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Primary mitochondrial diseases (PMDs) are among the most common inherited neurological disorders. They are caused by pathogenic variants in mitochondrial or nuclear DNA that disrupt mitochondrial structure and/or function, leading to impaired oxidative phosphorylation (OXPHOS). One emerging subcategory of PMDs involves defective phospholipid metabolism. Cardiolipin, the signature phospholipid of mitochondria, resides primarily in the inner mitochondrial membrane, where it is biosynthesized and remodelled via multiple enzymes and is fundamental to several aspects of mitochondrial biology. Genes that contribute to cardiolipin biosynthesis have recently been linked with PMD. However, the pathophysiological mechanisms that underpin human cardiolipin-related PMDs are not fully characterized. Here, we report six individuals, from three independent families, harbouring biallelic variants in PTPMT1 , a mitochondrial tyrosine phosphatase required for de novo cardiolipin biosynthesis. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome comprising developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy and white matter changes. Using patient-derived fibroblasts and skeletal muscle tissue, combined with cellular rescue experiments, we characterized the molecular defects associated with mutant PTPMT1 and confirmed the downstream pathogenic effects that loss of PTPMT1 has on mitochondrial structure and function. To further characterize the functional role of PTPMT1 in cardiolipin homeostasis, we created a ptpmt1 knockout zebrafish. This model had abnormalities in body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency. Together, these data indicate that loss of PTPMT1 function is associated with a new autosomal recessive PMD caused by impaired cardiolipin metabolism, highlighting the contribution of aberrant cardiolipin metabolism towards human disease and emphasizing the importance of normal cardiolipin homeostasis during neurodevelopment. [ABSTRACT FROM AUTHOR]

Idiopathic inflammatory myopathies (IIMs) are rare disorders characterized by inflammation of skeletal muscle, which can result in fatty replacement of muscle, muscle atrophy, and subsequent weakness. Therapeutic advancements have improved clinical outcomes but impose an economic impact on healthcare systems. We aimed to summarize the direct and indirect costs associated with IIMs in a systematic review (PROSPERO Registration #CRD42023443143). Electronic databases (MEDLINE, Embase, CINAHL, and Scopus) were systematically searched for full-length articles (excluding case reports) reporting costs specific to patients diagnosed with an IIM, published between database inception and April 19, 2023. Direct cost categories included inpatient, outpatient, medication, home/long-term care, and durable medical equipment such as mobility and respiratory aids. Indirect costs included lost productivity. Eligibility criteria were met by 21 of the 3,193 unique titles identified. Costs are expressed in 2023 United States of America dollars, with adjustments for differences in purchasing power applied to currency conversions. As no study reported on all cost categories, annualized cost of IIM per patient was estimated by calculating the mean cost per category, and then adding the means of the different cost categories. By this method, IIM was estimated to cost $52,210 per patient per year. Proportional contributions by category were lost productivity (0.278), outpatient care (0.214), medications (0.171), inpatient care (0.161), home/long-term care (0.122), and durable medical equipment (0.053). Newer findings with intravenous immunoglobulin considered first line therapy for IIM demonstrated markedly higher annual medication costs per patient, upwards of $33,900 compared to an average of $3,908 ± $1,042 in older studies. Future cost-effectiveness studies require updated cost-of-illness studies reflecting the evolving sub-classification and treatment options for IIM, and should consider the impact of IIM on patients and their families. [ABSTRACT FROM AUTHOR]

Persistent hyperCKemia results from muscle dysfunction often attributed to genetic alterations of muscle-related genes, such as the dystrophin gene (DMD). Retrospective assessment of findings from DMD analysis, in association with persistent HyperCKemia, was conducted. Evaluation of medical records from 1354 unrelated cases referred during the period 1996–2021. Assessment of data concerning the detection of DMD gene rearrangements and nucleotide variants. A total of 730 individuals (657 cases, 569 of Greek and 88 of Albanian origins) were identified, allowing an overall estimation of dystrophinopathy incidence at ~1:3800 live male births. The heterogeneous spectrum of 275 distinct DMD alterations comprised exon(s) deletions/duplications, nucleotide variants, and rare events, such as chromosome translocation {t(X;20)}, contiguous gene deletions, and a fused gene involving the DMD and the DOCK8 genes. Ethnic-specific findings include a common founder variant in exon 36 ('Hellenic' variant). Some 50% of hyperCKemia cases were characterized as dystrophinopathies, highlighting that DMD variants may be considered the most common cause of hyperCKemia in Greece. Delineation of the broad genetic and clinical heterogeneity is fundamental for actionable public health decisions and theragnosis, as well as the establishment of guidelines addressing ethical considerations, especially related to the mild asymptomatic patient subgroup. [ABSTRACT FROM AUTHOR]

