BACKGROUND AND AIMS:Patients with LMNA gene variants are at high risk for dilated cardiomyopathy and heart failure (HF), but no prediction model for severe HF events exists. This study aimed to describe the incidence of severe HF events and develop a prediction model in a large cohort of patients with adult-onset laminopathies. METHODS:From a population of 660 patients enrolled in the French LMNA nationwide registry, 470 adults were included in the derivation cohort. An independent international validation cohort included 245 additional patients. Baseline characteristics at genetic testing were assessed and the cumulative incidence of the primary endpoint HF-major adverse cardiac events (HF-MACE) was calculated, defined as HF hospitalization, HF-related death, mechanical circulatory support, or heart transplantation. Predictors of HF-MACE were studied after excluding patients with left ventricular ejection fraction (LVEF) <30% at baseline using a Fine-Gray competing risk model, adjusted hazard ratio (aHR) with 95% confidence interval (CI), and Harrell's concordance (C-) index. A secondary composite endpoint, without hospitalization, was also studied. RESULTS:Among 470 patients of the derivation cohort, HF-MACE occurred in 65 over a median follow-up of 7.1 years (interquartile range: 3.4-12.1). Four independent predictors of HF-MACE were identified: male sex (aHR 1.86; 95% CI 1.060-3.290), LVEF <50% (aHR 2.18; 95% CI 1.080-4.400), missense variants in head and rod domains (aHR 2.91; 95% CI 1.110-7.630), and complete left bundle branch block (aHR 2.99; 95% CI 1.400-6.400). The C-index of the model was 0.750 (95% CI 0.720-0.780) in the derivation cohort and 0.758 (95% CI 0.720-0.800) in the validation cohort. The 5-year cumulative incidence of HF-MACE was 1.5% (95% CI 0.6-3.6), 5.0% (95% CI 1.8-8.2), and 22.0% (95% CI 15.6-28.4) among patients with 0, 1, and ≥2 risk factors, respectively. In patients with LVEF <30% at baseline, the 1-year incidence of HF-MACE was 50%, and those patients were excluded from the risk score. CONCLUSIONS:The first prediction model for severe HF events in adult laminopathies was developed, which may facilitate early and optimal preventive management. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov Unique identifier: NCT03058185.

ObjectiveThis study is an example of the contribution of exome sequencing (ES) in selected prenatal indications, while illustrating the complexity of interpreting prenatal genetic testing. Therefore, one of the aims of this study was to better describe antenatal phenotypes.MethodsThis was a multicenter, comparative, prospective study assessing high-throughput sequencing performance (targeted gene panel versus exome sequencing) in selected prenatal indications.ResultsTrio-ES was performed on 86 fetuses, allowed making a definite etiological diagnosis in 28% of cases (24/86). One-third of diagnoses were obtained only after exome analysis (8/24, 33%). The diagnostic yield varied according to the indication and was the highest for vermian hypoplasia (5/12, 42%) and polymalformative syndromes (30%, 8/27) indications. The variants identified were mainly missense variants in ciliopathy (18%, 6/33) and cytoskeleton (15%, 5/33) genes. Among the etiological diagnoses, one fetus carried a postzygotic mosaic variant in RHOA.ConclusionIn selected indications, the diagnostic yield of ES was close to 30% and varied according to the indications, showing the importance of clearly define the malformations justifying this approach. An etiological diagnosis was made in 23 families, within a timeframe compatible with pregnancy, thus improving the management of the pregnancy and/or the unborn child.

