BackgroundLAMA2-related congenital muscular dystrophy (LAMA2-MD) is a genetically heterogeneous disorder defined by progressive muscle weakness, brain structural abnormalities, epilepsy, and multisystem involvement. The primary goal of this study was to characterize the clinical features, temporal progression, and genotype-phenotype correlations of LAMA2-MD.MethodsMedical records of patients with genetically confirmed LAMA2-MD were extracted from a clinical data repository and analyzed retrospectively. Clinical manifestations, laboratory findings, and neuroimaging features were systematically reviewed and compared across different age groups. Variant data were retrieved from public databases to perform comprehensive genetic analyses.ResultsA total of five patients (two males and three females) were enrolled, delayed motor milestones and varying degrees of ankle contractures and persistent motor impairment in all patients were the initial presenting symptom at diagnosis in all cases, and two patients also exhibited cognitive delays. Laboratory analysis of muscle enzymes showed varying degrees of abnormalities, with creatine kinase (CK) levels displaying the most significant elevation. Cranial magnetic resonance imaging (MRI) revealed symmetrical white matter abnormalities in four patients. Seizures were documented in three school-aged patients. All patients carried compound heterozygous variants in the LAMA2 gene. A literature review indicated that the most common variant types were stop-gain and missense variants: stop-gain variants were predominantly associated with complete merosin deficiency (MDC1A), whereas missense variants typically correlated with late-onset limb-girdle muscular dystrophy.ConclusionLAMA2-MD exhibits a broad phenotypic spectrum and a progressive disease course. Early manifestations include muscle weakness, delayed achievement of developmental milestones, joint contractures, seizures and characteristic intracranial abnormalities.

Genetic compensation is a common phenomenon in zebrafish in response to genetic alterations. Differences between genetic and morpholino-mediated zebrafish models of human diseases have led to significant difficulties in phenotypic interpretation and translatability. One form of compensation is the maternal deposit of mRNAs and proteins to the oocyte that supports developmental processes before zygotic genome activation. In this study, we generated a zebrafish model of severe congenital muscular dystrophy (CMD) by targeting protein O-mannose N-Acetylglucosaminyltransferase 2 (pomgnt2), a maternally provided gene that maintains cell-extracellular matrix interactions through glycosylation and leads to congenital muscular dystrophy when mutated. Zygotic knockouts (ZKOs) retain protein function in the first week post fertilization and survive to adulthood, only developing muscle disease later in life. In contrast, maternal-zygotic KOs (MZKOs) generated from ZKO females develop early-onset muscle disease, reduced motor function, neuronal axon guidance deficits, and retinal synapse disruptions recapitulating features of the human presentation. While assessing transcriptional changes linked to disease progression, the availability of embryos obtained from different breeding strategies also allowed for a direct comparison of ZKOs and MZKOs to define the impact of having a KO mother. We found that offspring from a ZKO mother, independently of genotype, show distinct expression patterns from animals obtained from heterozygous breedings. Some of these changes reflect changes in metabolic function, possibly stemming from maternal metabolic disruption. These findings will not only be applicable for other CMD models targeting maternally provided genes, but also provide new insight into modeling disease using maternal-zygotic mutants.

Terminal extubation of a patient with Fukuyama-type congenital muscular dystrophy at the end of life in the PICU

Hereditary neuromuscular disorders (NMDs) comprise a clinically and genetically heterogeneous group of conditions characterized by the involvement of the peripheral nervous system and skeletal muscles. This work presents a literature review focusing on brain neuroimaging findings in hereditary NMDs detected by magnetic resonance imaging. The aim of this work was to describe and synthesize current data on brain magnetic resonance imaging abnormalities across various hereditary NMDs, based on a literature review and a clinical case series, and to evaluate potential clinico-radiological correlations. A literature search was conducted in the PubMed database from 1984 to 2025 July using keywords including (white matter lesion) AND (myotonic dystrophy), (white matter lesion) AND (hereditary neuropathy), (white matter lesion) AND (Charcot–Marie–Tooth), (white matter lesion) AND (muscular dystrophy), (white matter lesion) AND (myasthenic syndrome), and (white matter lesion) AND (motor neuron disease). A total of 107 publications were included in the final review. A clinical case series with magnetic resonance imaging data is also presented, including Charcot–Marie–Tooth disease type 1X, myotonic dystrophy types 1 and 2, merosin-deficient congenital muscular dystrophy, and limb-girdle muscular dystrophy type 23. The reviewed literature indicates that brain magnetic resonance imaging can have both diagnostic and prognostic clinical significance in some hereditary NMDs, especially in myotonic dystrophies, merosin-deficient muscular dystrophy, and Charcot–Marie–Tooth disease type 1X. The presented case series illustrates the variety of magnetic resonance imaging patterns and their association with clinical manifestations, underscoring the importance of integrating neuroimaging into the diagnostic workup for hereditary NMDs.

