PURPOSE:Biallelic variants in RDH11, encoding retinol dehydrogenase 11, have been associated with a syndromic disorder, based on 4 individuals from 2 unrelated families. We aimed to profile the clinical variability, natural history and associated molecular spectrum of this condition. METHODS:In the frame of a collaborative effort, clinical and molecular data were collected using a semistructured survey. Structural modeling of RDH11 with NADH(P) was used to assess the functional impact of missense variants. RESULTS:Sixteen affected individuals from 9 unrelated families with biallelic RDH11 variants were assembled, frequently showing juvenile-onset progressive myopathy with vacuolar degeneration and prodromic asymptomatic hyperCKemia. Neurodevelopmental impairment, juvenile-onset cataract, and retinal dystrophy were confirmed as common features. Microcephaly and distinct craniofacial traits were also recurrent, whereas short stature was less frequent than previously reported. Most pathogenic variants were truncating, supporting RDH11 loss of function as the mechanism of disease. Consistently, the identified missense changes were predicted to affect RDH11 catalytic function. CONCLUSION:We refine the clinical and molecular spectra of RDH11-related disorder, reclassifying it as syndromic intellectual disability with muscular (juvenile myopathy) and ocular (retinal dystrophy) involvement. These insights are expected to improve diagnostic accuracy and patient care, guiding clinical evaluation, and genetic counseling.

Obsessive-Compulsive Disorder (OCD) traits are increasingly recognized as part of the broader psychopathological profile in Duchenne Muscular Dystrophy (DMD). However, standardized diagnostic data based on DSM-5 criteria are limited. This study aimed to systematically examine OCD traits in pediatric and young adult patients with DMD. In this single-center, cross-sectional observational study, 77 DMD patients were enrolled, regardless of disease severity or comorbidities. Standardized psychometric instruments were administered to assess cognitive functioning and obsessive-compulsive symptomatology. OCD traits were qualitatively identified in 68.8% of patients. Psychometric tests confirmed this high prevalence. OCD traits were significantly associated with reduced general functioning, underscoring the impact of psychopathological dimensions in DMD. Correlations emerged between the site of mutation in the DMD gene, cognitive performance and OCD traits. Interestingly, OCD traits were more frequent in patients with normal IQ, while in those with intellectual disability were more closely related to functional impairment. These findings highlight the need for nuanced clinical evaluation and individualized interventions addressing the interaction between genetic, cognitive, and psychopathological factors in DMD. The study underscores the importance of a holistic approach to care, emphasizing the recognition and management of OCD traits within this population.

BACKGROUND:Tubulin-folding cofactor E (TBCE) plays a central role in tubulin heterodimer formation and disaggregation. Both TBCE biallelic and monoallelic pathogenic variants have been associated with human diseases involving endocrine and/or neurologic system. This study aimed to expand current knowledge on the neurodegenerative phenotype associated with TBCE variants, and to explore possible genotype-phenotype correlations. METHODS:Subjects with a neurodegenerative syndrome caused by biallelic TBCE variants were recruited from three centers. Clinical, genetic, neuroimaging and neurophysiological data were collected retrospectively and, when available, longitudinally. A systematic literature review focusing on genotype-phenotype correlations was also performed. RESULTS:Thirteen subjects, including eight newly reported and five previously published, were enrolled. Data from 322 additional patients were available from systematic literature review, for a total of 335 TBCE mono- and biallelic patients. Sanjad-Sakati syndrome was the most frequent form (85%), while the neurodegenerative phenotype accounted for a minority (5%) of cases. TBCE-related neurodegeneration ranged from progressive spastic-ataxic tetraparesis, optic atrophy and distal motor axonal neuropathy, consistent with already named PEAMO (progressive encephalopathy with amyotrophy and optic atrophy) to milder complex spastic paraparesis. Brain imaging often revealed progressive thinning of the corpus callosum, cerebro-cerebellar atrophy, white matter abnormalities and possible iron accumulation in deep grey matter structures. Additional relevant features included scoliosis, respiratory and gastrointestinal dysfunctions. Genotype-phenotype correlation and a distinct geographic distribution were identified across phenotypes. CONCLUSION:Pathogenic biallelic TBCE variants present phenotypic heterogeneity, with at least four different phenotypes, with genotype-phenotype correlation. TBCE-related neurodegeneration is a severe multisystem disorder that requires multidisciplinary management.

