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Background: Despite similarities, neuromyelitis optica (NMO) can be distinguished from multiple sclerosis (MS) by clinical, radiological and serological findings.Objective: This case-control study aimed to determine whether patients with NMO or with MS in an Afro-Caribbean population originating from French West Indies shared the same or different HLA class I and II pattern distribution.Methods: The association with HLA class II (DRB1 and DQB1) alleles was tested in 42 NMO patients, 163 MS patients and 150 healthy controls. HLA-DRB1 and DQB1 typing was undertaken on genomic DNA extracted from peripheral blood leucocytes.Results: By comparison with healthy controls, significantly increased frequency of HLA-DRB1*03 (26.2% vs. 13%, odds ratio 2.4, 95% confidence interval 1.31—4.28, p after correction, cp 0.045) was observed in patients with NMO. By contrast, in MS patients, HLA-DRB1*15 (24.8% vs. 13%, odds ratio 2.21, 95% CI 1.45—3.36, cp < 0.0015), but not DRB1*03 allele, was positively associated with the disease. Moreover, a modest protective effect of HLA-DRB1*11 in the MS group, independently of DRB1*15 association, was found (13.7% vs. 7% in controls, odds ratio 0.48, p 0.006), but did not survive Bonferroni correction.Conclusion: In conclusion, comparison of the HLA-DRB1 and DQB1 distribution in NMO and MS in this Afro-Caribbean population shows important differences in the HLA associations among NMO and MS. [ABSTRACT FROM AUTHOR]

X-linked myotubular myopathy (XLMTM) is a rare neuromuscular disorder caused by mutations in the myotubularin (MTM1) gene, affecting 1:50000 male births. The clinical severity varies, however the need for ventilatory support is often inevitable. At present, no approved therapies are available for XLMTM. Patient management is mainly supportive. A first MTM1 gene replacement therapy tested in a clinical trial showed notable improvements on ventilator dependence and motor function but raised serious safety concerns. Forty patients have been enrolled in our European prospective natural history study of patients with XL-MTM designed to characterize the disease course by using standardized evaluations adjusted for age, ambulatory and respiratory status. At 3-year follow-up, data were available for 26 patients (65%) with a mean age of 14.3 (min 3.4, max 53.8) years. Drop-outs were due to loss to follow-up (n=1), death (n=1) and early withdrawal from the study (n=3). Nineteen percent (5/26) of patients were under the age of 6 years old. Among non-ambulant patients at baseline (n=19), only 1 acquired the ability to walk during the study. Respiratory function, strength and motor function did not statistically change. Muscle strength measured by MyoPinch and MyoGrip showed a mean decline of -1,04 kg (n=20) and -0.33kg (n=20) respectively. MFM D1 showed the most important decline of -2.98% at 36 months. Nine patients presented with a mean increase of grip strength of 1.5kg (SD 4.18) (n=13). Ten patients showed a mean increase of the pinch strength of 0.16kg (SD 0.71) (n=14). Correlation data will be presented. This first multicentric longitudinal natural history in all types of patients with XL-MTM demonstrates clearly that patients experience a decline over years that can be reliably measured. We have identified several strength-, functional and respiratory outcomes that can be used to build robust clinical trials in this population. [ABSTRACT FROM AUTHOR]

Nemaline myopathy (NM) is a congenital disorder associating muscle weakness with rods in muscle biopsy. Clinical presentation is variable spanning from severe to mild forms. Seven genes are associated with NM. The nebulin (NEB) gene is the most commonly mutated accounting for 50% of cases. We performed a muscle morphological analysis of thirteen NEB-mutated patients with different clinical forms to define pathological patterns and clinical-morphological correlations. Four groups were identified according to clinical severity and age at biopsy. Group 1 (n =4) comprises severe/lethal NM and biopsy in first days. Group 2 (n =3) comprehends severe NM and biopsy after one month. Group 3 (n =3) comprises typical NM and biopsy in childhood, and group 4 (n =2) patients with mild NM and biopsy in adulthood. Molecular diagnosis was done using dHPLC/Sanger-sequencing in six patients and next-generation sequencing in seven. Biopsies underwent histoenzymological, immunohistochemical and ultrastructural analysis. Fiber type distribution, rod characteristics, distribution and localization were investigated. All patients presented NEB mutations consistent with AR inheritance. G1 showed type 2 predominance and scattered squared rods in 1/3 of fibers. Ultrastructural analysis revealed high percentage of fibers with sarcomeric disarray. G2 showed a variable pattern of fiber type distribution spanning from slight type 2 predominance to type 1 uniformity. Rods presented variable distribution and shape. Ultrastructural analysis revealed rare fibers with sarcomeric disarray. In contrast, G3 and G4 presented a homogeneous type 1 uniformity associated with well-delimited subsarcolemmal and/or cytoplasmic elongated rods without sarcomeric alterations. In conclusions we (1) identified an unreported association of type 2 predominance in muscle biopsy of patients presenting severe NEB-related NM; (2) suggest a direct correlation between the association of sarcomeric disarray and clinical severity. [Copyright &y& Elsevier]

