genes (
EIF2B2, -4, and
-5) that were recently shown to cause childhood ataxia with central nervous system hypomyelination/vanishing white-matter disease leukodystrophy. The correlation we observed between the age at onset of the neurological deterioration and the severity of OF suggests a common pathophysiological pathway.
We reported the laboratory phenotype of a monoclonal IgM-lambda against disialylated gangliosides, in a 81-year-old man admitted to a neurological department because of the progressive development of ...distal paresthesias, gait unsteadiness, difficulty to walk and having falls. Serological studies revealed an IgM monoclonal protein with lambda light chain component of MGUS type. IgM level was 4 g/L. The positive laboratory studies showed high titers of IgM antibodies in excess of 1/10(5) against specific disialylated gangliosides including GD1b, GD3, GT1b and GQ1b. There was no serum IgM binding to MAG and SGPG/SGLPG. Clonality by in-house immunodot of ganglioside antibodies was demonstrated using kappa and lambda light chain specific antibodies. Light chain subtype of the anti-ganglioside antibody activity and monoclonal IgM was lambda subtype. The reactivity at high titers was against gangliosides containing the disialosyl epitope. The clinical and laboratory features have been described under the acronym CANOMAD: Chronic Ataxic Neuropathy with Ophthalmoplegia, M proteins, cold Agglutinins and Disialosyl antibodies. Administration of IVIg produced a significant neurological improvement during six years. Then the neuropathy became refractory in the IVIg and worsened in severity, a cure by Rituximab® was established. The patient died from a pneumopathy only two months later. Monoclonal IgM binding to disialylated gangliosides have high level of specificity for diagnosis of the CANOMAD syndrome.
Demyelinating Charcot–Marie–Tooth 4G (CMT4G) results from a recessive mutation in the 5′UTR region of the Hexokinase 1 (HK1) gene. HK participates in mitochondrial calcium homeostasis by binding to ...the Voltage-Dependent Anion Channel (VDAC), through its N-terminal porin-binding domain. Our hypothesis is that CMT4G mutation results in a broken interaction between mutant HK1 and VDAC, disturbing mitochondrial calcium homeostasis. We studied a cohort of 25 CMT4G patients recruited in the French gypsy population. The disease was characterized by a childhood onset, an intermediate demyelinating pattern, and a significant phenotype leading to becoming wheelchair-bound by the fifth decade of life. Co-IP and PLA studies indicated a strong decreased interaction between VDAC and HK1 in the patients' PBMCs and sural nerve. We observed that either wild-type HK1 expression or a peptide comprising the 15 aa of the N-terminal wild-type HK1 administration decreased mitochondrial calcium release in HEK293 cells. However, mutated CMT4G HK1 or the 15 aa of the mutated HK1 was unable to block mitochondrial calcium release. Taken together, these data show that the CMT4G-induced modification of the HK1 N-terminus disrupts HK1-VDAC interaction. This alters mitochondrial calcium buffering that has been shown to be critical for myelin sheath maintenance.
X-linked Myopathy with Excessive Autophagy (XMEA) is a rare autophagic vacuolar myopathy caused by mutations in the Vacuolar ATPase assembly factor
gene; onset usually occurs during childhood and ...rarely occurs during adulthood. We described a 22-year-old patient with XMEA, whose onset was declared at 11 through gait disorder. He had severe four-limb proximal weakness and amyotrophy, and his proximal muscle MRC score was between 2 and 3/5 in four limbs; creatine kinase levels were elevated (1385 IU/L), and electroneuromyography and muscle MRI were suggestive of myopathy. Muscle biopsy showed abnormalities typical of autophagic vacuolar myopathy. We detected a hemizygous, unreported, intronic, single-nucleotide substitution c.164-20T>A (NM_001017980.4) in intron 2 of the
gene. Fibroblasts derived from this patient displayed a reduced level of
transcripts (at 40% of normal) and protein, suggesting a pathogenicity related to an alteration of the splicing efficiency associated with an intron retention. This patient with XMEA displayed a severe phenotype (rapid weakness of upper and lower limbs) due to a new intronic variant of
, related to an alteration in the splicing efficiency associated with intron retention, suggesting that phenotype severity is closely related to the residual expression of the VMA21 protein.