OBJECTIVE:The aim of our study was to establish the prevalence of adverse events in a real-world setting in boys living with Duchenne muscular dystrophy (DMD) treated with givinostat as part of an Expanded Access Program (EAP) in Italy. METHODS:The cohort included 90 ambulant boys, with age when treatment started between 6 and 23 years (mean 10.1 years, SD: 3.2 years) and with a follow up between 6.0 and 14.6 months (mean 10.6 months; SD 2.6 months). RESULTS:Platelets count decrease and triglyceride levels increase were the most common adverse events, followed by diarrhea. A dose reduction was needed in 38 of the 90 boys following thrombocytopenia (n = 34), diarrhea (n = 2), and hypertriglyceridemia (n = 4), with two of the boys presenting both thrombocytopenia and hypertriglyceridemia. Eleven of the 38 boys with initial dose reduction (10 with thrombocytopenia and 1 with hypertriglyceridemia) required an additional dose reduction for persistence of values outside the threshold, with one of them discontinuing treatment because of persistent hypertriglyceridemia even with the lowest dose. INTERPRETATION:Our results confirm the safety profile observed in the pivotal study providing further evidence of the management of the drug in a real-world setting. In our experience, treatment with givinostat was well managed by maintaining a strict monitoring. This was facilitated by allowing families to perform blood tests in local labs, reducing the stress and burden of frequent visits to the hospital.

ABSTRACT Objective Onasemnogene abeparvovec (OA) is an AAV9‐based gene therapy for spinal muscular atrophy type I (SMA I). Real‐world outcomes show increased response variability compared to clinical trials, and follow‐up data beyond 12–18 months are limited. The aim of this 24‐month prospective observational study is to comprehensively describe the clinical outcomes of an Italian cohort of SMA I patients treated with OA. Methods Based on recent literature, patients' treatment status was categorized as: monotherapy (OA only), bridge therapy (transition to OA within 3 months of starting nusinersen or risdiplam), or switch therapy (transition to OA after > 3 months of 1st treatment). Linear mixed‐effects models examined predictors of improvement (CHOP‐INTEND), adjusting for baseline motor function, SMN2 copy number, age, and prior treatment. Descriptive analyses were used to show changes in motor, respiratory, and nutritional milestones. Results The cohort included 64 patients: 27 monotherapy, 9 bridge, and 28 switch. All patients showed significant improvement over 24 months (β = 20.40 points/year, p < 0.001). Patients who switched showed slower improvement (β = −3.76, p = 0.038) compared to monotherapy, while those who bridged showed no difference. Older age at treatment was associated with slower improvement (β = −1.48 points/year per month, p = 0.002). Of 49 non‐sitters at baseline, 39 (80%) achieved sitting and 5 (10%) achieved walking. No new safety signals emerged in the second year of follow‐up. Interpretation Age and baseline motor functional status significantly influence outcomes; however, substantial confounding, particularly the initial treatment, limits the ability to isolate individual effects. Longer follow‐up is essential for evaluating therapeutic responses in heterogeneous SMA I populations.

