Becker muscular dystrophy (BMD) is due to Duchenne muscular dystrophy gene variants allowing partial expression of dystrophin. A detailed description of disease trajectories in different genetic subgroups, and the identification of factors predicting progressive vs stable disease, are indispensable for designing and interpreting current and future clinical trials. We recruited male participants with a molecularly confirmed diagnosis of BMD at our Institution, and followed them up with an observational longitudinal design with functional evaluations, including North Star Ambulatory Assessment (NSAA), 6-minute walk test, and timed function tests. We recruited 107 participants. Time-to-event analyses of age at loss of ambulation estimated that only 25% of individuals with BMD lose ambulation by age 60 years. Functional measures, over a follow-up of a mean ± SD of 6.4 ± 3.5 evaluations per participant, and a time of 6.1 ± 3.6 years, showed a poor performance in the common deletions del 45–47 and del 45–48, and preserved muscle function with del 48 and deletions ending on exon 51. In the overall cohort, all measures declined significantly over time, but this decrease was more evident in genetic groups with more marked weakness, and in participants with baseline values of NSAA of 32/34 or lower. These data refine genotype-phenotype correlations in BMD; quantify the decline in several practical and reliable motor outcome measures, which can be directly applied to power calculations for clinical trials; and point to useful inclusion/exclusion criteria for trials. Long-term outcomes will serve as a comparator for “real-world” efficacy data of upcoming therapeutics.

Ryanodine receptor 1-related myopathies (RYR1-RM) are caused by RYR1 gene variants and comprise a wide spectrum of histopathological manifestations. Here, we focus on patients carrying RYR1 variants and muscle histopathology consistent with central core disease (CCD) or multi-minicore disease (MmD). RNA-sequencing analyses of skeletal muscle biopsies obtained from both CCD and MmD patients and from healthy controls were performed to better understand the molecular pathways activated by RYR1 variants. Our analyses revealed that, beyond the well-established role of RYR1 in calcium homeostasis, broader cellular pathways are implicated. In CCD, differentially expressed genes were enriched for pathways related to oxidative stress response, SMAD signalling, and apoptosis, consistent with the role of intracellular calcium dysregulation in promoting mitochondrial dysfunction and cell death. In contrast, MmD patients exhibited enrichment of pathways related to immune activation. This was corroborated by the upregulation of GTPase-regulating genes and the down-regulation of transcriptional repressors such as ZFP36 and ATN1. When considering all RYR1-RM patients collectively, Wnt signalling, immune-related pathways, and oxidative phosphorylation emerged as shared enriched pathways, indicating possible convergent mechanisms across histopathological phenotypes. Our study suggests that complex gene regulation driven by RYR1 variants may be a unifying feature in CCD and MmD, offering new insight into potential therapeutic targets.

Background: The impact of Long-Term Non-Invasive Ventilation (LT-NIV) on patient-relevant outcomes has yet to be clearly established in types 2 and 3 Spinal Muscular Atrophy (SMA). Objectives: The current study aimed to assess LT-NIV effect(s) on tracheostomy-free survival and the need for hospitalization. Its secondary aim was to identify patient characteristics that can be considered risk factors for an unsatisfactory response to treatment. Design: This study is a retrospective analysis of long-term outcomes in types 2 and 3 SMA patients receiving home LT-NIV. Methods:Patients and interventions: Eighteen types 2 and 3 SMA patients who were receiving home LT-NIV between 1 January 1990 and 31 March 2025 were included. Primary study endpoint: The endpoint comprised a composite of tracheostomy-free survival time and hospitalization rate. Results: Twelve patients (66.7%) had a positive response to LT-NIV (group A); the response was unsatisfactory in the remaining 6 (33.3%) (group B). Tracheostomy-free survival time was significantly reduced in the latter compared to the former [66 (range: 2–172) vs. 280 (range: 67–407) months; p = 0.010] and the hospitalization rate was significantly higher [0.35 (range: 0.06–1.44) vs. 0.07 (range: 0.00–0.18) episodes/yr; p = 0.007]. A correlation was found between an unsatisfactory response to LT-NIV and treatment initiation following an episode of acute respiratory failure (OR: 7.90; 95% CI, 0.99–123.2; p = 0.051). Conclusions: LT-NIV has a positive impact on tracheostomy-free survival and hospitalizations in types 2 and 3 SMA patients. The risk of an unsatisfactory response appears to be higher when the treatment is initiated in clinically unstable patients.

Piezo2 channels are mechanosensors expressed in dorsal root ganglia and Merkel cells, and involved in proprioception and touch sensation. PIEZO2 pathogenic variants cause rare autosomal dominant and recessive disorders. Dominant forms include distal arthrogryposis type 3, 5, and Marden-Walker syndrome, whereas the recessive form corresponds to distal arthrogryposis with impaired proprioception and touch (DAIPT). Given the rarity of these conditions, additional reports are essential to refine their phenotypic characterization. We conducted a multicenter, retrospective study to identify patients with genetically confirmed PIEZO2-related disorders. We collected clinical data through a standardized assessment. Previously published cases were included when more detailed phenotypic information was available. We identified 44 individuals with a clinical diagnosis of PIEZO2-related disorders. Among them, we selected 42 patients with a confirmed molecular diagnosis. Sixteen of them (10 males and 6 females; median age at diagnosis: 8 years; range 0.9-14) carried biallelic pathogenic PIEZO2 variants. They typically presented with neonatal hypotonia and respiratory distress with feeding difficulties. Distal arthrogryposis was associated with a variable multisystemic involvement, including the musculoskeletal system with scoliosis, hip dislocation and laryngomalacia. Twenty-five patients (11 males and 14 females; median age at diagnosis: 7 years; range 0.3-39 years) carried monoallelic variants, exhibiting a broad phenotypic spectrum. An additional prenatal diagnosis (at 23 weeks of gestation) was reported among heterozygous cases. In our cohort, ten previously unpublished causative variants were identified. A systematic assessment of skeletal muscle involvement revealed a severe myofibrillar disarray in one case. This study provides a comprehensive and systematic phenotypic characterization of patients across the spectrum of PIEZO2-related disorders. Our findings support a clear clinical distinction between recessive and dominant forms. The clinical manifestations extend beyond the peripheral nervous system and the Merkel cells, suggesting a broader PIEZO2 tissue expression during early developmental stages. Dominant PIEZO2-related disorders are heterogeneous, ranging from mild to severe forms. Our study also suggests that many patients exhibit a respiratory involvement, emphasizing the need for regular respiratory follow-up in the long-term clinical management of both dominant and recessive forms.