Objectives Charcot-Marie-Tooth disease is an inherited peripheral neuropathy marked by progressive loss of motor and sensory function. GDAP1 mutations are implicated in Charcot-Marie-Tooth disease, but the precise mechanism is not fully understood. This study aims to decipher the underlying genetic variant and its functional consequences in a consanguineous Indian family. Methods Clinical and electrophysiological examination was carried out in proband and family members. Whole-exome sequencing was done in proband and the identified variant validated among family members and healthy controls. Skin fibroblasts, derived from patient, family members, and controls were used to analyse mitochondrial structural and functional integrity using transmission electron microscopy, mitochondrial membrane potential measurements, reactive oxygen species quantification, and Seahorse-based extracellular flux assays. Results An 8-year-old boy born to consanguineous parents and affected younger sister presented with progressive motor and sensory limb involvement secondary to progressive severe distal axonal neuropathy. Whole-exome sequencing identified a novel homozygous frameshift variant (c.503_504delAG) in GDAP1 in proband that was segregated among the family members. Patient-derived fibroblasts demonstrated complete loss of protein expression and swollen mitochondria with disrupted cristae in the cultured fibroblasts of affected individuals. Altered mitochondrial membrane potential with elevated reactive oxygen species levels, and significantly reduced ATP production and oxygen consumption rate in affected individuals compared to unaffected parents and controls, indicated impaired mitochondrial bioenergetics. Conclusions We report a novel GDAP1 frameshift variant that disrupts mitochondrial structure and bioenergetics, underscoring GDAP1’s role in mitochondrial quality control. However, the other downstream mechanisms implicated in axonal degeneration remains to be elucidated.
Mouse models carrying specific subsets of mutations are particularly suitable for personalized medicine research. Nonetheless, mouse models do not completely mimic the human phenotype. This is the case for different Duchenne muscular dystrophy (DMD) mouse models, in which several aspects like muscle force, histopathology, cognition, and behavior can vary considerably, confounding the interpretation of therapy outcomes in preclinical studies. Two main common mutations in the DMD gene are exon 2 duplication and exon 45 deletion (1% and 4% of DMD patients respectively). Two mouse models carrying these mutations have been previously developed, named Dup2 and hDMDdel45, respectively. However, detailed studies on the locomotor, functional, behavioral, and histopathological aspects are lacking and would be beneficial for studies assessing treatment outcomes. This study also compares those features to the first mouse model identified for DMD, the mdx. We assessed histopathological features (fibrosis, inflammation, and centronucleation), isometric and isotonic (eccentric contraction) muscle force generation, locomotion (hang-wire and rotarod tests), and behavioral (open-field test) features in those mice. Our studies show that Dup2 and hDMDdel45 mice present significant deficits in function and behavior. Diaphragm and skeletal muscles have elevated levels of inflammation and fibrosis in comparison to wild-type controls. This study demonstrated that Dup2 and hDMDdel45 mice have the same degree of pathology as the classical DMD mouse model, the mdx.
Background Congenital myasthenic syndromes (CMS) are inherited disorders caused by defects in proteins essential for neuromuscular transmission. Methods In this nationwide, multicenter retrospective study, we analyzed 133 genetically confirmed CMS cases from 118 unrelated families between 2017 and 2024 across 28 centers in Türkiye. Clinical, electrophysiological, and genetic data were collected from medical records. In addition, we performed a PubMed-based review of previously reported genetically confirmed Turkish CMS cases to place our findings in a broader national context. Results The median age at symptom onset, and the median diagnostic delay were 6 months and 24 months, respectively. Ocular involvement was the most common clinical feature, followed by respiratory and bulbar involvement. High consanguinity (82%) contributed to a predominance of homozygous variants. Variants were identified in 16 CMS-associated genes, with COLQ (34.6%), CHRNE (24.1%), and CHAT (12.8%) being the most frequent. Postsynaptic CMS was the most common anatomical subgroup. Eighteen novel variants across 11 genes expanded the mutational spectrum of CMS. Review of 23 previously published studies from Türkiye identified 139 additional genetically confirmed cases, showing a broadly similar genetic distribution, with CHRNE and COLQ predominating, followed by CHAT, whereas other CMS-associated genes were reported only sporadically. Conclusions These findings define the clinical and genetic landscape of CMS in Türkiye and, together with previously published Turkish cases, provide a broad national overview based on 272 genetically confirmed cases. The results highlight the major contribution of a limited number of genes and underscore the importance of early molecular diagnosis in a population with high consanguinity.