BACKGROUND:Spinal Muscular Atrophy (SMA) is a genetic disorder resulting from deficiency of the survival motor neuron (SMN) protein. Emerging evidence indicates that SMA is associated with disruptions in neuroactive amino acid metabolism, contributing to altered neurotransmission. Taurine, the predominant inhibitory neuromodulator in the developing central nervous system (CNS), is critical for synaptic function, osmoregulation, and neuroprotection. Despite its physiological significance, the effects of SMN deficiency on taurine homeostasis and its potential role in SMA pathophysiology remain unexplored. METHODS:We used high-performance liquid chromatography (HPLC) to quantify taurine in the spinal cord, brainstem, cortex, and cerebellum in SMN∆7 mice, during postnatal development. We then translate our observation into the clinic by measuring taurine concentrations in the cerebrospinal fluid (CSF) from control individuals (n = 7) and SMA patients of varying disease severity (n = 37) before and after therapy with the SMN-inducing drug Nusinersen. RESULTS:Our data show a downregulation of taurine levels in the brainstem of SMN∆7 mice at late symptomatic stage relative to control littermates. Furthermore, we highlight a taurine reduction in the CSF of naïve SMA1 patients compared to controls. Importantly, Nusinersen treatment restored the taurine deficit in these SMA patients. CONCLUSIONS:These findings demonstrate that SMN deficiency dysregulates taurine homeostasis in the CNS of overt symptomatic mouse models and SMA1 patients. They also reveal the therapeutic efficacy of Nusinersen treatment in correcting this amino acid deficit. However, further research is needed to determine the mechanisms by which SMN deficiency causes taurine dysregulation and its potential contribution to SMA pathology.

Muscular dystrophies are a heterogeneous group of genetic disorders associated with an aberrant inflammatory response, that contributes to disease progression impairing regeneration and inducing fibrosis. Sarcoglycanopathies are recessively inherited limb-girdle muscular dystrophies (LGMDRs), in which the role of inflammation and its association with disease severity remains poorly understood, particularly in alpha-sarcoglycanopathy (LGMDR3). This study characterizes skeletal muscle and peripheral inflammatory signatures in 16 LGMDR3 patients and 8 unaffected individuals through bulk RNA sequencing with additional validation in Sgca-null mice. Patients were classified into mild and severe groups based on alpha sarcoglycan (SGCA) expression in muscle biopsy. Peripheral immunophenotype was assessed via flow cytometry analysis of peripheral blood mononuclear cells (PBMC). Principal component analysis showed a clear separation of severe LGMDR3 from mild LGMDR3 and unaffected individuals, with the latter two groups overlapping. Unsupervised hierarchical clustering analysis of the most variable genes identified distinct gene expression profiles between severe and mild LGMDR3 samples. Severe LGMD3 showed overexpression of innate immune system and T-cell activation pathways, with higher abundance of inflammatory infiltrate, mainly monocytes, cytotoxic T cells and dendritic cells. Notably, severe LGMDR3 were characterized by enrichment of M1-polarized macrophages and pro-inflammatory chemokines, whereas M2-polarized monocytes predominated in mild cases. Similar inflammatory profiles were observed in Sgca-null mice. PBMC analysis revealed significantly increased CD8+, TH1 CD4+ lymphocytes and activated monocytes in LGMDR3 patients compared with controls. Severe LGMDR3 patients additionally showed overexpression of genes governing fibrosis and muscle tissue regeneration and exhibited a clustering pattern similar to Duchenne muscular dystrophy patients. In conclusion, this study represents the first comprehensive characterization of LGMDR3 immunological profiles and demonstrated that inflammation plays a significant role in severe disease pathogenesis. The distinct immune signatures separating severe from mild cases provide a foundation for developing targeted anti-inflammatory therapies that may benefit severe LGMDR3 patients with severe phenotype.

