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.

Background: GSK3β is an intracellular regulatory kinase that is dysregulated in multiple tissues in Type 1 myotonic dystrophy (DM-1). Tideglusib inhibits GSK3β activity in preclinical models of DM-1 and promotes cellular maturation, normalising aberrant molecular and behavioural phenotypes. It is currently in clinical development for the treatment of paediatric and adult patients affected by congenital and juvenile-onset DM-1. Here, we summarise the development of a population pharmacokinetic model and subsequent characterisation of influential demographic and clinical factors on the systemic exposure to tideglusib. The availability of a population PK model will allow further evaluation of age-and weight-related changes in drug disposition, supporting the dose rationale and implementation of a paediatric extrapolation plan. Methods: Given the sparse pharmacokinetic sampling scheme in patients receiving tideglusib, model development was implemented in two steps. First, data from Phase I studies in healthy elderly subjects (i.e., 1832 plasma samples, n = 54) were used to describe the population pharmacokinetics of tideglusib in adults. Then, pharmacokinetic model parameter estimates obtained from healthy subjects were used as priors for the evaluation of the disposition of tideglusib in adolescent and adult DM-1 patients (51 plasma samples, n = 16), taking into account demographic and clinical baseline characteristics, as well as food intake. Secondary pharmacokinetic parameters (AUC, Cmax and Tmax) were derived and summarised by descriptive statistics. Results: Tideglusib pharmacokinetics was described by a two-compartment model with first-order elimination and dose-dependent bioavailability. There were no significant differences in disposition parameters between healthy subjects and DM-1 patients. Body weight was a significant covariate on clearance and volume of distribution. Median AUC(0-12) and Cmax were 1218.1 vs. 3145.7 ng/mL∙h and 513.5 vs. 1170.9 ng/mL, following once daily doses of 400 and 1000 mg tideglusib, respectively. In addition, the time of food intake post-dose or the type of meal appeared to affect the overall exposure to tideglusib. No accumulation, metabolic inhibition, or induction was observed during the treatment period. Conclusions: Even though clearance was constant over the dose range between 400 and 1000 mg, a less than proportional increase in systemic exposure appears to be caused by the dose-dependent bioavailability, which reflects the solubility properties of tideglusib. Despite large interindividual variability in the tideglusib concentration vs. time profiles, body weight was the only explanatory covariate for the observed differences. This finding suggests that the use of weight-banded or weight-normalised doses should be considered to ensure comparable exposure across the paediatric population, regardless of age or body weight.

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by the expansion of a noncoding triplet repeat. A cross-sectional study was performed to characterize pediatric patients with DM1 followed in a tertiary hospital over the last 29 years, comparing the congenital and the childhood/juvenile-onset forms. Thirty-seven patients (59.5 % male) were included, with a median age at the latest assessment of 16.8 years and a median follow-up of 7.7 years. Eleven patients were lost to follow-up, and two died. Twenty-five had congenital DM1 (CDM1), and this form had significantly higher triplet repeat length, history of polyhydramnios, lower median age at diagnosis, and first and last assessment. Common symptoms included distal skeletal muscle weakness (75.7 %) and facial involvement (94.6 %), along with dysphonia/dysarthria (73.0 %) and myotonia (73.0 %). Delayed independent ambulation frequency was significantly higher for CDM1 cases. Skeletal deformities affected 54.1 %, with talipes equinovarus and scoliosis occurring exclusively in CDM1 patients. Cognitive deficit was present in 75.7 % of cases. Polysomnograms revealed seven cases of obstructive sleep apnea and two of hypoventilation. Noninvasive ventilation was used in nine cases, and three had recurrent respiratory infections. The cardiovascular system was affected in 21.6 % of cases. Gastrointestinal issues included constipation (24.3 %), feeding difficulties (16.2 %), and cholelithiasis (5.4 %). Cataracts, epilepsy, and diabetes mellitus were reported in two cases each. Our study highlights the diverse spectrum of severity and multiorgan involvement of DM1 in pediatric patients. It underscores the importance of establishing a pediatric-specific standard of care to enhance health outcomes through comprehensive multidisciplinary management.

There is a high prevalence of neuropsychiatric disorders in myotonic dystrophy types 1 and 2 (DM1 and DM2), including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) in DM1, and depression and anxiety in both DMs. The aim of this systematic review and meta-analysis was to estimate the prevalence of ASD, ADHD, depression and anxiety in the population with DM, and their association with disease onset. A systematic search of Medline, Scopus, Web of Science, and the Cochrane Library was conducted from inception to November 2023. Observational studies estimating the prevalence of these disorders in DM1 or DM2 were included. A meta-analysis of the prevalence of these disorders and an association study with disease onset by prevalence ratio meta-analysis were performed. Thirty-eight studies were included. In DM1, the prevalence of ASD was 14%, with congenital onset being 79% more common than juvenile onset, while the prevalence of ADHD was 21%, with no difference between congenital and juvenile onset, and the prevalence of depression and anxiety were 14% and 16%. Depression was more common in the adult onset. Finally, the prevalence of depression in DM2 was 16%. A higher prevalence of neuropsychiatric disorders is observed in individuals with DM1 and DM2 than in the general population. Therefore, actively screening for congenital and juvenile neurodevelopmental disorders in DM1 and emotional disorders in DM1 and DM2 may improve the quality of life of those affected.

Myotonic dystrophy type 1 (DM1) is a multisystem, autosomal-dominant inherited disorder caused by CTG microsatellite repeat expansions (MREs) in the 3' untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene. Despite its prominence as the most common adult-onset muscular dystrophy, patients with congenital to juvenile-onset forms of DM1 can present with debilitating neurocognitive symptoms along the autism spectrum, characteristic of possible in utero cortical defects. However, the molecular mechanism by which CTG MREs lead to these developmental central nervous system (CNS) manifestations is unknown. Here, we showed that CUG foci found early in the maturation of three-dimensional (3D) cortical organoids from DM1 patient-derived induced pluripotent stem cells (iPSCs) cause hyperphosphorylation of CUGBP Elav-like family member 2 (CELF2) protein. Integrative single-cell RNA sequencing and enhanced cross-linking and immunoprecipitation (eCLIP) analysis revealed that reduced CELF2 protein-RNA substrate interactions results in misregulation of genes critical for excitatory synaptic signaling in glutamatergic neurons, including key components of the methyl-CpG binding protein 2 (MECP2) pathway. Comparisons to MECP2(y/-) cortical organoids revealed convergent molecular and cellular defects such as glutamate toxicity and neuronal loss. Our findings provide evidence suggesting that early-onset DM1 might involve neurodevelopmental disorder-associated pathways and identify N-methyl-d-aspartic acid (NMDA) antagonists as potential treatment avenues for neuronal defects in DM1.