Patients With Congenital Muscular Dystrophies Require Prospective Neurologic, Cardiologic, and Orthopedic Examinations.

Collagen VI has recently been strongly linked to poor outcomes in heart failure through increased endotrophin, a collagen VI-derived signaling molecule linked to fibrotic remodeling in cardiovascular disease. The mutation of collagen VI can result in Ullrich congenital muscular dystrophy and Bethlem myopathy, pointing to a critical function in muscle physiology. However, the functional role of collagen VI in the heart is poorly understood. In human heart failure with reduced ejection fraction, collagen VI is increased within the remodeled T-tubules, suggesting a possible role in tubular structure and Ca2+ dynamics. To investigate this hypothesis, a global knockout of the collagen VI alpha 1 gene (Col6a1-/-) was generated in the rat. T-tubule structure and ryanodine receptor cluster organization were unchanged, but echocardiography demonstrated reduced systolic function. Consistent with this, isolated trabeculae from Col6a1-/- hearts generated significantly less peak stress, confirming impaired contractile force at the tissue level. Paradoxically, isolated cardiomyocytes from the Col6a1-/- rat had increased Ca2+ transient amplitude and increased sarcoplasmic reticulum Ca2+ load that would be expected to increase force. β-adrenergic stimulation further increased Ca2+ transient amplitude and was associated with diastolic Ca2+ release events in Col6a1-/- cardiomyocytes. Furthermore, β-adrenergic stimulation of Col6a1-/- trabeculae exhibited spontaneous contractions, indicating an increased susceptibility to arrhythmic activity. Together, these results indicate collagen VI has a role in both force transduction and Ca2+ cycling in the heart.

Megaconial congenital muscular dystrophy (MCM) is a rare autosomal recessive mitochondrial myopathy caused by mutations in the CHKB gene, affecting lipid metabolism and mitochondrial function. It is characterized by enlarged mitochondria at the periphery of muscle fibers (“megaconia”). Clinical features include early-onset hypotonia, progressive muscle weakness, global developmental delay with intellectual disability, and cardiomyopathy. Some patients may present congenital heart defects, autistic traits, or ichthyosiform skin lesions. Diagnosis relies on elevated serum CK, electromyography showing a myogenic pattern, muscle biopsy revealing megaconia, and genetic confirmation of CHKB mutations. Management is multidisciplinary, involving physiotherapy, orthotic support, respiratory care, and symptomatic treatment. We report a 10-year-old child with MCM. Due to its multisystem involvement and broad clinical spectrum, differential diagnosis includes other neurometabolic and mitochondrial disorders. Prognosis depends on symptom severity and progression, particularly regarding cardiac and respiratory function.

Response to response to the letter to the editor "Decoding the pathophysiological role of Fukutin in Fukuyama congenital muscular dystrophy".

The extracellular matrix protein laminin-α2 is essential for preserving the integrity of skeletal muscle fibers during contraction. Its importance is reflected by the severe, congenital LAMA2-related muscular dystrophy (LAMA2 MD) caused by loss-of-function mutations in the LAMA2 gene. While laminin-α2 has an established role in structurally supporting muscle fibers, it remains unclear whether it exerts additional functions that contribute to the maintenance of skeletal muscle integrity. Here, we report that in healthy muscle, activated muscle stem cells (MuSCs) express Lama2 and remodel their microenvironment with laminin-α2. By characterizing LAMA2 MD-afflicted MuSCs and generating MuSC-specific Lama2 knockouts, we show that MuSC-derived laminin-α2 is essential for rapid MuSC expansion and regeneration. In humans, we identify LAMA2 expression in MuSCs and demonstrate that loss-of-function mutations impair cell-cycle progression of myogenic precursors. In summary, we show that self-secreted laminin-α2 supports MuSC proliferation post-injury, thus implicating MuSC dysfunction in LAMA2 MD pathology.