Tubulinopathies encompass a spectrum of disorders resulting from variants in genes encoding α- and β-tubulins, the key components of microtubules. While previous studies have linked de novo or dominantly inherited TUBA4A missense variants to neurodegenerative phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, spastic ataxia, and recently, an isolated congenital myopathy, the full phenotypic and genotypic spectrum of TUBA4A-related disorders remains incompletely characterised. In this multi-centre study, we identified one previously reported and 12 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Remarkably, individuals in 17 families presented with a myopathy without any CNS involvement or history of such disease. In the remaining two families, we observed probands with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness along with protein aggregation. The coexistence of neuromuscular and neurodegenerative features with protein aggregation defines a multisystem proteinopathy. These two families thus establish the first association between TUBA4A and multisystem proteinopathy. Our cohort exhibited diverse genotypes and inheritance patterns: four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had recessive inheritance due to homozygous variants, while the respective heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous variants were classified as sporadic cases. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. We observed a range of disease onset, from congenital to late adulthood. Creatine kinase levels were variable, ranging from normal to highly elevated. Cardiac function remained preserved across the cohort. Muscle biopsies showed heterogenous myopathic changes, including myofibre size variation, nemaline bodies, core-like regions, and internal nuclei. Immunohistochemical analysis revealed protein accumulations positive for TDP-43 (n=2), p62 (n=5), and TUBA4A (n=6). Complementary in silico and in vitro investigations suggested that the identified TUBA4A variants cause significant protein abnormalities and may differentially impact microtubule dynamics. Correlation analyses integrating clinical severity, variant location, and mechanistic readouts further demonstrated that domain specificity within TUBA4A influences both the pattern of muscle involvement and the extent of microtubule disruption. Our findings establish myo-tubulinopathies as distinct clinical entities, encompassing both primary myopathies and multisystem proteinopathies with muscle involvement. This study broadens the phenotypic and genotypic spectrum of TUBA4A-related disorders beyond autosomal dominant or de novo mechanisms and neurodegenerative presentations. These results underscore the importance of considering TUBA4A variants in the differential diagnosis of axial myopathies and multisystem proteinopathies, regardless of central nervous system (CNS) involvement.

IntroductionThe availability of disease modifying therapies in Spinal Muscular Atrophy (SMA) has highlighted the need for more structured registries for collecting reliable information both in treated and untreated individuals. Regulators recommendations have recently become available suggesting how registries should be designed or adapted for different purposes. These include the study of disease epidemiology/natural history in untreated individuals or the assessment in a real world setting of post treatment long term efficacy and safety in much wider cohorts than those included in pivotal trials. We report the adaptation of an academic registry to a nationwide registry describing the different steps of the process.MethodsAll Italian centres were asked to participate. The initial electronic case report form was adapted to be more compliant with recent regulators recommendations, including a more structured coding of adverse events. Training sessions were performed to guarantee data reliability. The governance system was also reviewed and integrated to optimize transparency, accuracy, and collaboration among stakeholders.ResultsAll centres agreed to be part of this effort and completed training sessions. A critical analysis of the performance of the registry shows a high compliance of the centres.DiscussionOur experience suggests that it is possible to keep the reliable structure of an academic registry even when enlarging the registry at national level and adopting a more structured approach in compliance with regulators recommendations. Such a registry can be a valuable source for research purposes and to inform decisions both in a clinical setting and at regulatory level.

BACKGROUND:Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by survival motor neuron (SMN1) deletion. While loss of ambulation in SMA type III typically occurs at a median age of 13.4 years, outcomes in the treatment era remain unclear. This study aims to address that gap by investigating ambulation outcomes in individuals with type III receiving disease-modifying therapies. METHODS:This retrospective study analysed prospectively collected international data. Time-dependent Cox models assessed the association between treatment initiation and age at loss of ambulation, adjusting for age at onset, sex, SMN2 copies, birth year and country. Treatment was modelled as a time-dependent covariate to avoid immortal time bias. Descriptive analyses used Mann-Whitney U and χ² tests. RESULTS:Among 555 individuals with type III, treatment halved the risk of ambulation loss (HR=0.50), with median loss at 44 vs 32 years in treated and untreated groups. Later onset, ≥4 SMN2 copies and female sex were also protective. The treatment effect was significant in type IIIA (HR=0.34) but not IIIB, with no significant interactions by sex, country or SMN2, though effects remained directionally protective. CONCLUSIONS:Treatment in type III reduced the risk of ambulation loss by 50%, extending median ambulation by 12 years, with the greatest benefit in type IIIA. Later onset, female sex and higher SMN2 copy number were also protective but did not modify treatment effect. These findings underscore the value of early treatment and support its broad use to preserve ambulation across clinical subgroups.