Comparative evidence between efgartigimod and intravenous immunoglobulin (IVIg) in generalized myasthenia gravis (gMG) remains limited, especially regarding outcomes beyond the first month. We evaluated the 6-month efficacy and safety of single-cycle intravenous efgartigimod versus IVIg in 51 patients with moderate-to-severe gMG (efgartigimod: 26; IVIg: 25) receiving concomitant immunosuppressive therapy in a real-world setting. At month 1, significantly more efgartigimod-treated patients achieved the primary endpoint of minimal symptom expression (MSE) without intensive immunotherapy (42.3% vs. 12.0%; P=0.023). Efgartigimod also demonstrated greater reductions in MG-ADL scores at month 1 compared with IVIg (adjusted mean difference, -2.37; 95% CI, -3.99 to -0.74; P=0.004). The median time to MSE was significantly shorter in the efgartigimod group (2.1 vs. 5.9 months; Breslow P=0.030). However, clinical differences became non-significant at months 3 and 6. Rates of disease relapse or exacerbation remained comparable between groups. Both treatments were well tolerated. In conclusion, single-cycle intravenous efgartigimod was associated with faster early clinical improvement compared with IVIg, while outcomes were comparable at months 3 and 6 in the context of real-world immunosuppressive therapies. These findings suggest that efgartigimod may represent an alternative therapeutic option for patients with gMG requiring rapid symptom control.
Postoperative recurrence remains an important concern in patients with myasthenia gravis (MG) after thymectomy. T-cell abnormalities are involved in MG pathogenesis, but the prognostic value of postoperative peripheral blood CD3+ T-cell percentage in non-thymomatous MG is unclear. We evaluated the association between postoperative peripheral blood CD3+ T-cell percentage and recurrence after thymectomy in patients with non-thymomatous MG. This retrospective cohort study used data from an existing MG thymectomy database. Patients with non-thymomatous MG who had available postoperative peripheral blood CD3+ T-cell percentage data and follow-up information were included. Patients were divided into low and high postoperative CD3+ T-cell groups according to the median value. Logistic regression was used to evaluate the association between postoperative CD3+ T-cell group and postoperative recurrence during follow-up, whereas time-to-event analyses were performed using Kaplan-Meier curves and Cox regression. The primary analysis included 275 patients, of whom 82 experienced postoperative recurrence. The low and high postoperative CD3+ T-cell groups included 136 and 139 patients, respectively. Recurrence occurred in 49 patients (36.0%) in the low postoperative CD3+ T-cell group and 33 patients (23.7%) in the high postoperative CD3+ T-cell group. In crude logistic regression, high postoperative CD3+ T-cell percentage was associated with lower odds of recurrence (OR=0.55, 95% CI [0.33, 0.93], p = 0.027). This association remained after adjustment for age at onset, sex, worst preoperative Myasthenia Gravis Foundation of America (MGFA) class, onset-to-thymectomy time, and preoperative immunotherapy (OR=0.57, 95% CI [0.33, 0.97], adjusted p = 0.037). In Cox regression, high postoperative CD3+ T-cell percentage showed a directionally consistent but statistically non-significant association with recurrence-free survival (HR=0.69, 95% CI [0.44, 1.08], adjusted p = 0.104). Sensitivity analyses generally supported the direction of the primary finding. In this retrospective cohort of patients with non-thymomatous MG after thymectomy, higher postoperative peripheral blood CD3+ T-cell percentage was associated with lower odds of postoperative recurrence. Time-to-event analyses showed a similar direction but did not reach statistical significance. These findings suggest that postoperative CD3+ T-cell percentage may be a clinically accessible marker associated with recurrence risk, but prospective validation is needed.