A number of muscular dystrophies are associated with the defective glycosylation of [alpha]-dystroglycan and many are now known to result from mutations in a number of genes encoding putative or known glycosyltransferases. These diseases include severe forms of congenital muscular dystrophy (CMD) such as Fukuyama type congenital muscular dystrophy (FCMD), Muscle-Eye-Brain disease (MEB) and Walker-Warburg syndrome (WWS), which are associated with brain and eye abnormalities. The defective glycosylation of [alpha]-dystroglycan in these disorders leads to a failure of [alpha]-dystroglycan to bind to extra-cellular matrix components and previous attempts to model these disorders have shown that the generation of "fukutin"- and "Pomt1"-deficient knockout mice results in early embryonic lethality due to basement membrane defects. We have used the zebrafish as an animal model to investigate the pathological consequences of downregulating the expression of the putative glycosyltransferase gene "fukutin-related protein" (FKRP) on embryonic development. We have found that downregulating "FKRP" in the zebrafish results in embryos which develop a range of abnormalities reminiscent of the developmental defects observed in human muscular dystrophies associated with mutations in "FKRP". FKRP morphant embryos showed a spectrum of phenotypic severity involving alterations in somitic structure and muscle fibre organization as well as defects in developing neuronal structures and eye morphology. The pathological phenotype was found to correlate with a reduction in [alpha]-dystroglycan glycosylation and reduced laminin binding. Further characterization of the developmental processes affected in FKRP morphant embryos may lead to a better understanding of the pathological spectrum observed in muscular dystrophies associated with mutations in the human "FKRP" gene.

The capacity to link records associated with the same individual across data sets is a key challenge for data-driven research. The challenge is exacerbated by the potential inclusion of both genomic and clinical data in data sets that may span multiple legal jurisdictions, and by the need to enable re-identification in limited circumstances. Privacy-Preserving Record Linkage (PPRL) methods address these challenges. In 2016, the Interdisciplinary Committee of the International Rare Diseases Research Consortium (IRDiRC) launched a task team to explore approaches to PPRL. The task team is a collaboration with the Global Alliance for Genomics and Health (GA4GH) Regulatory and Ethics and Data Security Work Streams, and aims to prepare policy and technology standards to enable highly reliable linking of records associated with the same individual without disclosing their identity except under conditions in which the use of the data has led to information of importance to the individual's safety or health, and applicable law allows or requires the return of results. The PPRL Task Force has examined the ethico-legal requirements, constraints, and implications of PPRL, and has applied this knowledge to the exploration of technology methods and approaches to PPRL. This paper reports and justifies the findings and recommendations thus far. [ABSTRACT FROM AUTHOR]

Objective: Dysferlin is a large transmembrane protein that functions in critical processes of membrane repair and vesicle fusion. Dysferlin‐deficiency due to mutations in the dysferlin gene leads to muscular dystrophy (Miyoshi myopathy (MM), limb girdle muscular dystrophy type 2B (LGMD2B), distal myopathy with anterior tibial onset (DMAT)), typically with early adult onset. At least 416 pathogenic dysferlin mutations are known, but for approximately 17% of patients, one or both of their pathogenic variants remain undefined following standard exon sequencing methods that interrogate exons and nearby flanking intronic regions but not the majority of intronic regions. Methods: We sequenced RNA from myogenic cells to identify a novel dysferlin pathogenic variant in two affected siblings that previously had only one disease‐causing variant identified. We designed antisense oligonucleotides (AONs) to bypass the effects of this mutation on RNA splicing. Results: We identified a new pathogenic point mutation deep within dysferlin intron 50i. This intronic variant causes aberrant mRNA splicing and inclusion of an additional pseudoexon (PE, we term PE50.1) within the mature dysferlin mRNA. PE50.1 inclusion alters the protein sequence, causing premature translation termination. We identified this mutation in 23 dysferlinopathy patients (seventeen families), revealing it to be one of the more prevalent dysferlin mutations. We used AON‐mediated exon skipping to correct the aberrant PE50.1 splicing events in vitro, which increased normal mRNA production and significantly restored dysferlin protein expression. Interpretation: Deep intronic mutations can be a common underlying cause of dysferlinopathy, and importantly, could be treatable with AON‐based exon‐skipping strategies. [ABSTRACT FROM AUTHOR]