Background: Fabry disease (FD) is a rare X-linked lysosomal disorder caused by alpha-galactosidase deficiency consecutive to a pathogenic variant in the GLA gene. Age at onset is highly variable, with a wide clinical spectrum including frequent renal, cardiac, skin and nervous system manifestations. Since pain can be an indicator of underlying FD, we wanted to estimate the prevalence of FD in a population of chronic pain patients., Methods: Two studies, DOUFAB and DOUFABIS, were carried out in expert centers for chronic pain to assess the prevalence of FD by measuring alpha galactosidase A activity in men and analysing the GLA gene in women., Results: Analysis of 893 patients, essentially adults, led to the diagnosis of FD in one female patient, now treated with enzyme replacement therapy., Conclusions: The prevalence of FD is estimated about 1/1000 in our population of men and women suffering from various chronic pain. This is nearly the prevalence of FD observed in other previously screened high-risk populations with renal failure., Significance: Although a systematic search for FD does not seem relevant in the context of unexplained chronic pain in adults, a positive family history of FD or the presence of additional FD related organ features must lead to consider this rare disease diagnosis. Therefore, pain specialists need to be aware of main features of FD, including pain characteristics., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Background: In 2017, a new treatment by nusinersen, an antisense oligonucleotide delivered by repeated intrathecal injections, became available for patients with spinal muscular atrophy (SMA), whereas clinical trials had mainly involved children. Since 2020, the oral, selective SMN2-splicing modifier risdiplam has been available with restrictions evolving with time. In this peculiar context of lack of data regarding adult patients, many questions were raised to define the indications of treatment and the appropriate follow-up in this population. To homogenize access to treatment in France, a national multidisciplinary team meeting dedicated to adult SMA patients, named SMA multidisciplinary team meeting, (SMDTs) was created in 2018. Our objective was to analyze the value of SMDTs in the decision-making process in SMA adult patients and to provide guidelines about treatment., Methods: From October 2020 to September 2021, data extracted from the SMDT reports were collected. The primary outcome was the percentage of cases in which recommendations on validating treatment plans were given. The secondary outcomes were type of treatment requested, description of expectations regarding treatment and description of recommendations or follow-up and discontinuation. Data were analyzed using descriptive statistics. Comparisons between the type of treatment requested were performed using Mann-Whitney test or the Student t test for quantitative data and the Fisher's exact test or the χ 2 test for qualitative data., Results: Cases of 107 patients were discussed at the SMDTs with a mean age of 35.3 (16-62). Forty-seven were SMA type 2, and 57 SMA type 3. Twelve cases were presented twice. Out of 122 presentations to the SMDTs, most of requests related to the initiation of a treatment (nusinersen (n = 46), risdiplam (n = 54), treatment without mentioning preferred choice (n = 5)) or a switch of treatment (n = 12). Risdiplam requests concerned significantly older patients (p = 0.002), mostly SMA type 2 (p < 0.0001), with greater disease severity in terms of motor and respiratory function compared to requests for nusinersen. In the year prior to presentation to the SMDTs, most of the patients experienced worsening of motor weakness assessed by functional tests as MFM32 or other meaningful scales for the most severe patients. Only 12% of the patients discussed had a stable condition. Only 49/122 patients (40.1%) expressed clear expectations regarding treatment. The treatment requested was approved by the SMDTs in 72 patients (67.2%). The most common reasons to decline treatment were lack of objective data on the disease course prior discussion to the SMDTs or inappropriate patient's expectations. Treatment requests were more likely to be validated by the SMDTs if sufficient pre-therapeutic functional assessment had been performed to assess the natural history (55% vs. 32%) and if the patient had worsening rather than stable motor function (p = 0.029). In patients with approved treatment, a-priori criteria to define a further ineffectiveness of treatment (usually after 14 months of treatment) were proposed for 67/72 patients., Conclusions: In the context of costly treatments with few controlled studies in adults with SMA, in whom assessment of efficacy can be complex, SMDTs are 'real-world observatories' of great interest to establish national recommendations about indications of treatment and follow-up., (© 2024. The Author(s).)