Mitochondrial diseases are a prevalent cause of metabolic disorders arising from nuclear or mitochondrial DNA mutations. Their clinical and genetic heterogeneity highlight their diagnostic complexity.A 55-year-old male patient with Kallmann syndrome, retinitis pigmentosa and congenital sensorineural hearing loss presented with a one-year history of generalized weakness and imbalance. Examination revealed generalized muscle atrophy, hyporeflexia, and mild tetraparesis. Following an electromyography suggestive of proximal myopathy, muscle biopsy was consistent with mitochondrial myopathy. Mitochondrial respiratory chain analysis demonstrated increased activity of complex II and residual increases in complex I and cytochrome C. Full mitochondrial DNA sequencing identified a heteroplasmic MT-TS2 variant (m.12257G>A), with 15% heteroplasmy in blood and nearly 100% in muscle tissue. This variant was classified as likely pathogenic.This case illustrates a new potentially pathogenic variant in the MT-TS2 gene. Comprehensive analysis of mitochondrial DNA is essential to establish a definitive diagnosis.
Paraproteinemic myopathies are rare but potentially treatable disorders caused by pathogenic monoclonal proteins, yet diagnosis is often delayed because of nonspecific clinical manifestations and the lack of standardized diagnostic approaches. The 294th ENMC International Workshop convened 21 experts from 12 countries and two patient representatives to establish international consensus on their diagnosis and management. The workshop reviewed current evidence on sporadic late-onset nemaline myopathy (SLONM), light-chain (AL) amyloid myopathy, vacuolar myopathy with monoclonal gammopathy and stiffness (VAMMGAS), and scleromyxedema-associated myopathy. Clinical red flags include age at symptom onset ≥40 years, subacute proximal and/or axial weakness, normal or mildly elevated creatine kinase levels (except in VAMMGAS), dysphagia, weight loss, systemic manifestations, and poor response to conventional immunotherapy. Consensus diagnostic criteria for SLONM and a diagnostic algorithm for paraproteinemic myopathies were established. Routine Congo red staining of muscle biopsies, particularly in patients with monoclonal protein, was recommended. The workshop endorsed replacing SLONM-MGUS with SLONM-MP to reflect the pathogenic role of the monoclonal protein and recommended plasma cell-directed therapy as the cornerstone of treatment for SLONM-MP and AL amyloid myopathy. These recommendations provide the first international consensus framework for the diagnosis and management of paraproteinemic myopathies and establish priorities for future collaborative research.
Duchenne and Becker muscular dystrophies (DMD/BMD) are caused by mutations in the dystrophin gene. The intron-62 promoter produces Dp71 and the putative shorter isoform Dp40, but antibody specificity and the existence of Dp40 protein remain controversial. Here, we systematically evaluated the reactivity of commonly used anti-dystrophin antibodies toward Dp71 isoforms and Dp40. The Abcam DMD and Novocastra/Leica DYS2 antibodies were Dp71d-specific, whereas the Proteintech DMD, 7A10, and N-terminal Dp71/40 antibodies recognized both Dp71d and Dp71f isoforms. Importantly, ectopic Dp40 was detected using only N-terminal Dp71/40 antibody, and signals previously attributed to Dp40 likely represent proteolytic fragments of Dp71. Sequence analysis further indicates that the Dp40 transcript does not appear to contain a functional polyadenylation signal within its intron 70-derived sequence and instead retains downstream exon-intron sequences, suggesting that it may represent an atypical transcript. These findings define antibody specificity and raise questions regarding the existence of Dp40 protein, providing a framework for future studies on Dp71 and Dp40.
