ERN EURO-NMD

The North Star ambulatory assessment (NSAA) is a functional motor outcome measure in Duchenne muscular dystrophy (DMD), widely used in clinical trials and natural history studies, as well as in clinical practice. However, little has been reported on the minimal clinically important difference (MCID) of the NSAA. The lack of established MCID estimates for NSAA presents challenges in interpreting the significance of the results of this outcome measure in clinical trials, natural history studies and clinical practice. Combining statistical approaches and patient perspectives, this study estimated MCID for NSAA using distribution-based estimates of 1/3 standard deviation (SD) and standard error of measurement (SEM), an anchor-based approach, with six-minute walk distance (6MWD) as the anchor, and evaluation of patient and parent perception using participant-tailored questionnaires. The MCID for NSAA in boys with DMD aged 7 to 10 years based on 1/3 SD ranged from 2.3-2.9 points, and that on SEM ranged from 2.9-3.5 points. Anchored on the 6MWD, the MCID for NSAA was estimated as 3.5 points. When the impact on functional abilities was considered using participant response questionnaires, patients and parent perceived a complete loss of function in a single item or deterioration of function in one to two items of the assessment as an important change. Our study examines MCID estimates for total NSAA scores using multiple approaches, including the impact of patient and parent perspective on within scale changes in items based on complete loss of function and deterioration of function, and provides new insight on evaluation of differences in these widely used outcome measure in DMD.

BACKGROUND: The EURO-NMD Registry collects data from all neuromuscular patients seen at EURO-NMD's expert centres. In-kind contributions from three patient organisations have ensured that the registry is patient-centred, meaningful, and impactful. The consenting process covers other uses, such as research, cohort finding and trial readiness. RESULTS: The registry has three-layered datasets, with European Commission-mandated data elements (EU-CDEs), a set of cross-neuromuscular data elements (NMD-CDEs) and a dataset of disease-specific data elements that function modularly (DS-DEs). The registry captures clinical, neuromuscular imaging, neuromuscular histopathology, biological and genetic data and patient-reported outcomes in a computer-interpretable format using selected ontologies and classifications. The EURO-NMD registry is connected to the EURO-NMD Registry Hub through an interoperability layer. The Hub provides an entry point to other neuromuscular registries that follow the FAIR data stewardship principles and enable GDPR-compliant information exchange. Four national or disease-specific patient registries are interoperable with the EURO-NMD Registry, allowing for federated analysis across these different resources. CONCLUSIONS: Collectively, the Registry Hub brings together data that are currently siloed and fragmented to improve healthcare and advance research for neuromuscular diseases.

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.

Background The p.Glu109Lys variant (Glu89Lys) is a rare cause of hereditary transthyretin amyloidosis (ATTRv) for which clinical spectrum remains unresolved. We sought to describe the clinical characteristics and outcomes of ATTR Glu89Lys amyloidosis and assess a potential founder effect in Spain.Methods Patients with the p.Glu109Lys ATTRv variant from 14 families were recruited at 7 centres. Demographics, complementary tests and clinical course were analysed. Haplotype analysis was performed in 7 unrelated individuals.Results Thirty-eight individuals (13 probands, mean age 40.4 ± 13.1 years) were studied. After median follow-up of 5.1 years (IQR 1.7–9.6), 7 patients died and 7 required heart transplantation (median age at transplantation 50.5 years). Onset of cardiac and neurological manifestations occurred at a mean age of 48.4 and 46.8 years, respectively. Median survival from birth was 61.6 years and no individual survived beyond 65 years. Patients treated with disease-modifying therapies exhibited better prognosis (p < 0.001). Haplotype analysis revealed a common origin from an ancestor who lived ∼500 years ago in southeast Spain.Conclusions Glu89Lys ATTRv is a TTR variant with a founder effect in Spain. It is associated with near complete penetrance, early onset and mixed cardiac and neurologic phenotype. Patients have poor prognosis, particularly if not treated with disease-modifying therapies.