The corneal endothelium is the innermost layer of the human cornea and it acts as a barrier between the aqueous humor and the corneal stroma, thus maintaining the hydration of the cornea. Both congenital dystrophies including (1) Fuchs' endothelial corneal dystrophy (FECD), (2) posterior polymorphous corneal dystrophy (PPCD), (3) congenital hereditary endothelial dystrophy (CHED), (4) X-linked endothelial corneal dystrophy (XECD) and age-related degenerations like (5) pseudoexfoliation-related (PEX) keratopathy, (6) pseudophakic bullous keratopathy (PBK), (7) iridocorneal endothelial (ICE) syndromes and endothelial graft rejection after keratoplasty can impair this function and are described in this review article.

Background. Dystroglycanopathies (DGPs) constitute a set of recessive, neuromuscular congenital dystrophies that result from impaired glycosylation of dystroglycan (DG). These disorders typically course with CNS alterations, which, alongside gradual muscular dystrophy, may include brain malformations, intellectual disability and a panoply of ocular defects. In this process, the protein products of 22 genes, collectively dubbed DGP-associated genes, directly or indirectly participate sequentially along a complex, branched biosynthetic pathway. POMGNT2 and POMGNT1 are two enzymes whose catalytic activity consists of transferring the same substrate, a molecule of N-acetylglucosamine (GlcNAc) to a common substrate, the O-mannosylated α subunit of DG. Despite their presumptive role in retinal homeostasis, there are currently no reports describing their expression pattern or function in this tissue. Purpose. This work focuses on POMGNT2 and POMGNT1 expression in the mammalian retina, and on the characterization of their distribution across retinal layers, and in the 661W photoreceptor cell line. Methods. The expression of POMGNT2 protein in different mammalian species’ retinas, including those of mice, rats, cows and monkeys, was assessed by immunoblotting. Additionally, POMGNT2 and POMGNT1 distribution profiles were analyzed using immunofluorescence confocal microscopy in retinal sections of monkeys and mice, and in 661W cultured cells. Results. Expression of POMGNT2 was detected in the neural retina of all species studied, being present in both cytoplasmic and nuclear fractions of the monkey and mouse, and in 661W cells. In the cytoplasm, POMGNT2 was concentrated in the endoplasmic reticulum (ER) and/or Golgi complex, depending on the species and cell type, whereas POMGNT1 accumulated only in the Golgi complex in both monkey and mouse retinas. Additionally, both proteins were present in the nucleus of the 661W cells, concentrating in the euchromatin and heterochromatin, as well as in nuclear PML and Cajal bodies, and nuclear speckles. Conclusions. Our results are indicative that POMGNT2 and POMGNT1 participate in the synthesis of O-mannosyl glycans added to α-dystroglycan in the ER and/or Golgi complex in the cytoplasm of mammalian retinal cells. Also, they could play a role in the modulation of gene expression at the mRNA level, which remains to be established, in a number of nuclear compartments in transformed retinal neurons.

Background/Objectives: To evaluate the prevalence, age at diagnosis, non-invasive ventilation pressures used in management, and clinical predictors for sleep disordered breathing (SDB) in pediatric patients with muscular dystrophies (MDs). Methods: A retrospective analysis of 195 polysomnography (PSG) studies conducted over 20 years for 98 children with different MDs was performed. Diagnosis of SDB was established if a child met the diagnostic criteria for one or more of the following conditions: obstructive sleep apnea (OSA), central apnea, nocturnal hypoxemia, or nocturnal hypoventilation. Outcomes were assessed and compared between MDs. Positive and negative predictive values (PPV, NPV), sensitivity, and specificity for detecting SDB were calculated for certain clinical parameters. Results: SDB was diagnosed in 73.6% of children with MDs, including OSA in 67%, followed by nocturnal hypoxemia (15.3%), nocturnal hypoventilation (7.7%), and central apnea (6.6%). The age at diagnosis and BiPAP pressures used varied between MDs. Patients with Congenital MD had the lowest mean age and required higher pressures (p < 0.05). PPV was high for maximum inspiratory or expiratory pressures (MIP, MEP) < 40% or <60%, forced vital capacity < 50% or <80%, total lung capacity < 60%, left ventricular ejection fraction < 50%, non-ambulation, and body mass index ≥ 95% for the presence of SDB. However, NPV, sensitivity, and specificity varied. Conclusions: SDB is common in pediatric patients with MDs, with OSA being the most prevalent disorder. The age at diagnosis and required BiPAP pressures for management differ among MD groups. Certain clinical measures may help identify some patients with the disease given the high PPV.

