Charlotte Mouraux

Background: Association between monoallelic STUB1 variant and expanded ATXN8OS alleles was recently reported, suggesting a pathogenic interaction that may influence spinocerebellar ataxia type 48 (SCA48) phenotype. Objectives: We investigated the frequency and clinical impact of ATXN8OS in a large cohort of STUB1 carriers compared to individuals with other ataxias and controls. Methods: Ataxic individuals and controls from the SPATAX/BIOMOV cohorts (Paris Brain Institute) were screened for ATXN8OS and other CAG expansions using polymerase chain reaction (PCR)/repeat‐prime PCR (RP‐PCR) and ExpansionHunter . STUB1 carriers underwent whole‐genome or exome sequencing. Results: Our cohort comprised 12 biallelic STUB1 carriers (SCAR16) and 67 monoallelic STUB1 carriers (SCA48) without other causative variants. ATXN8OS expansions (84–177 CTA/CTG repeats) were identified in seven SCA48 individuals (10.5%) who exhibited earlier onset (median age 28 vs. 47 years, P < 0.001) compared to other SCA48 individuals but with similar clinical presentation. ATXN8OS expansions were also found in two healthy controls older than 50 years (2/286, 0.7%) and in eight index cases with autosomal dominant ataxia (8/400, 2%), including four carrying another molecular diagnosis without any effect on the phenotype. Other intermediate expansions were identified in individuals with SCA48: seven (10.5%) carried intermediate TBP alleles (40–46 CAG/CAA) without any effect on dementia prevalence; four carried intermediate HTT alleles (28–29 CAG); and three carried intermediate ATXN1 expansions (38 CAG). Conclusions: ATXN8OS intermediate expansion acts as a genetic modifier in SCA48 but not in other ataxias. Moreover, expanded intermediate alleles in neurodegenerative disease genes were present in one‐third of SCA48 individuals. These alleles may increase polyglutamine burden, potentially saturating STUB1 E3 ubiquitin ligase activity. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The genetic and phenotypic heterogeneity of hereditary ataxias complicates the design of clinical trials since each ataxia progresses at different rates. Consequently, robust biomarkers are urgently needed to monitor therapeutic efficacy and safety of potential therapeutic interventions. Neurofilament light chain has emerged as a leading candidate, serving as a sensitive pharmacodynamic biomarker of neuronal injury and treatment response in neurodegenerative disorders. This review explores the utility of neurofilament light chain across various ataxias, including polyglutamine spinocerebellar ataxias, Friedreich’s ataxia, multiple system atrophy, and other genetic ataxias, such as ataxias associated with RCF1 and SPG7 genes. We synthesize evidence from recent studies that have used ultra-sensitive assays. These studies consistently demonstrate elevated neurofilament light chain levels in cerebrospinal fluid and blood, correlating with disease severity, progression and neuroimaging findings. Notably, neurofilament light chain levels rise during the presymptomatic stage in spinocerebellar ataxias, highlighting its potential for stratifying individuals for trial enrolment and tracking therapeutic effects. A treatment-induced reduction in neurofilament light chain could function as a surrogate endpoint for target engagement, analogous to its validated use in amyotrophic lateral sclerosis. Finally, we discuss the results of other studies conducted on other biomarkers, including glial fibrillary acidic protein, total tau and phosphorylated tau, which may reflect complementary aspects of neurodegeneration and glial activation. Glial fibrillary acidic protein may provide insights into astroglial reactivity and neuroinflammation. Similarly, alteration in total tau and phosphorylated tau levels may suggest dysfunction in neuronal cytoskeleton and axonal integrity. The review also focuses on target-engagement biomarkers, including polyglutamine-expanded ataxin proteins in spinocerebellar ataxias and frataxin in Friedreich’s ataxia, as critical tools to complement the ataxia biomarker toolkit. The quantification of mutant ataxin proteins provides a mechanistic readout for emerging gene-silencing or protein-lowering therapies. In parallel, the measurement of frataxin levels serves as a pharmacodynamic marker in therapeutic strategies aiming to restore frataxin expression. These target-engagement biomarkers are valuable in early phases of clinical trials, which mainly aim to demonstrate the biological activity of a treatment before later-phase trials assessing clinical efficacy. Finally, we report on somatic instability in polyglutamine spinocerebellar ataxias as an emerging and highly relevant therapeutic target. CAG repeat mosaicism is gene specific and correlates with disease progression. Integrating measures of repeat instability with neurodegenerative biomarkers could provide a comprehensive monitoring approach in clinical studies. This overview underscores the potential of fluid biomarkers, particularly neurofilament light chain, in accelerating therapeutic development for hereditary ataxias.

