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.

Titin, the largest human protein, is essential for sarcomere structure and function. The TTN gene, spanning 364 exons, undergoes extensive alternative splicing thus producing multiple isoforms. The M-band region, encoded by exons 359-364, plays a critical role in sarcomere integrity and mechanical stability. Exon 363 is of interest due to its involvement in titinopathies. Pathogenic truncating variants in this exon have been linked to recessive myopathies, including and mainly young-onset recessive distal titinopathy. A multicenter study was conducted on six patients from five unrelated families with confirmed recessive titinopathy and truncating variants in exon 363. Clinical evaluations were performed. Genetic testing and segregation analysis confirmed the phase of the variants. A novel truncating variant c.107578C>T, p.(Gln35860Ter) was identified in four unrelated patients of Eastern European ancestry, all carrying a second pathogenic variant in a canonical TTN exon. These patients exhibited juvenile/young-adult onset recessive distal titinopathy with progressive lower limb weakness, frequently asymmetric muscle involvement, and no cardiac or respiratory complications. A Belgian family presented with a congenital myopathy caused by a novel frameshift deletion c.107430delA, p.(Ser35811AlafsTer32) in exon 363, in compound heterozygosity with a truncating variant in exon 208. These patients showed a more severe phenotype. This study expands the spectrum of TTN-related myopathies, emphasizing exon 363's pathogenic significance. Truncating exon 363 variants contribute to young onset recessive distal and sometimes early onset titinopathy with contractures, and the phenotype severity is influenced by the second variant's location and exon usage.

GNE myopathy is a muscle disease due to mutations in the GNE gene, encoding for the key enzyme of sialic acid biosynthesis. This disorder firstly involves distal lower limb muscles and slowly progresses to scapular girdle and distal upper limb muscles. We describe a cohort of 13 patients (9/13 women and 4/13 men) affected by GNE myopathy, followed on average for 15 years. The diagnoses were based on clinical evaluation, EMG, muscle MRI/CT, muscle biopsy and genetic analysis. Our patients have a mean age of 44 years old. The onset of symptoms was between the second and third decade of life. In the early stage, every patient complained difficulty in walking caused by foot drop. Ten patients are now wheelchair-bound, and quadriceps is typically spared in each patient, as commonly described for GNE myopathy. Only one patient developed respiratory failure requiring non-invasive ventilation. EMG study revealed a myopathic pattern in quite all patients and muscle biopsy showed atrophic fibres with "rimmed" vacuoles. Finally, all our patients are genetically characterized: 4/13 present a homozygous mutation in GNE gene, 9/13 a compound heterozygous one. GNE myopathy is a very rare muscle disorder, probably under-diagnosed because of the large group of diseases manifesting with foot drop. Although that, it's necessary to suspect it in case of distal and bilateral lower limb muscles weakness with quadriceps sparing. Several aspects of this myopathy are still unclear and there is no approved therapy for, but novel therapeutic strategies continue to be explored.

Homozygous mutations in the DNAJB4 (NM_007034) gene impair HSP40 function, leading to early respiratory failure due to diaphragm involvement and rigid-spine-like characteristics. We describe the case of a 23-year-old male patient who was admitted for acute respiratory failure and motor deficit of the distal upper limbs. Creatine kinase values were elevated (10x upper normal limit), while the pulmonary function tests showed restrictive respiratory syndrome (forced vital capacity at 20% of theoretical values). The deltoid muscle biopsy findings were consistent with myofibrillar myopathy. Genetic analysis by NGS panel sequencing identified a homozygous deletion c.(?_1)_(1014_?)del, p.? (HGVS nomenclature) of the entire DNAJB4 gene, confirmed by qPCR. Both healthy parents exhibited the variant at the heterozygous state. Our results demonstrate that homozygous c.(?1)(1014_?)del, p.? deletion in DNAJB4 leads to a hereditary myopathy, further underscoring the gene's crucial role in muscle maintenance and function.

The J-domain proteins (JDPs), or HSP40s, are essential molecular co-chaperones that, in concert with HSP70, play a pivotal role in maintaining protein homeostasis, which is particularly critical in skeletal muscle. In recent years, pathogenic variants in several JDP-encoding genes have been identified as a cause of a growing group of inherited muscle diseases, termed JDP-related myopathies. This review provides a comprehensive overview of the current understanding of the molecular genetics, clinical phenotypes, muscle pathology, and pathomechanisms of myopathies caused by mutations in DNAJB6, DNAJB4, and DNAJB2. These disorders present with a wide spectrum of clinical features, including limb-girdle or distal weakness, and, in some cases, severe early-onset respiratory failure with axial rigidity. Pathologically, they are often characterized by rimmed vacuoles and sarcoplasmic protein inclusions. The underlying molecular mechanisms all involve disruption of the JDP-HSP70 chaperone system, but they are driven by distinct molecular events specific to each gene and mutation type. While loss-of-function is a primary mechanism for recessive forms of DNAJB4 and DNAJB2 myopathy, a toxic gain-of-function mediated by a dysregulated interaction with HSP70 is emerging as a central pathomechanism for dominant myopathies caused by DNAJB6 and DNAJB4 variants. A dominant-negative effect is proposed for dominant DNAJB2 neuromyopathy. This evolving mechanistic understanding is crucial as it informs the development of targeted therapeutic strategies, moving beyond supportive care. Potential future therapies include gene replacement for loss-of-function disorders, and for gain-of-function diseases, approaches including small molecule inhibitors of the JDP-HSP70 interaction or allele- and isoform-specific knockdown.