Introduction: The correct phenotypic classification of patients with facioscapulohumeral muscular dystrophy (FSHD) is crucial for directing genetic diagnosis and for the definition of outcome measures in clinical trials.Methods: Our objective was to ascertain the utility of the Comprehensive Clinical Evaluation Form (CCEF), the clinical classification proposed by the Italian Clinical Network for FSHD, in an independent FSHD patient population from the UK FSHD Patient Registry. We subdivided the patients into group 1, classic FSHD phenotype/category A of CCEF, and group 2, facial sparing phenotypes/category B1 of CCEF.Results: Among 642 patients with FSHD1, 68.1% reported facial and shoulder weakness, whereas 24.1% reported shoulder weakness without facial impairment. The phenotype in group 2 was milder, with a higher mean age at onset (P < 0.0001) and less severe motor disability.Discussion: Patients with different FSHD phenotypes may have different disease courses. Muscle Nerve 59:711-713, 2019. [ABSTRACT FROM AUTHOR]

We conducted a prospective multinational study of muscle pathology using magnetic resonance imaging (MRI) in patients with limb-girdle muscular dystrophy 2I (LGMD2I). Thirty eight adult ambulant LGMD2I patients (19 male; 19 female) with genetically identical mutations (c.826C>A) in the fukutin-related protein (FKRP) gene were recruited. In each patient, T1-weighted (T1w) imaging was assessed by qualitative grading for 15 individual lower limb muscles and quantitative Dixon imaging was analysed on 14 individual lower limb muscles by region of interest analysis. We described the pattern and appearance of muscle pathology and gender differences, not previously reported for LGMD2I. Diffuse fat infiltration of the gastrocnemii muscles was demonstrated in females, whereas in males fat infiltration was more prominent in the medial than the lateral gastrocnemius (p = 0.05). In the anterior thigh of males, in contrast to females, median fat infiltration in the vastus medialis muscle (45.7%) exceeded that in the vastus lateralis muscle (11.2%) (p<0.005). MRI is non-invasive, objective and does not rely on patient effort compared to clinical and physical measures that are currently employed. We demonstrated (i) that the quantitative Dixon technique is an objective quantitative marker of disease and (ii) new observations of gender specific patterns of muscle involvement in LGMD2I. [ABSTRACT FROM AUTHOR]

Limb-girdle muscular dystrophy type 2A (LGMD2A) is a recessive genetic disorder caused by mutations in the cysteine protease calpain 3 (CAPN3) that leads to selective muscle wasting. We previously showed that CAPN3 deficiency is associated with a profound perturbation of the NF-κB/IκBα survival pathway. In this study, the consequences of altered NF-κB/IKBα pathway were investigated using biological materials from LGMD2A patients. We first show that the antiapoptotic factor cellular-FLICE inhibitory protein (c-FLIP), which is dependent on the NF-κB pathway in normal muscle cells, is down-regulated in LGMD2A biopsies. In muscle cells isolated from LGMD2A patients, NF-κB is readily activated on cytokine induction as shown by an increase in its DNA binding activity. However, we observed discrepant transcriptional responses depending on the NF-κB target genes. IκBα is expressed following NF-κB activation independent of the CAPN3 status, whereas expression of c-FLIP is obtained only when CAPN3 is present. These data lead us to postulate that CAPN3 intervenes in the regulation of the expression of NF-κB-dependent survival genes to prevent apoptosis in skeletal muscle. Deregulations in the NF-κB pathway could be part of the mechanism responsible for the muscle wasting resulting from CAPN3 deficiency. [ABSTRACT FROM AUTHOR]

