Myotonic dystrophy type 1 (DM1) is a multisystemic and heterogeneous disorder caused by the expansion of CTG repeats in the
3' UTR of the
myotonic dystrophy protein kinase (DMPK) gene. There is a congenital form (CDM1) of the disease characterized by severe
hypotonia,
respiratory insufficiency as well as developmental delays and
intellectual disabilities. CDM1 infants manifest important brain structure abnormalities present from birth while, in contrast, older patients with adult-onset DM1 often present neurodegenerative features and milder progressive cognitive deficits. Promising
therapies targeting central molecular mechanisms contributing to the symptoms of adult-onset DM1 are currently in development, but their relevance for treating
cognitive impairment in CDM1, which seems to be a partially distinct
neurodevelopmental disorder, remain to be elucidated. Here, we provide an update on the clinical presentation of CDM1 and review recent in vitro and in vivo models that have provided meaningful insights on its consequences in development, with a particular focus on the brain. We discuss how enhanced toxic gain-of-function of the mutated DMPK transcripts with larger CUG repeats and the resulting dysregulation of
RNA-binding proteins may affect the developing cortex in utero. Because the methylation of CpG islets flanking the trinucleotide repeats has emerged as a strong
biomarker of CDM1, we highlight the need to investigate the tissue-specific impacts of these
chromatin modifications in the brain. Finally, we outline promising potential therapeutic treatments for CDM1 and propose future in vitro and in vivo models with great potential to shed light on this disease.