BackgroundFukuyama congenital muscular dystrophy (FCMD) is a severe autosomal recessive α-dystroglycanopathy caused by biallelic variants in the FKTN gene, characterized by muscular, neurological, and ocular involvement. This study aimed to evaluate the ophthalmologic manifestations associated with specific FKTN variant subtypes in Korean patients with FCMD.MethodsWe conducted a retrospective review of nine patients with genetically confirmed FCMD who were followed at a single tertiary referral center between 2005 and 2024. Comprehensive ophthalmologic evaluations were correlated with molecular genotyping, including detection of founder retrotransposon (RT) insertions and splice-disrupting variants in the FKTN gene.ResultsSeven of nine patients (77.8%) harbored compound heterozygous variants comprising the RT insertion and deep intronic splice-site variants, while two patients carried non-founder variants. The mean age at last ophthalmic evaluation was 7.59 ± 4.74 years. High myopia (44.4%), strabismus (22.2%), and nystagmus (11.1%) were frequently observed. Fundus examination revealed optic disc abnormalities in 77.8% of patients, including small discs (55.6%), pale discs (33.3%), and peripapillary fibrotic membranes (33.3%). Additional retinal features included dark without pressure (33.3%), tessellated fundus (33.3%), and peripheral pigmentary degeneration (44.4%). Notably, rare but vision-threatening anomalies, such as persistent fetal vasculature and tractional retinal detachment, were observed only in patients with compound heterozygous variants and were absent in those carrying non-founder variants.ConclusionThis study demonstrates that Korean patients with FCMD carrying compound heterozygous variants comprising the RT insertion and deep intronic splice-site variants exhibit a recognizable ophthalmic phenotype characterized by optic disc and retinal abnormalities, highlighting the need for targeted and ophthalmologic surveillance in this patient population.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12886-025-04432-x.

LAMA2 encodes the alpha-2 subunit of a protein called Laminin. It consists of three subunits Y; alpha, beta and gamma. Alpha2 subunit from LAMA2 gene along with beta-2 and gamma-2 forms laminin-2 protein. This protein is necessary for assembly of basement membrane in skeletal muscle cells, Schwann cells, astrocytes and pericytes. More than 100 LAMA2 variant identified so far which cause recessive form of muscular dystrophy (MD) either a severe form, congenital (CMD) or mild form, limb-girdle (LGMD). Patient with LAMA2 MD suffered from muscle weakness, elevated creatine kinase, facial dysmorphism, peripheral motor neuropathy, epilepsy/seizure, developmental delay, and white matter changes in brain MRI. In this study, we conducted whole exome sequencing (WES) to investigate molecular etiology of patients with CMD in one family with non-consanguineous marriage from Iran. WES has identified a novel compound heterozygous variant, [c.2049_2050del (p.Arg683Serfs*21)]; [c.2857–2 A > G (p.?)], in the proband. The identified variant was confirmed by Sanger sequencing and its segregation within the family was verified. Subsequently, in-silico analysis was performed to map the protein–protein interaction network between LAMA2 and proteins implicated in CMD pathogenesis. Our findings may be considered valuable molecular and clinical insights for improving our understanding of CMD, particularly regarding LAMA2 variants. Furthermore, this finding gives new insights to laboratorians, genetic counselors and clinicians for determining at-risk couples in the prenatal diagnosis (PND) program.