Autoantibodies (Abs) are biomarkers for many disease conditions and are increasingly used to facilitate diagnosis and treatment decisions. To guarantee high sensitivity and specificity, the choice of their detection method is crucial. Via cell-based assays, we recently found 21 patients with neurological diseases positive for antibodies against argonaute (AGO), 10 of which having a neuropathy (NP). Here, we established a simple and conformation-sensitive ELISA with the aim to distinguish between AGO1 Abs against conformational epitopes and non-conformational epitopes and to reveal further characteristics of AGO1 antibodies in NP and autoimmune disease (AID). In a retrospective multicenter case/control and observational study, we tested 434 patients with NP, 274 disease controls with AID, and 116 healthy controls (HC) for AGO1 Abs via conformation-stabilizing ELISA. Seropositive patients were also tested for conformation-specificity via comparative denaturing/stabilizing ELISA (CODES-ELISA), CBA positivity, AGO1 titers and IgG subclasses, and AGO2 reactivity. These parameters were statistically compared among different epitope-specific patient groups. We found Abs in 44 patients, including 28/434 (6.5%) NP, 16/274 (5.8%) AID, and 0/116 (0%) HC. Serum reactivity was consistently higher for AGO1 than AGO2. Globally among the 44 AGO1 Abs-positive patients, 42 were also tested in CBA for AGO1 Abs positivity and 15 (35.7%) were positive. Furthermore, 43 were tested for conformation-specificity and 32 (74.4%) bound a conformational epitope. Among the subgroups of highly positive patients (ELISA z-score &amp;gt;14) with sera binding conformational epitopes (n=23), 14 patient sera were also CBA positive and 9 bound a second conformational but CBA-inaccessible epitope. A third, non-conformational epitope was bound by 11/43 (15.6%). Among the epitope-specific patient subgroups, we found significant differences regarding the Abs titers, IgG subclass, and AGO2 reactivity. When comparing AGO1 Abs-positive NP versus AID patients, we found the conformation-specific and CBA inaccessible epitope significantly more frequently in AID patients. We conclude that 1) conformational ELISA was more sensitive than CBA in detecting AGO1 Abs, 2) serum reactivity is higher for AGO1 than for AGO2 at least for NP patients, 3) AGO1 Abs might be a marker-of-interest in 6.5% of NP patients, 4) distinguishing epitopes might help finding different patient subgroups.

-dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1-related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1-typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy.

Background: Physical activity may help to promote health in patients with Limb-girdle muscular dystrophy (LGMD) and Charcot-Marie-Tooth disease (CMT). Objective: To investigate associations between functional ability and other variables, with physical activity in people with LGMD and CMT grouped according to the International Classification of Functioning, Disability, and Health (ICF). Methods: We did a cross-sectional study, recruiting respondents from the Norwegian registry of inherited neuromuscular disorders. We used the Norwegian version of Barthel index of Activities of Daily Living (ADL) to measure functional ability and the International Physical Activity Questionnaire –short form (IPAQ-sf) to classify physical activity. We used multivariable logistic regression analysis to investigate associations between variables. Results: 145 subjects were recruited (79 with CMT and 66 with LGMD). 55.6% of the subjects met a minimum recommendation of physical activity. Participants with moderate to severe functional ability were more likely to be physically inactive compared to those with normal functional ability (OR 19.7; 95% CI 3.1–127.2). Mildly decreased functional ability also showed higher odds of being physically inactive compared to participants with normal functional ability (OR 4.1; 95% CI 1.1–15.6). Higher education was associated with inactivity. Fatigue, participation in physiotherapy, and participation in adapted physical activity programs were not associated with physical activity. Conclusions: Low functional ability was associated with physical inactivity in both LGMD and CMT. Association between higher education and inactivity might indicate the need to provide more understanding about physical activity benefit in this group.

Background Myosin heavy chain 7 ( MYH7 )-related myopathies ( MYH7 -RMs) are a group of muscle disorders linked to pathogenic variants in the MYH7 gene, encoding the slow/beta-cardiac myosin heavy chain, which is highly expressed in skeletal muscle and heart. The phenotype is heterogeneous including distal, predominantly axial or scapuloperoneal myopathies with variable cardiac involvement. Methods We retrospectively analysed the clinical, muscle MRI, genetic and myopathological features of 57 MYH7 patients. Patients received a thorough neurological (n=57, 100%), cardiac (n=51, 89%) and respiratory (n=45, 79%) assessment. Muscle imaging findings and muscle biopsies were reappraised in 19 (33%) and 27 (47%) patients, respectively. Results We identified three phenotypes with varying degrees of overlap: distal myopathy (70%), scapuloperoneal (23%) and axial with peculiar cervical spine rigidity called the ‘sphinx’ phenotype (7%). 14% of patients had either dilated cardiomyopathy, hypertrophic cardiomyopathy or left ventricular non-compaction cardiomyopathy. 31% of patients had prominent respiratory involvement, including all patients with the ‘sphinx’ phenotype. Muscle MRI showed involvement of tibialis anterior, followed by quadriceps, and erector spinae in patients with axial phenotype. Cores represented the most common myopathological lesion. We report 26 pathogenic variants of MYH7 gene, 9 of which are novel. Conclusions MYH7 -RMs have a large phenotypic spectrum, including distal, scapuloperoneal or axial weakness, and variable cardiac and respiratory involvement. Tibialis anterior is constantly and precociously affected both clinically and on muscle imaging. Cores represent the most common myopathological lesion. Our detailed description of MYH7 -RMs should improve their recognition and management.

Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.

Some muscular dystrophies may have a negative impact on fertility. A decreased ovarian reserve is 1 of the factors assumed to be involved in fertility impairment. AMH (anti-Müllerian hormone) is currently considered the best measure of ovarian reserve.A total of 21 females with myotonic dystrophy type 1 (MD1), 25 females with myotonic dystrophy type 2 (MD2), 12 females with facioscapulohumeral muscular dystrophy (FSHD), 12 female carriers of Duchenne muscular dystrophy mutations (cDMD) and 86 age-matched healthy controls of reproductive age (range 18 - 44 years) were included in this case control study. An enzymatically amplified 2-site immunoassay was used to measure serum AMH level.The MD1 group shows a significant decrease of AMH values (median 0.7 ng/mL; range 0 - 4.9 ng/mL) compared with age-matched healthy controls (P < .01). AMH levels were similar between patients and controls in terms of females with MD2 (P = .98), FSHD (P = .55) and cDMD (P = .60).This study suggests decreased ovarian reserve in women with MD1, but not in MD2, FSHD and cDMD.

BACKGROUND: Systemic sclerosis (SSc) is considered by many to be one of the most severe autoimmune rheumatic diseases with lower prevalence observed in Northern Europe. No previous studies on the prevalence of SSc in Latvia have been conducted and the aim was to study the demographic and clinical data of patients with SSc in northeastern Europe country. METHODS: This study was conducted in two main Latvian hospitals for adults and includes patients with SSc who were consulted between 2016 and 2021. RESULTS: During the study period, 159 patients with SSc were consulted. The point prevalence on 1 January 2021 was 84.0 per million. Female to male ratio was 4.67:1, and highest gender ratio was observed in the age group 70-79-year (6.75:1). Antinuclear antibodies were present in 82.58% of patients, without gender difference. Centromere pattern was more frequently observed in females (40.19% vs. 19.04%), in contrast to speckled pattern (50.98% vs. 57.14%). At disease onset females tended to be younger (46.51 ± 13.52) than males (50.5 ± 16.64). Males had more diffuse cutaneous subtype, interstitial lung disease, pulmonary hypertension and esophageal dysmotility. More than half of patients received treatment with glucocorticoids at any point of the disease (68.31%), without gender difference. CONCLUSIONS: Systemic sclerosis is less common in Latvia than in other countries and regions. Due to its location, the data from Latvia are consistent with a north-south gradient in Europe. Gender ratio differences persisted in older age groups as well. Antinuclear antibodies presence did not differ between genders, but in female's centromere pattern was much more likely to be present. Males had more severe disease course, but in both genders more than half of patients received treatment with GCs at any point of the disease.

Purpose To translate ABILHAND-NMD and ACTIVLIM into Norwegian and assess their psychometric properties in adults with Myotonic Dystrophy type 1(DM1).Methods ABILHAND-NMD and ACTIVLIM were translated into Norwegian through a standardized translation process. Psychometric properties of the translated questionnaires were tested. Intraclass correlation coefficient (ICC3.1) was used to assess test-retest reliability and Cronbach’s α for internal consistency. The validity of the questionnaires was also assessed.Results A total of 39 adults with DM1 were included. We found excellent test-retest reliability on ABILHAND-NMD (ICC 0.91) and ACTIVLIM (ICC 0.93). We found a good internal consistency of ABILHAND-NMD with Cronbach’s α (95%CI) of 0.80 (0.69–0.88) and ACTIVLIM with Cronbach’s α (95%CI) of 0.88 (0.82–0.93) An expert group of healthcare professionals and a pilot group reported good face and content validity. We found a high correlation between ABILHAND-NMD and ACTIVLIM (r = 0.75), p < 0.001 implying good convergent validity. ABILHAND-NMD and ACTIVLIM showed no floor effect, but a potential for ceiling effect.Conclusion The Norwegian versions of ABILHAND-NMD and ACTIVLIM are reliable and valid patient reported outcome measures for Myotonic Dystrophy type 1. The questionnaires are easy to administer as they take a short time to answer, and the participants reported no problems understanding the questions.

Pompeho nemoc (glykogenóza II. typu) je vzácné autosomálně recesivní dědičné metabolické onemocnění. Průběh onemocnění a celkovou dobu přežití lze ovlivnit enzymovou substituční terapií. Neuromuskulární centrum 2. LF UK a FN Motol a Neuromuskulární centrum FN Brno realizují projekt, jehož cílem je odhalit dosud nepoznané případy Pompeho nemoci a nově diagnostikovaným pacientům poskytnout dispenzární péči a substituční terapii.