OBJECTIVES:This study aims to analyze the use of patient-reported outcomes measures (PROMs), observer-reported outcome measures (ObsROMs), and caregiver-reported outcome measures (CROMs) in spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). The objectives are twofold: (1) to identify and characterize available instruments to be used in research and clinical practice, and (2) to assess their inclusion in drug development and regulatory assessment processes. METHODS:A systematic search was conducted using PubMed, Google Scholar, Scopus, and the ePROVIDE database to identify PROMs, ObsROMs, and CROMs for SMA and DMD. The identified instruments were analyzed for validation, psychometric properties, Minimal Clinically Important Difference (MCID), and recall period. Additionally, clinical trial protocols, relative study publications, European Public Assessment Report (EPAR), and Italian Medicines Agency (AIFA) reports for innovativeness recognition on medicines for SMA and DMD (i.e., nusinersen, onasemnogene abeparvovec, risdiplam, and ataluren) were reviewed to evaluate the inclusion of these measures in drug development and regulatory assessment. RESULTS:The initial search identified 50 questionnaires, including 40 PROMs, 5 ObsROMs, and 5 CROMs. Of these, 15 (30.0%) instruments were included in pivotal clinical trial protocols, with none designated as primary endpoints. Only 6 (12.0%) instruments were mentioned in EPARs, and MCID determination was reported for 6 (12.0%) of the instruments. Generic instruments like the PedsQL were frequently used but criticized for limited specificity. CONCLUSIONS:Despite the availability of PROMs, ObsROMs, and CROMs for SMA and DMD, their use in clinical trials and regulatory documents is limited and inconsistent. Greater standardization and systematic inclusion of these measures are needed to support patient-centered drug development and evaluation.

BACKGROUND:Plasma neurofilament light chain (pNfL) is increasingly investigated as a biomarker of axonal damage in several neurological disorders, including hereditary spastic paraplegias (HSPs). Currently, very few studies are focused on pediatric HSPs. METHODS:Plasma NfL levels were measured in 40 pediatric (e.g., <18 years) subjects affected by genetically solved or unsolved HSPs. For 31 subjects, longitudinal NfL evaluation was also available. Potential correlation between pNfL and disease-specific or non-specific features were explored. RESULTS:Median age at enrollment was 11.53 years, with a median disease duration of 9 years and a median NfL level of 8.5 pg/mL. At baseline, pNfL did not differ across SPG, vs non-SPG HSPs, GMFCS levels, pure vs complex phenotype (with a non-statistically significant increase in the latter) and early- vs childhood-onset forms. Higher levels were observed in subjects with shorter disease duration from onset. Genetically unsolved individuals exhibited non-significant reduced levels compared with genetically confirmed cases. Plasma NfL presented a similar age-related trajectory as in the healthy pediatric population, with a possible trend of increase in younger children. Finally, no differences were observed at longitudinal NfL evaluation after a median period of 9 months. CONCLUSIONS:This study is the first pediatric-focused work exploring utility of pNfL in HSPs. NfL levels showed a tendency of increase especially in complex forms, in younger subjects and with shorter disease duration from onset. Lower levels were observed in genetically unsolved individuals. Larger and longer studies are warranted to further define NfL utility as a clinically relevant biomarker in pediatric HSPs.