Background: Mitochondrial membrane protein-associated neurodegeneration (MPAN) is caused by mutations in the C19orf12 gene. MPAN typically appears in the first two decades of life and presents with progressive dystonia-parkinsonism, lower motor neuron signs, optic atrophy, and abnormal iron deposits predominantly in the basal ganglia. MPAN, initially considered as a strictly autosomal recessive disease (AR), turned out to be also dominantly inherited (AD)., Objectives: Our aim was to better characterize the clinical, molecular, and functional spectra associated with such dominant pathogenic heterozygous C19orf12 variants., Methods: We collected clinical, imaging, and molecular information of eight individuals from four AD-MPAN families and obtained brain neuropathology results for one. Functional studies, focused on energy and iron metabolism, were conducted on fibroblasts from AD-MPAN patients, AR-MPAN patients, and controls., Results: We identified four heterozygous C19orf12 variants in eight AD-MPAN patients. Two of them carrying the familial variant in mosaic displayed an atypical late-onset phenotype. Fibroblasts from AD-MPAN showed more severe alterations of iron storage metabolism and autophagy compared to AR-MPAN cells., Conclusion: Our data add strong evidence of the realness of AD-MPAN with identification of novel monoallelic C19orf12 variants, including at the mosaic state. This has implications in diagnosis procedures. We also expand the phenotypic spectrum of MPAN to late onset atypical presentations. Finally, we demonstrate for the first time more drastic abnormalities of iron metabolism and autophagy in AD-MPAN than in AR-MPAN. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Introduction: The epidemiology of Juvenile Dermatomyositis (JDM) in non-Caucasian population is poorly described. We performed a study of patients followed up in the French West Indies for JDM. We aimed to describe clinical and biological specificities during childhood., Methods: Retrospective study covering the period from Januarys 2000-2023. Listings of patients were obtained from multiple sources, namely computerized hospital archives, registry of referent pediatricians and adult specialists in internal medicine and the French National Registry for rare diseases. JDM and organ involvement were defined according to the international ILAR criteria., Results: Twenty-one patients were included over a 23 year-period. Median age at onset was 8.1 years (Range: 2.5-13.9) with a median follow up of 8 years (Range: 2-19). Two-thirds (14/21) had dysphagia at onset and 33% had respiratory involvement. Thirteen had specific autoantibodies (58%), most frequently anti-Mi-2. The median number of flares during childhood was three (1-9). During childhood, 76% had calcinosis lesions. Clinical evolution seemed to be more aggressive for boys than girls (respectively 4.2 versus 2.2 flares (p = 0.04) and 50% vs 18% needing more than one background therapy, p = 0.03)., Conclusion: This retrospective study is the largest cohort of pediatric patients of Afro-Caribbean and Black African descent treated for JDM in a high-income health system, and the first to describe the incidence and immunological profile in a population of African descent. They had higher rate of calcinosis and similar respiratory involvement. Overall outcomes during childhood were similar to North America and European countries., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Amyotrophic Lateral Sclerosis (ALS) is a rare neurological disorder that causes degeneration of upper and lower motor neurons and their axons. ALS is mostly sporadic, but there are familial forms. In more than half of the familial forms, a pathogenic variant is found in one of the following genes: C9ORF72 , SOD1 , TDP-43 , FUS , and VCP . SOD1 is the 2nd most common gene involved in genetic forms of ALS. Genotype-phenotype relationships are occasionally established in genetic forms of ALS associated with SOD1 mutations pathogenic variants. The c.281G > T (p.[G93V]) variant in SOD1 is associated with a rarely described and unexplained anticipation phenomenon. We report a large family from Martinique in whom ALS is associated with a c.281G > T (p.[G93V]) pathogenic variant in SOD1 and a statistically suggested anticipation. A whole-exome study and detection of CNVs (CoDESeq) from 3 affected members of this family revealed the presence of variants of uncertain signification (VUS) in other ALS genes. VUS in DCTN1 and NEFH were present in patients of the 2nd generation, and CNVs involving UBQLN2 and C21orf2 were found in the youngest case of the family.

Whole mitochondrial DNA (mtDNA) sequencing is now systematically used in clinical laboratories to screen patients with a phenotype suggestive of mitochondrial disease. Next Generation Sequencing (NGS) has significantly increased the number of identified pathogenic mtDNA variants. Simultaneously, the number of variants of unknown significance (VUS) has increased even more, thus challenging their interpretation. Correct classification of the variants' pathogenicity is essential for optimal patient management, including treatment and genetic counseling. Here, we used single muscle fiber studies to characterize eight heteroplasmic mtDNA variants, among which were three novel variants. By applying the pathogenicity scoring system, we classified four variants as "definitely pathogenic" (m.590A>G, m.9166T>C, m.12293G>A, and m.15958A>T). Two variants remain "possibly pathogenic" (m.4327T>C and m.5672T>C) but should these be reported in a different family, they would be reclassified as "definitely pathogenic." We also illustrate the contribution of single-fiber studies to the diagnostic approach in patients harboring pathogenic variants with low level heteroplasmy., (© 2020 Wiley Periodicals LLC.)