Small nuclear RNAs (snRNAs) are essential components of the spliceosome. De novo variants in snRNA genes RNU4-2 (ReNU syndrome), RNU5B-1 and RNU2-2 have been linked to dominant neurodevelopmental disorders (NDDs), revealing a large unexpected contribution of noncoding RNA genes to genetic diseases. Here, through international collaborations, we analyze systematically 200 potentially functional snRNA genes in a French cohort of 34,329 people with rare disorders. We report RNU2-2 variants in 141 individuals, including 35 with recurrent dominant pathogenic variants and 91 affected members from 73 families with biallelic variants. Recessive RNU2-2 NDD is at least twice as frequent as the dominant form and often involves a de novo variant in trans with an inherited allele, consistent with the high mutability of snRNA genes. Dominant and recessive RNU2-2 NDDs share overlapping clinical features, with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our results support a gradient-of-impact model bridging dominant and recessive inheritance, and establish RNU2-2 variants as a principal contributor to NDDs, nearly as prevalent as ReNU syndrome.

Spinal muscular atrophy (SMA) was recently included in the French national newborn screening (NBS) program. The aim of this study was to assess the public health impact and cost–utility of SMA NBS in the French setting. A cost–utility model combining a decision tree with a lifetime state transition model (six health states) was adapted from a previous model. The model simulated a cohort of 700,000 newborns annually, aligned with French birth statistics. Clinical inputs were derived from SMA trials. Cost and utility estimates reflected French healthcare system data and societal burden studies. Analyses were conducted from a societal perspective, with key outcomes including the incremental cost–utility ratio (ICUR), quality-adjusted life years (QALYs), and incremental net monetary benefit (INMB). Deterministic, probabilistic, and scenario analyses were performed. With NBS, 66.5 patients are expected to be treated presymptomatically each year. At age 15 years, mortality is reduced to 2

Safety and efficacy of tamoxifen in boys with Duchenne muscular dystrophy was assessed in the double-blind, randomised, placebo-controlled, multicenter phase 3 trial (TAMDMD), which was followed by an 48 weeks open label extension study. The aim of the open label extension study was to investigate if earlier initiation of tamoxifen could reduce the progression of the disease compared to delayed initiation of tamoxifen. Of the initial TAMDMD trial participants, 66 patients were enrolled in the open label extension (OLE). The objective was to investigate the efficacy of prolonged treatment with tamoxifen 20 mg daily, adjunct to corticosteroids, in individuals with DMD over 48 weeks. We aimed to analyse the sustained effect and the timing effect of tamoxifen in patients with DMD on the basis of a set of motor function tests. The sustained effect corresponds to the treatment effect seen in the tamoxifen treatment arm of the RCT phase of the trial being sustained after all patients got the treatment in the OLE phase. The timing effect addresses if patients with earlier tamoxifen initiation show more favourable disease trajectory than patients with delayed tamoxifen initiation. This study was registered with ClinicalTrials.gov (NCT03354039). Between May 28th 2019 and July 28th 2021, 66 patients in 10 study centres in seven European countries could be enrolled into the OLE phase. Of those, 32 had previously been treated with tamoxifen and 34 had been assigned to placebo. The efficacy outcome defined as the change in the motor function did not differ significantly between the early tamoxifen treatment group and the delayed tamoxifen treatment group. There was neither a sustained nor a timing effect of tamoxifen. Overall tamoxifen was well tolerated. No deaths or life-threatening serious adverse events occurred. The OLE phase of the TAMDMD trial showed that treatment with tamoxifen continued to be well tolerated overall; however, there was neither a sustained nor a timing effect of tamoxifen treatment in patients with DMD. We cannot provide statistical nor clinical evidence that prolonged treatment with tamoxifen is effective in delaying disease progression in DMD when used as an adjunct to corticosteroids.