Myotonic dystrophy type 1 (DM1) is a progressive, multisystemic disorder in which gastrointestinal (GI) involvement is prevalent but frequently underestimated in routine clinical care. This study aimed to evaluate the GI manifestations and symptom burden in patients with adult-onset DM1. We performed a retrospective study in patients with genetically confirmed adult-onset DM1. GI symptom burden was assessed through three sources: (1) patient-reported outcome measures (PROMs), specifically the Gastrointestinal Symptom Rating Scale (GSRS) and the Sydney Swallow Questionnaire (SSQ), (2) an open-ended question asking patients to name their five most bothersome symptoms, and (3) GI symptoms and diagnoses documented in their medical records. Associations between GI symptoms and sex, age, disease duration, Body Mass Index (BMI), and CTG repeat size were analysed. Ninety-five patients with adult-onset DM1 were included (57% female; mean age 44.2±11.8 years). GI symptoms imposed a substantial burden, as 54% of patients exceeded the GSRS clinical threshold and 53% exceeded the SSQ threshold. In open-ended reporting, 31% of patients named a gastrointestinal problem among their most bothersome symptoms, ranking it fourth among all complaints, 13% named swallowing difficulties. In line with the PROM findings, medical record review demonstrated a high prevalence of GI manifestations, including dysphagia (59%), diarrhoea (35%), and constipation (33%). Female sex was strongly associated with higher odds of constipation (OR 9.25,p<0.01), diarrhoea (OR 3.45,p=0.02), and abdominal pain (OR 7.40,p<0.01). Increasing age and longer disease duration were associated with higher odds of constipation, dysphagia, cholelithiasis, and non-alcoholic liver steatosis (p<0.05). No associations were observed for CTG repeat size or BMI. GI symptoms are highly prevalent and burdensome in adult-onset DM1. Female sex, longer disease duration, and older age were associated with a higher symptom prevalence. Structured screening using PROMs should be integrated into multidisciplinary care to ensure that these symptoms are detected promptly and addressed adequately.
Gene therapy with onasemnogene abeparvovec (OA) has dramatically improved the prognosis of spinal muscular atrophy (SMA) since its approval. Thrombotic microangiopathies (TMA), including atypical complement-mediated hemolytic uremic syndrome (aHUS), represent rare but potentially life-threatening complications associated with OA. Complement activation and immune response against the viral vector capsid are considered the main pathogenic mechanisms. We report a 10-month-old girl with SMA type 1 and three SMN2 gene copies, initially eligible for OA. Baseline assessment revealed persistently undetectable Complement Component 3 (C3) levels (<0.29 g/L) and multiple concurrent infections. Next-generation sequencing identified likely pathogenic heterozygous C3 (c.3489+1G>A) and heterozygous CFI gene variants of uncertain significance (c.148C>G, p.Pro50Ala), both associated with increased risk of aHUS. The multidisciplinary team considered the patient at high risk and OA was withheld to prevent a potentially fatal TMA event. This case highlights how systematic complement screening prior to gene therapy may help identify high-risk individuals.
Spinal muscular atrophy with congenital bone fractures type 2 (SMABF2) is an ultra-rare neuromuscular disorder caused by pathogenic variants affecting the ASC-1 complex, most commonly ASCC1. The disorder is typically characterized by severe congenital hypotonia, prenatal or congenital fractures, and early respiratory failure. We report a girl with a novel homozygous intronic donor-site variant, c.95+5G>C, in ASCC1. In contrast to the classic SMABF2 phenotype, she had no congenital fractures and survived until 7 years of age. Her clinical presentation included generalized hypotonia, areflexia, minimal spontaneous movements, dysmorphic features related to fetal hypomobility, progressive respiratory insufficiency requiring tracheostomy and gastrostomy, and cardiac involvement. This case expands both the genetic and phenotypic spectrum of ASCC1-associated disease. The comparatively prolonged survival and absence of congenital fractures suggest that not all ASCC1 variants result in a fully loss-of-function phenotype. However, this interpretation remains hypothetical because functional RNA studies were not performed.