Background: Subtelomeres are variable regions between telomeres and chromosomal-specific regions. One of the most studied pathologies linked to subtelomeric imbalance is facioscapulohumeral dystrophy (FSHD). In most cases, this disease involves shortening of an array of D4Z4 macrosatellite elements at the 4q35 locus. The disease also segregates with a specific A-type haplotype containing a degenerated polyadenylation signal distal to the last repeat followed by a repetitive array of β-satellite elements. This classification applies to most patients with FSHD. A subset of patients called FSHD2 escapes this definition and carries a mutation in the SMCHD1 gene. We also recently described patients carrying a complex rearrangement consisting of a cis -duplication of the distal 4q35 locus identified by molecular combing., Methods: Using this high-resolution technology, we further investigated the organisation of the 4q35 region linked to the disease and the 10q26 locus presenting with 98% of homology in controls and patients., Results: Our analyses reveal a broad variability in size of the different elements composing these loci highlighting the complexity of these subtelomeres and the difficulty for genomic assembly. Out of the 1029 DNA samples analysed in our centre in the last 7 years, we also identified 54 cases clinically diagnosed with FSHD carrying complex genotypes. This includes mosaic patients, patients with deletions of the proximal 4q region and 23 cases with an atypical chromosome 10 pattern, infrequently found in the control population and never reported before., Conclusion: Overall, this work underlines the complexity of these loci challenging the diagnosis and genetic counselling for this disease., Competing Interests: Competing interests: A patent application (No. EP08165310.7) on molecular combing for the diagnosis of FSHD1 and exploration of D4Z4 has been registered by Genomic Vision, University of the Mediterranean, and Public Assistance of the Hospitals of Marseille. NL is a co-inventor of the patent., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Because X-linked myotubular myopathy (XLMTM) is a rare neuromuscular disease caused by mutations in the MTM1 gene with a large phenotypic heterogeneity, to ensure clinical trial readiness, it was mandatory to better quantify disease burden and determine best outcome measures., Methods: We designed an international prospective and longitudinal natural history study in patients with XLMTM and assessed muscle strength and motor and respiratory functions over the first year of follow-up. The humoral immunity against adeno-associated virus serotype 8 was also monitored., Results: Forty-five male patients aged 3.5 months to 56.8 years were enrolled between May 2014 and May 2017. Thirteen patients had a mild phenotype (no ventilation support), 7 had an intermediate phenotype (ventilation support less than 12 hours a day), and 25 had a severe phenotype (ventilation support 12 or more hours a day). Most strength and motor function assessments could be performed even in very weak patients. Motor Function Measure 32 total score, grip and pinch strengths, and forced vital capacity, forced expiratory volume in the first second of exhalation, and peak cough flow measures discriminated the 3 groups of patients. Disease history revealed motor milestone loss in several patients. Longitudinal data on 37 patients showed that the Motor Function Measure 32 total score significantly decreased by 2%. Of the 38 patients evaluated, anti-adeno-associated virus type 8 neutralizing activity was detected in 26% with 2 patients having an inhibitory titer >1:10., Conclusions: Our data confirm that XLMTM is slowly progressive for male survivors regardless of their phenotype and provide outcome validation and natural history data that can support clinical development in this population., Clinicaltrialsgov Identifier: NCT02057705., (© 2019 American Academy of Neurology.)

Objective: To genotypically and phenotypically characterize a large pediatric myotonic dystrophy type 1 (DM1) cohort to provide a solid frame of data for future evidence-based health management., Methods: Among the 2,697 patients with genetically confirmed DM1 included in the French DM-Scope registry, children were enrolled between January 2010 and February 2016 from 24 centers. Comprehensive cross-sectional analysis of most relevant qualitative and quantitative variables was performed., Results: We studied 314 children (52% females, with 55% congenital, 31% infantile, 14% juvenile form). The age at inclusion was inversely correlated with the CTG repeat length. The paternal transmission rate was higher than expected, especially in the congenital form (13%). A continuum of highly prevalent neurodevelopmental alterations was observed, including cognitive slowing (83%), attention deficit (64%), written language (64%), and spoken language (63%) disorders. Five percent exhibited autism spectrum disorders. Overall, musculoskeletal impairment was mild. Despite low prevalence, cardiorespiratory impairment could be life-threatening, and frequently occurred early in the first decade (25.9%). Gastrointestinal symptoms (27%) and cataracts (7%) were more frequent than expected, while endocrine or metabolic disorders were scarce., Conclusions: The pedDM-Scope study details the main genotype and phenotype characteristics of the 3 DM1 pediatric subgroups. It highlights striking profiles that could be useful in health care management (including transition into adulthood) and health policy planning., (© 2019 American Academy of Neurology.)