Pathological cellular hallmarks of Duchenne muscular dystrophy (DMD) include, among others, abnormal calcium homeostasis. Changes in the expression of specific receptors for extracellular ATP in dystrophic muscle have been recently documented: here, we demonstrate that at the earliest, myoblast stage of developing dystrophic muscle a purinergic dystrophic phenotype arises. In myoblasts of a dystrophin-negative muscle cell line established from the mdx mouse model of DMD but not in normal myoblasts, exposure to extracellular ATP triggered a strong increase in cytoplasmic Ca2+ concentrations. Influx of extracellular Ca2+ was stimulated by ATP and BzATP and inhibited by zinc, Coomassie Brilliant Blue-G, and KN-62, demonstrating activation of P2X7 receptors. Significant expression of P2X4 and P2X7 proteins was immunodetected in dystrophic myoblasts. Therefore, full-length dystrophin appears, surprisingly, to play an important role in myoblasts in controlling responses to ATP. Our results suggest that altered function of P2X receptors may be an important contributor to pathogenic Ca entry in dystrophic mouse muscle and may have implications for the pathogenesis of muscular dystrophies. Treatments aiming at inhibition of specific ATP receptors could be of a potential therapeutic benefit. [ABSTRACT FROM AUTHOR]

Reports on the design of a minigene of agrin, a protein known for its role in the formation of the neuromuscular junction, to restore muscle function in a mouse model for congenital muscular dystrophy. Amendment of muscle pathology by a mechanism that includes agrin-mediated stabilization of alpha-dystroglycan and the laminin alpha5 chain; Provision of in vivo evidence on the use of a non-homologous protein in combination with rational protein design, to devise therapeutic tools that may restore muscle function in human muscular dystrophies.

• SMA-PME is rare inherited disease with bi-allelic mutations in the ASAH1 gene. • SMA-PME characterized by progressive myoclonic epilepsy, proximal weakness. • A novel variant c.109C>T(p. Pro37Thr) was reported for SMA-PME in this study. Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a rare inherited autosomal recessive disease due to bi-allelic mutations in the ASAH1 gene. SMA-PME is characterized by progressive muscle weakness from three to seven years of age, accompanied by epilepsy, intractable seizures, and sometimes sensorineural hearing loss. To the best of our knowledge, 47 cases have been reported. The present study reports five patients from four different families affected by SMA-PME characterized by progressive myoclonic epilepsy, proximal weakness, and lower motor neuron disease, as proven by electrodiagnostic studies. Genetic analysis identified two different mutations in the ASAH1 (NM_177924.4) gene , a previously reported pathogenic variant, c.125C>T (p.Thr42Met), and a novel likely pathogenic variant c.109C>A (p.Pro37Thr). In addition to reporting a novel pathogenic variant in the ASAH1 gene causing SMA-PME disease, this study compares the signs, phenotypic, and genetic findings of the case series with previous reports and discusses some symptomatic treatments. [ABSTRACT FROM AUTHOR]

Muscle fibers and myoblasts can participate in immune cell interactions and may play an important role in initiating or perpetuating muscle-derived or directed immune responses. Up-regulation of major histocompatibility (MHC) class I and II antigens under pathological conditions is essential for the interaction of muscle with CD8 cytotoxic T cells and CD4 T helper cells, as observed in the idiopathic inflammatory myopathies. Human muscle cells can present antigens to CD4 T cells and are able to modulate T cell responses via accessory molecules. The expression of B7 costimulatory molecules distinct from B7.1/2; (CD80/CD86) has been postulated but lacks molecular definition and characterization of its functional significance. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction/Aim Methods Results Discussion Patients with myotonic dystrophy type1 (DM1) have reduced lifespan. This study aimed to quantify mortality risks, and evaluate causes and time trends in DM1.We identified 1021 DM1 patients and 15,104 matched DM1‐free controls from the United Kingdom (UK) Clinical Practice Research Datalink. We used Cox proportional hazards regression models to assess differences in all‐cause or cause‐specific mortality between DM1 patients and matched controls, and computed standardized mortality ratios (SMRs) for comparisons of DM1 patients with the UK general population.DM1 patients were at higher risk of death compared with matched DM1‐free controls (hazard ratio [HR] = 2.9, 95% confidence interval [CI] = 2.5–3.4) or the general UK population (SMR = 8.1, 95% CI = 7.3–9.1). The excess risk was primarily attributed to deaths from respiratory failure (HR = 26.7, p < 0.001), aspiration pneumonia (HR = 15.8, p < 0.001), arrythmia, and conduction defects (HR = 15.7, p < 0.001). No mortality risk difference between DM1 patients and matched DM1‐free cohort was noted for all cancers combined (p = 0.52). No significant calendar time‐related changes in overall survival were seen for DM1 patients (p trend = 0.19). In mortality cause‐specific analysis, and compared with patients diagnosed before 1993, death from cancer was on the rise (HR = 2.35, and 5.82 for patients diagnosed 1993–2003, and 2004–2016).Most DM1 patients died of known disease complications. This highlights the need for integrated clinical approaches with more careful and frequent monitoring. [ABSTRACT FROM AUTHOR]