Michel Fardeau (1929-2024) was the undisputed pioneer of French myology, internationally recognized for his foundational work on congenital myopathies and muscular dystrophies. A leading specialist in neuromuscular diseases, he described several major forms, including desmin-overload cardiomyopathies and deficiencies in sarcoglycan, merosin, and calpain-3, making decisive contributions to the classification and pathophysiological understanding of these disorders. He also initiated the first clinical gene therapy trials for Duchenne muscular dystrophy, marking a milestone in targeted treatments. His scientific approach, combining morphological, biochemical, and clinical perspectives, revolutionized the diagnosis and management of neuromuscular diseases, and his work remains a global reference that continues to inspire researchers and clinicians worldwide.

Induced pluripotent stem cells (iPSCs) have been used in research for the development of treatments for various intractable diseases due to their unlimited proliferative and multipotent potential. We are aiming to develop novel therapies for intractable muscular diseases using iPS cells by two approaches i.e. cell therapy and drug screening. In this presentation, I focus on the cell therapy research. We have developed a differentiation induction method that mimics the developmental stages and have succeeded in inducing skeletal muscle stem cells that are applicable to cell transplantation therapy. We have found that cell transplantation into Duchenne muscular dystrophy (DMD) model mice is effective in regenerating more than 10% of dystrophin-positive fibers. In addition, some of the cells have been engrafted as satellite cells in vivo, and it is expected that the therapeutic effect will continue for a long period of time. As for the efficacy to the motor function, we have recently revealed that the regeneration of dystrophin positive myofibers in DMD model mice mainly ameliorates muscle fatigue tolerance rather than maximal contraction force in vivo. We have also developed a differentiation method to induce mesenchymal stromal cells (MSCs) from iPSCs. Transplantation of iPSC-derived MSCs (iMSCs) into Ullrich congenital muscular dystrophy (UCMD) model mice enabled the restoration of collagen type VI which resulted in enhancement of muscle regeneration. Interestingly, somatic MSCs such as bone marrow-derived MSC or adipose-derived MSC do not have therapeutic effect even they can also restore collagen type VI by the transplantation. We have recently found one of the candidates which is responsible for the muscle regeneration and is specifically expressed in the iMSCs.

Laminin-α2–related congenital muscular dystrophy (LAMA2-CMD) is a severe neuromuscular disorder caused by mutations in the LAMA2 gene, leading to loss of heterotrimers laminin-211/221, key components of the skeletal muscle extracellular matrix. Their absence disrupts adhesion between the cytoskeleton and extracellular matrix, resulting in progressive muscle wasting. Laminin-211/221 interacts with adhesion complexes such as the dystrophin/utrophin glycoprotein complex and α7β1-integrin. However, the regulatory mechanisms of these laminin-binding complexes and the broader role of laminin’s influence on the formation of the macromolecular network in skeletal muscle remain unclear. We previously demonstrated that delivering mouse laminin-111 to the dyW–/– mouse model of LAMA2-CMD prevented disease progression, improved strength, and extended survival. We hypothesize that laminin-111, the embryonic laminin isoform, restores key adhesion-signaling networks. Using spatial proteomics on patient and mouse muscle, we identified loss of essential signaling components: heat shock proteins 27 and 70, c-Jun N-terminal kinase, and glucose transporter 1 in laminin-α2–deficient muscle. Treatment with recombinant human laminin-111 (rhLAM-111) restored protein localization, reduced ROS, and promoted glycolytic, prosurvival signaling. These findings highlight laminin’s role in maintaining muscle homeostasis and metabolism and support the therapeutic potential of rhLAM-111 for treating LAMA2-CMD by restoring adhesion and intracellular signaling in dystrophic muscle.