Missense variants in TTN pose a major challenge in genetic diagnostics due to their high frequency in the general population, the large size of the gene, and the complex multidomain architecture of the titin protein. While the contribution of truncating variants (TTNtv) to titinopathies is well established, the role of rare TTN missense variants remains poorly defined. Advances in computational prediction and functional testing offer new tools to assess their potential pathogenicity, which however are currently not fully utilized for clinical application. We analyzed an international cohort of unsolved myopathy cases selected based on the presence of a rare missense variant in trans with a TTNtv. Clinical data were collected from neuromuscular centers worldwide. In silico predictions were generated using AlphaMissense and complemented by minor allele frequency (MAF) and exon usage information. Additional inclusion criteria were based on a MAF < 0.010 and an AlphaMissense score ≥ 0.792 for the missense variants, in accordance with the latest ClinGen guidelines. Selected missense variants were characterized in vitro through protein expression and cell imaging assays to assess their effects on domain solubility and aggregation. Thirty patients with TTNtv/missense combinations were identified, presenting with heterogeneous myopathic phenotypes, ranging from congenital to adult onset. An in-depth analysis on AlphaMissense predictions highlighted those changes most frequently predicted as possibly pathogenic. Functional assays showed that three selected variants with changes to proline, located in β-sheets of Ig domains, led to impaired folding, cytoplasmic aggregation and co-localisation with proteostasis markers. In our cohort, all non-proline mutations occurred at buried sites, while some proline substitutions affected exposed residues. Notably, the variant p.(Gln7023Pro) was identified in 5 unrelated families sharing a conserved haplotype, indicating a common ancestor. This variant and the previously reported p.(Arg25480Pro) now meet ACMG criteria for classification as likely pathogenic. By integrating clinical, computational, and functional evidence, we propose a framework for interpreting TTN missense variants. Combining multiple lines of evidence is essential for variants’ classification and interpretation, especially given TTN complexity. Advancing diagnostic accuracy will require tailored interpretation guidelines and a global effort in data sharing and functional validation.

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. In addition to motor neuron survival, SMN deficiency affects the integrity and function of afferent synapses that provide glutamatergic excitatory drive essential for motor neuron firing and muscle contraction. However, it is unknown whether deficits in the metabolism of excitatory amino acids and their precursors contribute to neuronal dysfunction in SMA. To address this issue, we measured the levels of the main neuroactive D- and L-amino acids acting on glutamatergic receptors in the central nervous system of SMN∆7 mice as well as the cerebrospinal fluid (CSF) of SMA patients of varying severity before and after treatment with the SMN-inducing drug Nusinersen. Our findings reveal that SMN deficiency is associated with disruption of glutamate and serine metabolism in the CSF of severe SMA patients, including decreased concentration of L-glutamate, which is partially corrected by Nusinersen therapy. Moreover, we identify dysregulated l-glutamine/L-glutamate ratio as a shared neurochemical signature of altered glutamatergic synapse metabolism that implicates neuron-astrocyte dysfunction in both severe SMA patients and mouse models. Lastly, consistent with hypo-glutamatergic neurotransmission in SMA, we show that daily supplementation with the NMDA receptor co-agonist d-serine improves neurological deficits in SMN∆7 mice. Altogether, these findings provide direct evidence for central dysregulation of D- and L-amino acid metabolism linked to glutamatergic neurotransmission in severe SMA and have potential implications for treating this neurological disorder.

BACKGROUND:Non-selective sodium leak channel (NALCN) protein encoded by the NALCN gene is of key importance for neuronal cell excitability. Previous reports showed that biallelic NALCN pathogenic variants cause infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1) while monoallelic variants lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD). In our work, we aimed to expand the heterozygous NALCN-related clinical spectrum, presenting two affected individuals and a literature review. METHODS:We describe two new unrelated subjects harboring monoallelic NALCN pathogenic variants identified through clinical exome sequencing and review the current literature of other heterozygous NALCN patients. RESULTS:The c.3542G > A (p.Arg1181Gln) and the novel c.3423C > A (p.Phe1141Leu) heterozygous missense variants were disclosed in two subjects manifesting a similar phenotype characterized by congenital ataxia with progressive cerebellar atrophy, camptodactyly, and hypertrichosis of the arms (CAPCACH). Other NALCN subjects with overlapping features have already been reported. A combination of these clinical and neuroimaging findings suggests the definition of the new CAPCACH phenotype. CONCLUSION:We expand the heterozygous NALCN-related clinical spectrum from the more severe CLIFFAHDD to the milder CAPCACH phenotype. These conditions should be considered in the differential diagnosis of syndromic congenital ataxias, and the presence of camptodactyly and/or hypertrichosis may represent peculiar diagnostic clues.