La maladie de Charcot-Marie-Tooth de type 1 (CMTX1) ne dispose actuellement d’aucun traitement curatif, mais des essais précliniques émergents laissent espérer des études cliniques à venir. Il sera ...alors nécessaire de constituer des groupes comparables.
Cependant nous manquons de donner sur les corrélations phénotype-génotype. Notre objectif est d’apporter davantage de connaissance sur ces corrélations, afin de faciliter la formation de groupes de patients bien comparables dans les essais cliniques à venir.
Nous avons mené une évaluation rétrospective de patients CMTX provenant de 12 centres de référence en France. Les données génétiques, cliniques et la conduction nerveuse ont été recueillies. La gravité de la maladie a été évaluée à l’aide du score fonctionnel CMTES. Les patients ont été classés en fonction de l’interprétation ACMG de leurs variants, soit telles que documentées dans ClinVar, soit telles qu’évaluées via la plateforme Franklin Genoox.
Nous avons analysé les corrélations génotype-phénotype chez 276 patients CMTX appartenant à 160 familles non apparentées et portants 87 variants différents. Les patients présentant des variants affectant les domaines transmembranaires étaient significativement plus graves, avec un score CMTES de 10,7, contre 7,3 pour ceux présentant des variants dans les domaines intracellulaires et 8,8 pour ceux présentant des variants de domaine extracellulaire. Ces patients débutaient plus précocement leur maladie, ont montré des vitesses de conduction du nerf ulnaire plus lentes et une perte axonale plus importante (Fig. 1).
Nous n’avons pas observé de différences significatives selon le type de mutations. Les variantes de signification incertaine (VUS) présentaient des caractéristiques cliniques comparables à celles observées dans les variantes pathogènes et probablement pathogènes.
Cette étude confirme la présence d’une corrélation entre le domaine de la protéine mutée et le phénotype clinique. Par conséquent, la prise en compte des génotypes des patients sera indispensable dans les futurs essais cliniques.
La maladie de Charcot-Marie-Tooth liée à l’X de type 1 (CMTX1) en lien avec une mutation de la connexine 32 est caractérisée par des différences cliniques entre les sexes. Les femmes sont ...généralement moins affectées.
La présentation clinique des femmes atteintes de CMTX semble cependant être hétérogène. Notre objectif est d’étendre la description phénotypique des femmes atteintes de CMTX.
Nous avons évalué rétrospectivement 263 patients atteints de CMT1X provenant de 11 centres de référence français. Des données démographiques, cliniques et de conduction nerveuse motrice ont été recueillies. Le phénotype a été évalué par les scores CMTES et ONLS. Nous avons recherché une force musculaire asymétrique, des VCM hétérogènes et des blocs de conduction moteur.
L’étude a porté sur 137 femmes et 126 hommes. Les femmes présentaient des déficits moteurs et des VCM significativement plus asymétriques que les hommes. Deux groupes de femmes ont été identifiés après 46 ans. Le premier groupe représentait 59 %, avec des femmes évoluant aussi sévèrement que les hommes, mais avec un âge d’apparition des symptômes plus tardif. Le second groupe présentait des symptômes légers. Au total, 41 % des femmes présentaient un bloc de conduction moteur.
Nous avons identifié deux sous-groupes de femmes atteintes de CMTX1 âgées de plus de 46 ans. Nous avons également montré que les femmes atteintes de CMTX peuvent avoir une présentation clinique atypique, ce qui peut conduire à un mauvais diagnostic. Quatre femmes ont reçu de l’immunoglobuline par voie intraveineuse avant d’être diagnostiquées CMTX1.
Chez une femme atteinte de neuropathie chronique, la présence d’une asymétrie clinique, d’une VCM hétérogène et/ou d’un CB moteur doit faire penser à une neuropathie CMTX1.
Influenza vaccines are effective in decreasing hospitalizations and mortality related to influenza and its complications. However, the Vaccine Coverage Rate of influenza remains low and multifaceted ...efforts are required to improve it. The aim of this study was to assess the impact on influenza vaccine perception using a digital tool among outpatients and health care workers (HCWs).
