Myotonic dystrophy type 1 (DM1) is a multisystemic disorder frequently associated with central nervous system (CNS) involvement, especially in congenital and childhood-onset forms. However, behavioral alterations in preclinical models have so far been only partially characterized, underscoring the need for more comprehensive analyses to support the development of targeted therapeutic approaches. This study aimed to provide a comprehensive behavioral characterization of DMSXL mice, a transgenic model carrying large CTG repeat expansions in the human DMPK gene, to identify robust and translational CNS-relevant phenotypes for preclinical studies. Using both longitudinal and cross-sectional designs, we assessed a wide range of behavioral domains including motor function, emotional reactivity, cognition, and social interaction over time in DMSXL mice. The study was conducted in two independent laboratories with complementary expertise in DM1 pathophysiology and behavioral phenotyping. DMSXL mice displayed a consistent pattern of behavioral alterations reflecting CNS dysfunction. These alterations included dysregulation of emotional responses such as altered anxiety-like behavior and impaired risk evaluation, subtle deficits in object recognition and spatial memory, and reduced sociability and social discrimination. Sensorimotor gating and goal-directed behaviors were also affected, while working memory and general locomotion during open field exploration were largely preserved. This study defines a constellation of behavioral impairments in DMSXL mice that mirror CNS symptoms in DM1 patients and establishes a set of sensitive, age-dependent endpoints suitable for CNS-targeted therapeutic evaluation. The behavioral framework presented here offers valuable guidance for the design of future preclinical trials in DM1.

Myotonic dystrophy type 1 (DM1) is the most common adult muscular dystrophy, with variable pediatric presentations. Data on quality of life (QoL) and fatigue in children are limited. This study evaluated clinical features, QoL, and fatigue in pediatric DM1. We conducted a cross-sectional study of 24 children with genetically confirmed DM1 followed at a tertiary pediatric neuromuscular clinic between January 2020 and January 2024. Clinical data were retrospectively reviewed, and patients were categorized into congenital, childhood-onset, or juvenile-onset subtypes. QoL and fatigue were assessed using the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales, Neuromuscular Module, and Multidimensional Fatigue Module, with both parent-proxy and self-reports obtained during routine visits. The cohort (median age 14 years, IQR:8.5-15.75) comprised congenital (n = 4), childhood-onset (n = 11), and juvenile-onset (n = 9) cases. The most common presenting symptoms were hand stiffness(75 %), weakness(54 %), and learning difficulties(50 %). Intellectual disability or learning difficulties were present in 79 %. Multisystem involvement included cardiac (25 %), respiratory (17 %), gastrointestinal (42 %), and ophthalmologic (42 %) complications. Parent-proxy reports revealed reduced QoL across all subgroups (median total scores 43.5-62.0 vs. ≥80 in healthy children). Fatigue was prominent, with sleep/rest fatigue most impaired, particularly in juvenile-onset patients (median 20.8 vs. 79.2 in childhood-onset, p = 0.007). Children with DM1 exhibit significant multisystem morbidity and marked impairments in QoL and fatigue. Cognitive and behavioral difficulties are prevalent, supporting the need for routine neuropsychological assessment and educational support. Multidisciplinary care should incorporate systematic QoL and fatigue evaluation, with targeted interventions such as sleep management to optimize long-term outcomes.

Myotonic dystrophy type 1 (DM1) is a genetically mediated, multisystemic neuromuscular disorder with significant phenotypic heterogeneity. This review aimed to summarize recent advances in clinical understanding, natural history, and therapeutic development, with a focus on cardiac, respiratory, cognitive, and pediatric aspects of DM1. Longitudinal studies are refining the natural history of both adult and pediatric DM1. Advances in biomarker discovery, including composite ribosomal nucleic acid splicing metrics and imaging findings, are improving disease monitoring and treatment assessment. Cardiac risk stratification is evolving, although respiratory management remains challenging due to adherence issues. Increasing attention is being given to cognitive and behavioral impairments, particularly in congenital and childhood-onset DM1. Although disease-modifying therapies remain in development, real-world data on symptomatic treatments such as mexiletine and nonpharmacological interventions, including exercise and cognitive behavioral therapy, provide valuable clinical insights. Recent literature highlights substantial progress in understanding DM1 across different age groups and organ systems. Although no approved disease-modifying therapies exist, ongoing clinical trials and biomarker advancements offer hope. This review synthesizes these developments to inform clinical management and guide future research efforts.

To investigate the timing of type 1 myotonic dystrophy (DM1) diagnosis in parents of affected children and describe children's perinatal characteristics and developmental outcomes. This was a descriptive case series of children with congenital myotonic dystrophy (CDM) and childhood-onset myotonic dystrophy (ChDM). Parental timing of DM1 diagnosis and the perinatal, motor, and cognitive outcomes of paediatric patients were recorded. A total of 139 children followed by 12 highly specialized tertiary care neuromuscular centres in Italy and one tertiary neuromuscular centre in the USA were included: 105 children with CDM and 34 children with ChDM (mean age 8 years 8 months and 12 years 2 months respectively; 49 males and 17 males respectively). Seventy (50%) parents were diagnosed with adult-onset DM1 after the affected child was diagnosed. Only 12 (17%) of the 69 parents known to be affected had prenatal testing. Of the 105 children with CDM, 98% had maternally inherited CDM, 36% were born preterm, 83% required a stay in the neonatal intensive care unit for more than 48 hours, 84% and 79% had ambulation and speech delay, and 84% had an IQ lower than 70. Of the 34 children with ChDM, 59% had paternally inherited ChDM, 91% were born at term, and 36% had an IQ lower than 70. Delay in diagnosing DM1 affects family planning. The prenatal and perinatal outcomes of the affected offspring emphasize the need for proactive counselling as parents may be reluctant to conduct prenatal testing.