Introduction: Heterozygous pathogenic variants in MYH3 are known to be responsible for distal arthrogryposis. Case report: We report a consanguineous family of four children with two likely pathogenic MYH3 homozygous variants associated with complex movement disorders, especially prominent lingual dystonia, along with skeletal abnormalities. The two variants in MYH3 (c.3445G>A and c.4760T>C) have already been described in patients with congenital arthrogryposis. No other significant variation was found using long-read whole genome sequencing. Discussion: We have extended the phenotype of MYH3-associated arthrogryposis to include movement disorders, which may have been underdiagnosed to date. Highlights This article extends the phenotype of MYH3-associated arthrogryposis to include movement disorders, illustrating a family of four children presenting MYH3 skeletal disorders and lingual dystonia. Two homozygous likely pathogenic variants have been identified in the four sibs and appear to be causative for both skeletal and neurological phenotypes.

Background: Patients with neuromuscular diseases (NMD) have undergone considerable technological progress in terms of diagnosis and treatment over the past few years. Specifically, next-generation sequencing (NGS) has significantly expanded genetic diagnosis. Despite this, some patients remain undiagnosed and therefore without access to specific treatments. Analyses of epidemiology and diagnostic approaches in reference centers are required to determine effective strategies to improve diagnostic rates. Methods: We studied the proportion of each NMD and associated investigations in the patient population of the Neuromuscular Reference Center (NMRC) of Liege, Belgium, in 2023. The investigation tools used included laboratory testing, muscle biopsy, muscle imaging, single-gene sequencing, targeted NGS panels, and whole-exome sequencing (WES). Results: Of the 1084 patients who were regularly followed up, more than one-third had neuropathies (36.6%) that were divided equally between genetic and acquired causes. The second most common disorder was muscular dystrophies, which represented more than a quarter (27.5%). Third, 11.2% of the patients had motor neuron diseases. The other NMD (i.e., myopathies, ataxias, spastic paraplegias, and channelopathies) ranged from 2.1% to 6. %. A total of 13.7% of the patients had unconfirmed diagnoses, 31.5% had confirmed acquired disorders, and 54.9% had genetically confirmed disorders. Among the genetic diagnoses, 32.7% were obtained by NGS. The remaining 67.3% were determined using other genetic testing methods [i.e., array comparative genomic hybridization (aCGH), multiplex ligation-dependent probe amplification (MLPA), polymerase chain reaction (PCR), southern blotting (SB)]. Conclusion: More than two-thirds of patients received a definitive diagnosis without the use of next-generation sequencing. Although innovative technologies such as whole genome sequencing and long-read sequencing are expected to eventually replace NGS panels and traditional methods (e.g., MLPA, PCR, aCGH), their current cost and the complexity of variant interpretation limit their widespread use in routine clinical practice. As a result, these older techniques remain relevant and valuable in current diagnostic workflow.

ATP1A2 and CACNA1A genes encode proteins forming transmembrane channels, Na+/K+/ATPase transporter, and voltage-gated calcium channels, respectively. Pathogenic variants in these genes are associated with hemiplegic migraines, movement disorders, and developmental and epileptic encephalopathy.We report a child presenting epileptic encephalopathy with cognitive and behavioral troubles. He carries a likely pathogenic variant in the ATP1A2 gene, inherited from his mother who presents hemiplegic migraines, and a variant of uncertain significance in the CACNA1A gene, inherited from his asymptomatic father and also found in his brother, who presents a milder neurodevelopmental disorder (NDD). No other significant copy number or single nucleotide variations were identified after an in-depth genetic study including whole exome sequencing, array comparative genomic hybridization, and screening for Fragile X and Prader–Willi/Angelman syndromes.We illustrate the synergetic impact of ATP1A2 and CACNA1A genes in NDDs.

Background: In spinal muscular atrophy, clinical trial results indicated that disease-modifying treatments are highly effective when given prior to symptom onset, which has prompted newborn screening programs in growing number of countries. However, prognosis of those patients cannot be inferred from clinical trials conducted in presymptomatic individuals, as in some cases disease presents very early. Methods: we conducted a systematic review of articles published up to January 2023. Results: Among 35 patients with three SMN2 copies treated before 42 days of age and followed-up for at least 18 months, all but one achieved autonomous ambulation. Of 41 patients with two SMN2 copies, who were non-symptomatic at treatment initiation, all achieved a sitting position independently and 31 were able to walk. Of 16 patients with two SMN2 copies followed-up for at least 18 months who presented with symptoms at treatment onset, 3 achieved the walking milestone and all but one were able to sit without support. Conclusions: evaluation of data from 18 publications indicates that the results of early treatment depend on the number of SMN2 copies and the initial neurological status of the patient.