Circulating microRNAs (miRNAs) are promising non-invasive biomarkers across various diseases, including neuromuscular disorders; however, their clinical utility in myotonic dystrophy type 1 (DM1) and facioscapulohumeral muscular dystrophy type 1 (FSHD1) requires validation in diverse cohorts. We profiled serum miRNAs in patients with DM1 (n = 27), FSHD1 (n = 36), and healthy controls (n = 17) to identify differentially expressed candidates. We performed differential expression analyses, and explored the biological pathways modulated by the differentially expressed miRNAs (DEmiRNAs). In DM1, 34 DEmiRNAs were identified (log₂FC -8.97 to +4.99); hsa-miR-1306-5p, hsa-miR-483-3p, and hsa-miR-885-5p remained significant after false discovery rate (FDR) adjustment (q < 0.05). Core pathways included CREB signaling in neurons, cardiac hypertrophy signaling, and molecular mechanisms of cancer, alongside toxicity-related signatures like renal necrosis. However, these computational predictions should be interpreted with caution. In FSHD1, multiple DEmiRNAs were detected at nominal p < 0.05. However, none remained significant after FDR correction. Phenotype-miRNA analyses linked hsa-miR-208b-3p in DM1 to higher serum creatine kinase (p = 0.008). In FSHD1, hsa-miR-2277-5p correlated with later onset (p = 0.020), and detectable hsa-let-7i-3p was associated with better function. Circulating miRNAs were associated with DM1 and FSHD1 and may represent potential biomarker candidates in these disorders. In DM1, miR-1306-5p, miR-483-3p, and miR-885-5p were among the most robust candidates. Further validation studies are required to establish their clinical utility.
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.
Valosin-containing protein (VCP) pathogenic variants cause a multisystem proteinopathy characterized by myopathy, Paget disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis (ALS). We evaluated 82 affected individuals, 14 presymptomatic carriers, and 36 unaffected first-degree relatives from 48 families to identify sensitive measures for disease monitoring. Mean age of onset was ∼42 years for myopathy, Paget disease, or ALS, and 53 years for dementia. Functional assessments included the Inclusion Body Myositis Functional Rating Scale (IBMFRS), ALSFRS-R, Fatigue Severity Scale (FSS), and six-minute walk test (6MWT). Affected individuals demonstrated progressive functional decline, with IBMFRS decreasing 1.9% annually, FSS increasing 4.4%, and 6MWT decreasing 6% annually when modeled against disease duration. Women declined more rapidly on IBMFRS but showed slower ambulatory and fatigue progression. Potential genotype-specific effects were observed, with earlier onset and shorter survival in p.Arg155Cys compared to later onset in p.Arg155His. Strong correlations among IBMFRS, FSS, and 6MWT indicate these as accessible endpoints for longitudinal monitoring and clinical trials. Rapid decline with ALS and dementia necessitates multidisciplinary support, while longer survival after myopathy or Paget onset offers a window for preventive and supportive interventions.
Spinal Muscular Atrophy (SMA) is a rare, inherited neuromuscular disease affecting infants to adults. 5q-SMA is primarily caused by a homozygous deletion of exon 7/8 in the SMN1 gene. The disease is classified into 5 subtypes (SMA type 0-4) based on the age of disease onset and highest level of motor function attained. However, knowledge about the adult SMA population and the natural progression of the disease in this group remains limited. To address this gap and gain a comprehensive understanding of the natural history of SMA in the UK, the Adult SMA REACH data collection study was launched in 2020. This study supports the implementation and approval process of disease-modifying therapies for adults living with SMA - further information can be found from ClinicalTrials.gov with trial identifier NCT06978985, (https://clinicaltrials.gov/study/NCT06978985). Adult SMA REACH study collected data nationally from 19 sites over a period of four years. In this report, we present baseline data from 376 adults with SMA, captured before or at the initiation of treatment as part of the Adult SMA REACH study. We here characterise the cohort by SMA type and functional status at treatment onset using demographics and a series of functional outcome measures used in SMA.
Females heterozygous for a variant in the DMD gene may develop dilated cardiomyopathy; however, progression to severe heart failure is uncommon, and heart transplantation in this population has rarely been reported. We describe nine females with dystrophinopathy and severe cardiac involvement: five underwent heart transplantation, one received a left ventricular assist device, one died from end-stage heart failure, and two remain on medical therapy. Overall, heart transplantation was well tolerated and effective, with 8-11 years of follow-up available for four patients. Immunostaining of explanted hearts from two patients showed mosaic dystrophin expression without evidence of skewed X-chromosome inactivation, suggesting additional genetic or environmental modifiers. These findings highlight the importance of regular cardiac surveillance in all females heterozygous for a DMD variant-particularly during pregnancy and the postpartum period and in families with severe cardiac involvement-and support heart transplantation as a viable option in end-stage heart failure.