Defects in transcription and DNA repair pathways underlie a growing spectrum of rare neurodevelopmental disorders, including MEDopathies and transcription-coupled repair (TCR)-related syndromes like Cockayne Syndrome (CS). Here, we report biallelic variants in MED20, encoding a core subunit of Mediator, in eight individuals presenting intellectual disability, brain atrophy, dystonia and developmental delay. Patient-derived fibroblasts exhibit mild but consistent defects in TCR, alongside transcriptional abnormalities reminiscent of CS. Functional modeling of MED20 variants in yeast and nematode recapitulates UV sensitivity, transcriptional impairment and neurodevelopmental defects. At the molecular level, MED20 variants disrupt interactions within the Mediator complex, disturbing the pre-initiation complex and reducing transcriptional output. Collectively, these findings identify MED20 pathogenic variants as a cause of neurodevelopmental disorder at the interface of transcription and DNA repair and position Mediator-dependent transcriptional regulation upstream of TCR. This work establishes a direct link between inherited defects in basal transcription machinery and human transcription-DNA repair syndromes.

Introduction La réalité virtuelle (RV) est une distraction immersive et multisensorielle efficace pour réduire douleur et anxiété dans divers contextes cliniques. Son utilisation lors d’injections intrathécales (IT) reste inexplorée. Objectifs Évaluer l’efficacité de la RV en sus des soins courants (SoC) pour atténuer l’anxiété lors d’injections IT de nusinersen chez des patients atteints de SMA et l’expérience RV des patients/soignants. Méthodes REALITY (NCT05354414) est un essai prospectif, randomisé, croisé, ouvert, mené dans 15 centres français. Des patients≥7 ans recevant des injections IT de nusinersen tous les 4 mois (doses de maintien) étaient randomisés 1:1 pour recevoir lors de leurs prochaines injections IT1/IT2, RV+SoC puis SoC ou inversement. Les critères d’évaluation incluaient : auto-évaluation de l’anxiété et de la douleur, usage d’antalgiques/anxiolytiques, satisfaction et acceptabilité rapportées par les patients et les équipes médicales. Résultats Au total, 59 patients (âge médian 19,7 ans ; SMA II, 40,7 % ; III, 54,2 %) ont eu≥1IT. Aucune réduction significative de douleur, d’anxiété ou de consommation médicamenteuse n’était observée entre RV+SoC vs SoC, bien que les besoins en distractions supplémentaires aient été moindres avec la RV (15,2 % vs 30,9 %). La satisfaction était élevée chez les patients et les soignants. Quatre événements indésirables non graves liés à la RV ont été rapportés. Discussion En France, le SoC assure déjà une prise en charge efficace de l’anxiété, pouvant limiter la détection d’un bénéfice additionnel de la RV. Des études supplémentaires seraient nécessaires pour explorer le moment optimal d’utilisation de la VR (avant vs pendant l’injection IT) et identifier les sous-groupes les plus susceptibles d’en bénéficier. Conclusion La RV associée aux soins courants lors des injections IT semble bien acceptée par patients et soignants, même sans réduction significative de la douleur ou l’anxiété comparée au SoC seul.

Congenital nemaline myopathies are rare genetic disorders that typically manifest at birth or in childhood, with muscle weakness and respiratory distress. They are characterized by the presence of rod-like structures on the muscle biopsy, or a mix of rods with cores, focal areas with disorganization of oxidative activity. Pathogenic variants in the NEB gene represent a main cause of these conditions. However, significant phenotypic variability exists, hampering disease prognosis, healthcare, and genetic counseling. This study is aimed at further characterizing the clinical and genetic features of nebulin-related congenital myopathies and exploring genotype-phenotype correlations in a novel large cohort of patients. In a total of 49 patients from 48 families with nebulin-related myopathies, a substantial proportion (23/49) exhibited a typical form of the disease, with childhood onset and preserved ambulation beyond 11 years of age. Respiratory insufficiency was observed in 33/49 patients, with a median age of 16 years for the initiation of ventilatory support. Facial muscle weakness was common (32/49), whereas severe bulbar symptoms were less frequent, with only 14/49 requiring nutritional support, all in cases where respiratory assistance was necessary. Patients with rods (n = 28) or core-rods (n = 11) exhibited no significant clinical differences. Genetic analysis identified 76 NEB variants, including 7 recurrent, with a mutational hotspot detected between Exons 169 and 175 in 25/49 patients. Furthermore, our analyses suggest an association between the type of variant and five groups of patients with different levels of clinical severity. Additionally, our data raise the possibility that ophthalmoplegia may be preferentially observed in patients harboring variants located in Exon 143. Overall, these findings will contribute to facilitating and expediting genetic diagnosis in future cases with suspected NEB involvement, ultimately improving patient care and management.