Aberrant activity of histone deacetylases (HDACs) is a pathological phenomenon in several diseases, including Duchenne muscular dystrophy (DMD). In DMD, the upregulation of HDACs is driven by the disassembly of the dystrophin-associated protein complex (DAPC), which, under normal physiological conditions, provides mechanical stability to muscle fibres and acts as a signalling hub anchoring signalling proteins and molecules to their functional sites. In dystrophic muscle, DAPC disassembly causes delocalisation of signalling proteins and, therefore, disrupts signalling pathways. Displacement of epigenetic signalling molecules leads to the uncontrolled activity of HDACs and excessive removal of acetyl groups from histone proteins. Consequently, chromatin becomes tightly bound, preventing the expression of genes involved in muscle homeostasis. The pathological consequences of increased HDAC activity extend beyond muscle fibres, affecting several cell types, translating into a chronically activated immune system, promoting fibrotic and adipose tissue formation and impairing muscle regeneration. Here, we review the current evidence implicating HDACs as a key driver in DMD disease development and progression. We describe the mechanism of HDAC overactivity and the downstream consequences that contribute to the pathogenesis of the disease by disrupting muscle repair and regeneration. Finally, we highlight HDACs as targets for inhibition, offering a novel therapeutic strategy to counteract the multiple pathological events in DMD.

Spinal Muscular Atrophy (SMA) is a progressive neuromuscular disorder caused by homozygous loss of the survival motor neuron 1 (SMN1) gene, leading to reduced SMN protein expression. Increasing evidence implicates neurotransmission deficits in the pathophysiology of SMA. In particular, alterations in neuroactive amino acids involved in glutamatergic neurotransmission have recently been identified in both the cerebrospinal fluid (CSF) of SMApatients and the spinal cord of SMNΔ7 mouse models. L-arginine, a precursor of nitric oxide, plays a critical role in glutamatergic receptor signalling, influencing neurotransmitter release, synaptic plasticity, and neuroprotection. However, it remains unclear whether SMN deficiency affects L-arginine metabolism in SMA. To address this, we used high-performance liquid chromatography to investigate whether SMN deficiency alters L-arginine homeostasis in the central nervous system of SMNΔ7 mice and in the CSF of SMA patients with varying disease severity, both before and after treatment with the SMN-inducing therapy Nusinersen. Notably, we observed significantly reduced L-arginine levels in the brainstem and spinal cord of symptomatic SMA mice compared to age-matched wild-type littermates. Consistent with these findings, we revealed lower L-arginine levels in severe SMA1 patients compared to milder SMA2 and SMA3 patients and healthy controls, enhancing the translational strength of our findings. Importantly, Nusinersen-mediated SMN upregulation fully restored L-arginine homeostasis in the CSF of severe SMA1 patients. In conclusion, our results demonstrate a dysregulation of L-arginine in SMA and highlight a role for SMN-enhancing therapies in restoring neurochemical alterations observed in patients with this neurodegenerative disease.

Background: Congenital myopathies are a group of neuromuscular disorders that typically present at birth or early childhood with hypotonia and non-progressive or slowly progressive muscle weakness. They are classically subclassified by characteristic structural changes and histopathological findings in skeletal muscle. Variants in over 40 genes have been described to date in patients with various forms of congenital myopathy with overlapping phenotypic and histological features, which poses a challenge for laboratories and clinicians in interpreting genetic findings. Objective: The purpose of this study was to evaluate the evidence supporting each gene-disease relationship and provide an expert-reviewed classification for the clinical validity of genes involved in congenital myopathies. Methods: The ClinGen Neurological Disorders Clinical Domain Working Group assembled the Congenital Myopathies Gene Curation Expert Panel (CongenMyopathy-GCEP), a group of clinicians and geneticists with expertise in congenital myopathies tasked to perform evidence-based curation of 50 gene-disease relationships using the ClinGen semiquantitative framework to assign clinical validity. Results: Our curation effort resulted in 35 (70%) Definitive, eight (16%) Moderate, six (12%) Limited, and one (2%) Disputed disease relationship classifications. The summary of each curation is made publicly available on the ClinGen website. Conclusions: Expert-reviewed assignment of gene-disease relationships by the CongenMyopathy-GCEP facilitates accurate molecular diagnoses for congenital myopathies and can allow genetic testing to focus on genes with a validated role in disease.