Background: Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013.Method: The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies.Results: Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients.Conclusion: Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate. [ABSTRACT FROM AUTHOR]

Abstract: Mutations in alpha-B crystallin gene (CRYAB) have been described to cause congenital cataracts, dilated cardiomyopathy and myofibrillar myopathy. For skeletal myopathy, only three different mutations have been reported within the last decade. Here we describe for the first time the missense mutation p.Gly154Ser to be associated with a late-onset distal vacuolar myopathy with protein aggregates without respiratory or cardiac dysfunction, and without significant cataracts. The mutation affects a residue in a highly preserved domain of alpha-B crystallin and has been identified earlier in patients with isolated cardiomyopathy. [Copyright &y& Elsevier]

Introduction Congenital myasthenic syndrome (CMS) consists of a diverse group of inherited neuromuscular junction disorders due to altered mechanisms at pre/post synaptic/synaptic cleft. Methods Phenotypic characterization, electromyography (EMG–surface and needle) and decrement pattern using slow rate 3 Hz repetitive nerve stimulation (RNS) in facial, proximal and distal limb muscles among different subtypes of CMS. 75 cases underwent initial hot spot screening followed by targeted sequencing of known CMS genes. Results 59 cases were genetically confirmed. Frequency: CHRNE 42(one fast channel); DOK7 8; GMPPB 4; MUSK 2; RAPSYN, AGRN, DPAGT1 one each. 16/59 had novel mutations. The common recurring mutations [CHRNE-c.1327del G; DOK7-c.1124_1127dup; GMPPB-c.1000G>A]. The mean age at onset was 4.62 ± 8.53 years (0–36). Mean age at presentation 19.09 ± 13.32 years (1–50). Mean duration to the first symptom 14.47 ± 10.79 years (1–50). M:F is 1.1:1. Consanguinity-40/59; Family history-27. Initial symptom [ptosis/opthalmoparesis-40; limb fatigue-16; other symptoms-3]. Clinically ptosis in 55/59; myopathic features-14; bulbar weakness-29. All had preserved or brisk tendon reflexes. Mean creatine kinase-382.6 ± 871.6 U/L (12–4547). Anti AchR antibodies positive in 6; Anti-MuSK antibodies in 3. Muscle biopsy done in 6/59 [2-normal; 2-subtle myopathic features; 2 GMPPB-dystrophic features]. RNS was performed in 47/59. None had double CMAP. Needle EMG- myopathic potentials in 9/59. The mean decrement ( Δ D1-4) in the muscles were: [Orbicularis oculi (36/47 cases)-22.1 ± 13.1% (Range, 15–68, no decrement (ND) in 13.8% cases); Nasalis (22/47)-22.1 ± 11.8% (Range, 13–48, ND-22%); Trapezius (31/47)-23.0 ± 12.2% (Range, 17–46, ND-16.1%); Deltoid (13/47)-33.6 ± 9.2% (Range, 21–51); Anconeus (3/47)-19.6 ± 14.1% (Range, 18–30); Abductor digiti minimi (ADM-21/47) 18.7 ± 8.5% (Range, 13–38, ND-57.2%); Abductor pollicis brevis (APB-11/47) 16.3 ± 3.5% (Range, 13–23, ND-36.3%); Quadriceps (4/47) 38.3 ± 25.3% (Range, 15–60)]. The pattern of decrement is a decrease in CMAP size within the initial 4–5 responses followed by an increment/stable CMAP with subsequent stimuli. RNS was sensitive for orbicularis oculi in all subtypes except 3 cases of CHRNE and the MUSK, AGRN cases. Nasalis was negative in 4 CHRNE cases and in AGRN. Quadriceps and deltoid were sensitive in all subtypes followed by trapezius. ADM and APB had low sensitivity except for chronic cases of CHRNE/post synaptic disorders with distal limb weakness. All responded well to pyridostigmine/salbutamol/fluoxetine. DOK7 worsened with pyridostigmine. Conclusion This is the largest cohort of CMS from a single center reported till now with distinct clinical phenotypes. Slow rate RNS still remains as an effective, sensitive, less time consuming tool in CMS. The proximal limb muscles should be the first choice for RNS in all the genotypes followed by facial muscles. ADM/APB are less sensitive and anconeus is a better alternative. [ABSTRACT FROM AUTHOR]