Introduction Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorders with 150 to 200 potential new cases per year in France, characterized by progressive muscular atrophy. As there is very little information available in France about DMD costs, a baseline assessment is needed in view of new treatments’ development, as their impact on patient’s life will have an impact on the numerous expenses related to the disease. The objective was to describe the consumption of all resources not eligible for reimbursement related to the care provided to DMD patients in terms of direct medical costs, direct non-medical costs, medical social costs, informal care costs and indirect costs. Methods Patients with DMD diagnosis and their caregivers were recruited through the National Rare Disease Data Bank and questioned about resource consumption related to DMD using “ad-hoc” questionnaires. Results 25 families with 26 patients were recruited. The average total cost of resources not eligible for reimbursement was €104,144 /year/patient. Direct costs were €67,177/year/patient, among which informal care accounted for €43,090/year/patient. Productivity loss was €48,057/year/patient. Families’ out of pocket expense per year was €5,302. Financial assistance received in the context of DMD and disability amounted to an average of €14,980 /year/patient, with monthly allowances up to €14,237/year/patient. Conclusion This study provides a first inventory of the major financial and time burden borne by DMD patients and their caregivers in France, and confirms the high level of non-reimbursed resource consumption by DMD patients as well as the enormous time commitment from their families. Trial registration NCT06861270 (Initial Release: 09/25/2024)

Importance:Therapeutic advances have transformed the prognosis of spinal muscular atrophy (SMA). Given the lifelong implications of these innovative therapies, comparative data on their efficacy are urgently required. Objective:To compare clinical outcomes of nusinersen and onasemnogene abeparvovec gene therapy as first-line treatments in children with SMA type 1 (SMA1). Design, Setting, and Participants:This comparative effectiveness study used data from the French National SMA Registry from September 2016 to July 2024. The follow-up period started at treatment initiation and continued until July 22, 2024, or death. Children with genetically confirmed SMA1 (types a, b, or c) treated within 6 months of diagnosis with either nusinersen or gene therapy as first-line therapy and followed up for at least 24 months were included. Matching criteria included age, baseline score on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders, and respiratory and nutritional status at treatment initiation. Exposure:First-line treatment with either nusinersen or gene therapy. Main Outcomes and Measures:Outcomes included respiratory and nutritional support needs, motor function, and unsatisfactory clinical response (UCR)- a composite of death, treatment switch (or, for gene therapy, addition) due to inadequate response, initiation of feeding support, and/or failure to achieve independent sitting. Results:Among 1366 patients enrolled in the registry, 309 were diagnosed with SMA1. Twenty-four children in 12 matched pairs met inclusion criteria (14 [58%] male; mean [SD] age at treatment initiation, 6.1 [3.0] months [range, 2.3-11.9 months]). Three patients (1 receiving gene therapy [8%], 2 receiving nusinersen [17%]) died within the first year of treatment. At 2 years posttreatment, 1 of the 11 surviving patients treated with gene therapy (9%) required nutritional support vs 5 of 10 (50%) treated with nusinersen, and nocturnal ventilation was required in 5 of 11 (45%) receiving gene therapy vs 8 of 10 (80%) receiving nusinersen. Motor outcomes were comparable between groups (mean [SE] intrapair difference in CHOP-INTEND score evolution, -1.69 [1.24] points; P = .17). UCR occurred in 8 of 12 patients (67%) receiving nusinersen and 3 of 12 (25%) receiving gene therapy. Conclusions and Relevance:In this comparative effectiveness study of children with SMA1, gene therapy was associated with lower incidence of UCR and fewer supportive care needs vs nusinersen. These exploratory findings warrant confirmation in larger studies.