A study was performed among outpatients and the HCWs of 23 hospital departments from 4 hospitals affiliated to Lyon university Hospitals (France), between October 2022 and February 2023. By scanning QR (Quick Response) codes, displayed on posters for patients, their companions, as well as in the letters sent to HCWs, users accessed anonymously to a web-application (ELEFIGHT®), which provided information on influenza and invited them to initiate a discussion on influenza prevention with their physicians during the consultation. Patients were also invited to complete a questionnaire regarding their perception of influenza vaccination before and after reading the information on ELEFIGHT®. The retention rate (RR = proportion of people who remain on the page for >2 s), the conversion rate (CR = proportion of people who click on the “Call-To-Action” button) and the absolute variation (difference in the perception before/after) and relative variation (absolute change as a percentage of the initial perception) in perception regarding influenza vaccination before and after consulting the application were calculated.
3791 scans were performed by 3298 patients and/or their companions with a RR of 52% and a CR of 55.1% and 253 scans by 221 HCWs with a RR of 71.2% and a CR of 115.3%. Participants spent an average of 47 s on the application. The questionnaire on influenza vaccination perception was completed by 1533 participants (46.5%); 1390 (90.7%) maintained the same position (neutral, favorable or unfavorable) on this vaccination before and after consulting the application. The relative variations in favor of vaccination were + 7.2% (unfavorable then favorable) and + 19.8% (neutral then favorable).
This study suggests that a facilitated direct access to medical information through QR codes disseminated in health settings can help nudge people to foster their awareness of influenza and its prevention. Future deployments in a similar context or to other populations could be envisaged. Other vaccine-preventable and/or chronic diseases could also be the target of similar projects as part of public health programs.
•The target influenza vaccine coverage rate (VCR) is 75% for some populations•Different approaches should be combined to achieve a high VCR•A direct access to information through QR codes can raise awareness on influenza•The relative variations in favor of vaccination were + 27%
Il s’agit d’un patient de 64 ans, qui a présenté en 09/2018 un tableau de gonflements articulaires, névralgie thoraco-abdominale, paralysie faciale périphérique gauche puis de paresthésies ...quadri-distales et de troubles de l’équilibre. Le bilan réalisé a mis en évidence une méningite lymphocytaire avec hyperprotéinorachie, une sérologie Lyme positive en IgG et en IgM dans le sang et dans le LCR ainsi qu’une synthèse intra-thécale en IgG. Le patient est traité pendant un mois par Rocéphine 2g/j, ce qui permet une amélioration nette en une dizaine de jours des douleurs neuropathiques et modérée de l’équilibre, mais il persistait un déficit de la flexion dorsale des deux pieds prédominant à gauche. L’évolution clinique est marquée par l’apparition un mois plus tard d’un déficit sensitivomoteur dans le territoire ulnaire des deux côtés. Après une deuxième ligne d’antibiothérapie par Doxycycline, on constate une aggravation clinique du déficit moteur dans le territoire ulnaire des deux côtés et l’apparition de dysesthésies dans le territoire radial gauche et persistance d’un déficit de la flexion dorsale des deux pieds. L’étude ENMG fin 11/2018 mettait en évidence un bloc de conduction sur le nerf ulnaire gauche en sous coude, un allongement diffus des ondes F, des activités spontanées et tracés neurogènes dans le territoire ulnaire gauche. L’ENMG de contrôle fin 02/2019 montre l’apparition de blocs de conduction dans le territoire fibulaire commun droit et gauche en sous col, ulnaire droit en sous coude et la persistance du bloc de conduction ulnaire gauche, une baisse des amplitudes sensitives dans ces territoires et des activités spontanées et tracés neurogènes dans ces territoires tronculaires. La biopsie du nerf sural gauche montre une discrète inflammation périvasculaire sans signes de nécrose. Un mois après une 1ère cure d’IgIV, on constate une amélioration clinique nette. Le traitement est poursuivi par 2 cures d’IgIV. Le contrôle ENMG montre la disparition des blocs de conduction et une perte axonale stable. L’évolution clinique est à ce jour favorable avec une récupération quasi-complète en dehors d’un déficit sensitivomoteur ulnaire gauche minime. Cette présentation clinique et électrique pourrait être compatible avec un syndrome de « Lewis-Sumner like » déclenché par un trigger infectieux. Dans la littérature, nous n’avons pas retrouvé de présentation identique. Un cas a été publié avec présence de blocs de conduction multiples (diagnostic de NMMBC retenu) s’améliorant sous Ig (Rupprecht et al.).
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 (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 (ICU) 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 patients did not worsen during adulthood and RAPSN patients, often severely affected in early childhood, subsequently improved.
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