OBJECTIVE: Variant transthyretin (ATTRv) amyloidosis is a rare genetic multisystem disease inducing progressive morbidity. Evidence about its economic burden is scarce. This study estimated annual use and costs of healthcare-resource-utilization (HRU) and indirect costs for ATTRv mutation carriers and patients with polyneuropathy from a societal perspective in Spain. METHODS: A cross-sectional, retrospective non-interventional multicenter study was conducted in 2018-2020 to characterize asymptomatic carriers of mutations in the TTR gen (AC) and Coutinho stage 1 transthyretin amyloidosis polyneuropathy patients (PA). HRU, associated costs, and indirect wages were assessed during 12 months prior to enrollment. RESULTS: < 0.001). CONCLUSIONS: Both AC and early-stage ATTRv-PN patients showed a meaningful economic burden to the National Health System and society. We observed an annual incremental economic burden of €1,771.5 in PA versus AC.

BACKGROUND: Pregnancy and family planning for individuals living with rare and low prevalence diseases present unique medical, psychological, and logistical challenges. The European Reference Networks (ERNs) were established to address healthcare disparities and enhance patient care for rare diseases across Europe. The ERN Transversal Working Group on Pregnancy and Family Planning was created to identify common unmet needs and to develop targeted actions to improve healthcare delivery. As part of this initiative, a survey was conducted to gather insights from patients, caregivers, and family members about their experiences and challenges related to pregnancy and family planning. METHODS: The survey was co-designed by healthcare professionals and patient representatives from 20 ERNs. It covered various domains, including fertility preservation, pre-conceptional counselling, psychological support in the pre-conceptional counselling, pre-implantation diagnosis, prenatal diagnosis, family planning, pregnancy monitoring, post-pregnancy monitoring, lactation and newborn management. The survey, available in multiple languages, was distributed via online platforms between February and July 2022. Quantitative responses were analysed descriptively, while qualitative data from open-ended questions were processed using word frequency analysis. RESULTS: A total of 769 responses were collected, with 574 from patients and 155 from caregivers. The majority of respondents were female (90%) and aged 31-40 years, primarily from Germany, France, Spain, and Italy. The most pressing concerns identified included lack of access to accurate medical information, limited psychological support, inadequate pre-conceptional counselling, and challenges related to pregnancy monitoring and postpartum care. The need for multidisciplinary healthcare teams and improved education on reproductive health was emphasised. Word frequency analysis highlighted key concerns, with "inform," "support," and "risk" being the most recurrent terms. CONCLUSIONS: This study underscores the widespread need for comprehensive, patient-centred approaches in pregnancy and family planning for individuals with rare and low prevalence diseases. Improved access to specialised healthcare teams, psychological support, and clear, standardised medical information is essential. These findings advocate for the development of harmonised European policies and multidisciplinary strategies to enhance reproductive healthcare. People living with rare diseases often face extra challenges when it comes to pregnancy and family planning. To better understand these issues, a group of experts and patient representatives from 20 European Reference Networks (ERNs) worked together to conduct a survey. A European survey of 769 people, mostly women aged 31 to 40 from Germany, France, Spain, and Italy, revealed significant gaps in care. The most common concerns shared by patients included difficulty finding clear medical information, not enough psychological support, gaps in counselling, and challenges with checking on health during and after pregnancy. Many felt that better teamwork among different healthcare providers and improved education on reproductive health would make a big difference. In summary, this study underscores the urgent need for better reproductive healthcare for people with rare diseases.

Introduction: Shotgun metagenomic sequencing (mNGS), an untargeted approach that sequences all nucleic acids in a sample, has emerged as a powerful tool for pathogen detection and genome characterization. However, its implementation in clinical diagnostics remains limited due to technical challenges such as contamination and reduces sensitivity, especially in low-biomass samples. Methods: We applied mNGS to 144 clinical samples representing chronic infections, acute infections, and respiratory co-infections. To address contamination, we established a framework integrating negative controls, lab-specific contaminant watchlists, and computational filtering. Viral detection performance and genome recovery were assessed across sample types and viral loads. Results: Viral load was shown to be the primary determinant of sensitivity, with reliable recovery achieved only at higher titers. Our framework substantially improved contamination management, reducing false-positive signals and enhancing viral genome recovery. mNGS enabled the detection of clinically relevant co-infections and refined viral classification beyond targeted diagnostics, while also revealing the substantial risk of spurious detections in the absence of contamination-aware workflows. Discussion: These findings define practical sensitivity thresholds for clinical mNGS and underscore the need for contamination-aware workflows, particularly for low-biomass samples, while providing an open-source contaminants watchlist that enhances reliability and utility of clinical metagenomics.

Report the clinical characterization and high-throughput SNP genotyping of the first p.A5V-SOD1 (rs121912442) Spanish ALS kindred, providing detail on a possible common founder.