Status epilepticus is a life-threatening neurological emergency that requires rapid and effective treatment to prevent long-term complications or death. Traditionally, phenytoin and its prodrug fosphenytoin have been used as second-line therapies following benzodiazepines. However, intravenous levetiracetam has emerged as a promising alternative because of its favorable safety profile and ease of administration, particularly in pediatric populations. This study aimed to evaluate whether intravenous levetiracetam was non-inferior to intravenous fosphenytoin as a second-line treatment for managing pediatric status epilepticus. From November 2021 to May 2023, we implemented an updated local protocol that replaced fosphenytoin with levetiracetam as the second-line treatment for status epilepticus. Following this change, we conducted a 2-year multicenter study to evaluate its impact. For comparison, we also included patients treated under the previous protocol during the 2 years prior to the change, as a control group. An inverse probability of treatment weighting approach, based on the propensity score, was used to adjust for baseline characteristics between the two groups. Bayesian regression models were used to assess treatment effects in the weighted cohort. Treatment effectiveness was assessed using a composite measure of need for subsequent interventions, recurrence of status epilepticus within 24 h, seizure duration and length of hospital stay. We tested non-inferiority hypotheses for effectiveness criteria and if the probability of non-inferiority was greater than 95

Variants in spliceosomal small nuclear RNA (snRNA) genes RNU4-2 (ReNU syndrome), RNU5B-1, and RNU2-2 have recently been linked to dominant neurodevelopmental disorders (NDDs), revealing a major, previously overlooked role for noncoding snRNAs in human disease. Here, we systematically analysed 200 potentially functional snRNA genes in a French cohort comprising 26,911 individuals with rare disorders and through international collaborations. We identify de novo and biallelic variants in RNU2-2 associated with both dominant and recessive NDDs in 126 individuals from 108 unrelated families. Recessive RNU2-2 NDD is at least twice as frequent as the dominant NDD caused by n.4G>A and n.35A>G, and often arises from a de novo variant in trans with an inherited allele, reflecting the high mutability of snRNA genes. Dominant and recessive RNU2-2-NDDs share overlapping clinical features with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our findings support a gradient-of-impact model and a continuum between dominant and recessive inheritance, establishing RNU2-2 variants as a frequent cause of NDDs, nearly as prevalent as ReNU syndrome.

Most patients with Duchenne muscular dystrophy (DMD) are non-ambulant. Preserving proximal motor function is crucial, rarely studied. Tamoxifen, a selective oestrogen receptor modulator, reduced signs of muscular pathology in a DMD mouse model. Our objective was to assess the safety and efficacy of tamoxifen over 48 weeks in non-ambulant DMD patients. In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at six European centres boys aged 10-16 years with genetically diagnosed DMD, non-ambulant and off corticosteroid treatment for >= 6 months, randomly assigned (1:1) to either 20 mg/day tamoxifen orally or placebo were included. The primary outcome was change in D2 motor function measure from baseline to week 48. Of 15 nonambulant male patients with DMD screened, 14 were enrolled from January 24th, 2019, to January 6th, 2021. Eight patients were randomised to the treatment and six to the placebo group. The primary efficacy outcome did not differ significantly between tamoxifen and placebo (7.8 percentage points, 95 % CI, -26.82 to 11.22, p = 0.359) with a trend not favouring tamoxifen. No deaths or life-threatening serious AEs occurred. Tamoxifen was safe but due to insufficient clinical evidence, it cannot be recommended as a treatment option for DMD. Trial registration: ClinicalTrials.gov (NCT03354039).