Mutations in the Lamin A (LMNA) gene, which encodes the Lamin A and C proteins, cause severe human diseases collectively known as laminopathies. These conditions are often devastating and lack effective therapies. In this study, we developed precise base editing (BE) strategies targeting the human LMNA gene variants L35P and R249Q, which cause congenital muscular dystrophy (CMD) and dilated cardiomyopathy with conduction defects (DCM-CD), respectively. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carrying the R249Q mutation displayed nuclear aberrations, DNA damage, and abnormal Ca2+ transients. Similarly, L35P iPSC-CMs exhibited abnormal contraction, DNA damage, and reduced Lamin A/C protein expression. We also generated "humanized" mouse models carrying these pathogenic human mutations. R249Q homozygous mice exhibited cardiac conduction abnormalities, cardiac arrhythmias, and premature death. Mice with the homozygous L35P mutation displayed severe muscle-wasting and reduced lifespan, while heterozygous L35P mice displayed DCM. We developed an adenine base editing (ABE) approach for correcting the R249Q mutation and a cytosine base editing (CBE) strategy for the L35P variant. Precise correction of these mutations in iPSC-CMs successfully rescued all of the in vitro abnormalities. Furthermore, delivery of the BE components using adeno-associated virus prevented the pathological phenotypes and extended longevity of mice carrying the LMNA L35P and the R249Q mutations. These results demonstrate the efficacy of ABE and CBE in correcting pathogenic LMNA mutations that cause cardiac disease, highlighting BE as a promising therapeutic approach for human laminopathies.

Collagen VI is an extracellular matrix component encoded by COL6A1, COL6A2 and COL6A3 genes. Causative variants in these genes are associated with the following collagen VI-related myopathies: severe Ullrich congenital muscular dystrophy (UCMD), milder Bethlem myopathy (BM) and intermediate phenotypes (INT). We report the mutation landscape of COL6A genes in 138 Italian patients affected with a collagen VI-related phenotype. The patient cohort included 44 (32%) UCMD, 9 (7%) INT, 61 (44%) BM and 21 (15%) INT/BM patients; 3 patients (2%) with a myosclerosis myopathy (MM) phenotype were also considered. We identified 104 different variants: 26 in COL6A1 (25%), 52 in COL6A2 (50%) and 26 in COL6A3 (25%). The variant spectrum includes missense, splicing, small indel, frameshifting and nonsense variants. Glycine substitutions in the triple helical domain of the collagen VI protein are the commonest variants and occur in all phenotypes. Our genetic profiling disclosed a unique mutation scenario and phenotypic association of the COL6A2 gene with respect to COL6A1 and COL6A3, which may be related to a different evolutive history. Landscape mutation analysis of variants occurring in ultrarare conditions, such as collagen VI-related myopathies, is crucial to better understand the variations’ profile and to gain insight into fundamental knowledge about gene structure and its evolutive origin.

SNUPN-related muscular dystrophy or LGMDR29 is a new entity that covers from a congenital or childhood onset pure muscular dystrophy to more complex phenotypes combining neurodevelopmental features, cataracts, or spinocerebellar ataxia. So far, 12 different variants have been described. Here we report the first family with SNUPN-related muscular dystrophy presenting an adult-onset myopathy as well as novel ultrastructural findings. Clinical evaluation, muscle and brain magnetic resonance imaging (MRI), and muscle histopathological and electron microscopy analysis were conducted. Functional studies including protein modelling and interaction, immunofluorescence and splicing analysis were also performed. Two siblings carrying two novel deleterious variants in the SNUPN gene (p.Arg27Cys and p.Cys174Tyr) showed adult-onset proximo-distal and axial muscle weakness with early respiratory involvement. One patient presented with asymptomatic cerebellar atrophy. Muscle MRI identified involvement in the paravertebral, triceps brachii, sartorius and gracilis muscles. The histopathology revealed dystrophic changes and an abnormal pattern of cytoskeletal and myofibrillar proteins, while electron microscopy disclosed the proliferation of granules and vesicles associated with features of nuclear envelope and sarcolemma remodelling. Functional studies showed that SNUPN variants impair snurportin-1 function through reduced binding affinity to importin-β and impaired folding, leading to disturbed nuclear import of small nuclear ribonucleoproteins and downstream splicing. Our work expands the phenotype of SNUPN-related muscular dystrophy and provides more insights into their pathological profile. We advise SNUPN testing in patients with late-onset proximo-distal and axial weakness with early respiratory impairment and features reminding inclusion body myositis (IBM). Granular deposits suggestive of biomolecular condensates perturbed cell organelle traffic and membrane homeostasis, opening new avenues to understand the pathomechanisms involved in this novel disease.