The major spliceosome contains five small nuclear RNAs (snRNAs; U1, U2, U4, U5 and U6) essential for splicing. Variants in RNU4-2, encoding U4, cause a neurodevelopmental disorder called ReNU syndrome. We investigated de novo variants in 50 snRNA-encoding genes in a French cohort of 23,649 individuals with rare disorders and gathered additional cases through international collaborations. Altogether, we identified 145 previously unreported probands with (likely) pathogenic variants in RNU4-2 and 21 individuals with de novo and/or recurrent variants in RNU5B-1 and RNU5A-1, encoding U5. Pathogenic variants typically arose de novo on the maternal allele and cluster in regions critical for splicing. RNU4-2 variants mainly localize to two structures, the stem III and T-loop/quasi-pseudoknot, which position the U6 ACAGAGA box for 5' splice site recognition and associate with different phenotypic severity. RNU4-2 variants result in specific defects in alternative 5' splice site usage and methylation patterns (episignatures) that correlate with variant location and clinical severity. This study establishes RNU5B-1 as a neurodevelopmental disorder gene, suggests RNU5A-1 as a strong candidate and highlights the role of de novo variants in snRNAs.

SLC6A1 (Solute Carrier Family 6 Member 1) variants are associated with SLC6A1-neurodevelopmental disorders (SLC6A1-NDD), which manifest as early-onset epilepsy, intellectual developmental disorder, and autism spectrum disorder. There have been over 300 reported cases so far. A retrospective analysis of 14 patients with de novo SLC6A1 variants was conducted to assess their developmental milestones, epilepsy progression, antiseizure medication, and, for some, a comprehensive neurodevelopmental evaluation. Data from 14 additional families were also collected using the GenIDA participatory database, aiming to better characterize the natural history of genetic forms of NDDs.Most patients exhibited normal early motor development, but delays in communication and language skills were observed. Their intellectual functioning varied, mostly falling within the low average to moderate intellectual developmental disorder range, with a predominant expressive and receptive language disorder. More than half of the group displayed autistic features, particularly stereotypic behavior. Behavioral disorders such as hyperactivity, anxiety, impulsivity, or inhibition were common concerns for parents.The first seizures occurred between 14 months and 5 years, mainly presenting as generalized seizures (atonic falls, absences, atypical absences, myoclonic-atonic seizures). EEG results frequently showed bursts of rhythmic delta activity, persisting from childhood to adulthood, with epilepsy primarily responding well to antiseizure medication in most of the reported cases.This study exhibited a distinct electroclinical and neurodevelopmental phenotype in young children, suggesting the importance of early genetic testing for SLC6A1-NDD diagnosis.

BACKGROUND:Myotonia is the main feature of both myotonic dystrophy (DM) and non-dystrophic myotonia (NDM). It is felt as stiffness, pain, fatigue, and weakness. In France, mexiletine, a non-selective voltage-gated sodium channel blocker, is approved for the treatment of myotonia in adults with NDM, and it has a temporary recommendation for use in the symptomatic treatment of DM in adults. However, it is not currently licensed for treating myotonia in children due to the lack of studies on its use in pediatrics. This has meant heterogeneous practices in its utilization and has led to prescriber reluctance, which has jeopardized accessibility. We undertook a professional practice survey of French pediatric neuromuscular centers to determine their prescribing habits for mexiletine, assessing indications, doses, efficacy, and tolerance. METHODS:One medical pediatric professional from each French pediatric neuromuscular center belonging to the national neuromuscular network (FILNEMUS) was invited to complete an anonymous questionnaire. RESULTS:In total, 34 healthcare professionals responded. Of these, 16 had already treated a child for myotonia with mexiletine. Mexiletine was prescribed in one third of pediatric patients with NDM, but it was used in only 3% of DM type 1 patients and in no DM type 2 patients. Pre-treatment assessment always included a cardiac evaluation; however, the method of introduction (inpatient vs. outpatient basis), dosage adjustment, and efficacy evaluation ranged widely. More than half of the respondents reported a high efficacy of mexiletine in their patients; only three reported moderate adverse events (dyspepsia, loss of appetite, and asthenia). CONCLUSION:The findings of this first survey on mexiletine for pediatric myotonia in France lend support for the creation of future national guidelines.

BackgroundSpinal muscular atrophy (SMA) is a severe neurodegenerative disease affecting children. Three innovative disease-modifying therapies (DMTs)-nusinersen, risdiplam, and onasemnogene abeparvovec-are available for treatment.ObjectiveTo provide a descriptive overview of patients enrolled in the Registre SMA France until July 22, 2024.MethodsRegistre SMA France is a multicenter, national observational registry that includes patients with SMA-children and adults, treated or untreated. Data collection began retrospectively in 2016 and prospectively in 2020, with a 10-year follow-up plan. The coordinating center is the neuropediatric department of Garches Hospital (AP-HP), while methodological and, regulatory and operational management, are provided by the Clinical Research Unit of AP-HP Paris-Saclay. Financial support is provided through unrestricted grants from Biogen, Novartis, and Roche. Data on patient characteristics, medical and surgical follow-up, treatments, adverse events, and quality of life are recorded via structured forms, with additional modules developed as required (e.g., hematological monitoring post-gene therapy in 2021). Data quality is ensured through routine checks and periodic monitoring.ResultsBy July 22, 2024, 1299 patients from 59 centers were enrolled (299 SMA1, 502 SMA2, 469 SMA3, 19 SMA4, 10 presymptomatic). Of these, 76.2% received DMT (nusinersen: 46.1%, risdiplam: 23.2%, onasemnogene abeparvovec: 9.2%), with 21.5% undergoing sequential or combination therapy. Major complications included ventilatory support (SMA1: 69.9%, SMA2: 64.5%, SMA3: 18.1%), enteral feeding (SMA1: 56.2%SMA1), and spine surgery (SMA2: 24.5%). Survival was significantly higher in treated SMA1 and SMA2 cases.ConclusionThis registry serves as a key resource for understanding the clinical course and treatment outcomes of SMA in the real world, supporting future research and informing clinical and policy decisions in the era of DMTs.Trial registrationNCT04177134.

OBJECTIVE:Autophagy is a fundamental biological pathway with vital roles in intracellular homeostasis. During autophagy, defective cargoes including mitochondria are targeted to lysosomes for clearance and recycling. Recessive truncating variants in the autophagy gene EPG5 have been associated with Vici syndrome, a severe early-onset neurodevelopmental disorder with extensive multisystem involvement. Here, we aimed to delineate the extended, age-dependent EPG5-related disease spectrum. METHODS:We investigated clinical, radiological, and molecular features from the largest cohort of EPG5-related patients identified to date, complemented by experimental investigation of cellular and animal models of EPG5 defects. RESULTS:Through worldwide collaboration, we identified 211 patients, 97 of them previously unpublished, with recessive EPG5 variants. The phenotypic spectrum ranged from antenatally lethal presentations to milder isolated neurodevelopmental disorders. A novel Epg5 knock-in mouse model of a recurrent EPG5 missense variant featured motor impairments and defective autophagy in brain areas particularly relevant for the neurological disorders in milder presentations. Novel age-dependent neurodegenerative manifestations in our cohort included adolescent-onset parkinsonism and dystonia with cognitive decline, and myoclonus. Radiological features suggested an emerging continuum with brain iron accumulation disorders. Patient fibroblasts showed defects in PINK1-Parkin-dependent mitophagic clearance and α-synuclein overexpression, indicating a cellular basis for the observed neurodegenerative phenotypes. In Caenorhabditis elegans, EPG5 knockdown caused motor impairments, defective mitophagic clearance, and changes in mitochondrial respiration comparable to observations in C. elegans knockdown of parkinsonism-related genes. INTERPRETATION:Our findings illustrate a lifetime neurological disease continuum associated with pathogenic EPG5 variants, linking neurodevelopmental and neurodegenerative disorders through the common denominator of defective autophagy. ANN NEUROL 2025;98:932-950.