Abstract
BACKGROUND: LAMA2-related muscular dystrophy is a disorder that causes muscle weakness and varies in severity, from a severe, congenital type to a milder, late-onset form. However, the disease does not only affect the muscles, but has systemic involvement and can lead to alterations such as brain malformation, epilepsy and intellectual disability. OBJECTIVE: Describe the frequency of cortical malformations, epilepsy and intellectual disability in LAMA2-RD in a Brazilian cohort and correlate the neurological findings to genetic and motor function. METHODS: This is an observational study of 52 LAMA2-RD patients, who were divided into motor function subgroups and compared based on brain MRI findings, epilepsy, intellectual disability, and type of variants and variant domains. RESULTS: 44 patients (84.6%) were only able to sit, and 8 patients (15.4%) were able to walk. 10 patients (19.2%) presented with cortical malformations (polymicrogyria, lissencephaly-pachygyria, and cobblestone),10 patients (19.2%) presented with epilepsy, and 8 (15.4%) had intellectual disability. CNS manifestations correlated with a more severe motor phenotype and none of the patients able to walk presented with cortical malformation or epilepsy. There was a relation between gene variants affecting the laminin-α2 LG-domain and the presence of brain malformation (P = 0.016). There was also a relation between the presence of null variants and central nervous system involvement. A new brazilian possible founder variant was found in 11 patients (21,15%) (c.1255del; p. Ile419Leufs*4). CONCLUSION: Cortical malformations, epilepsy and intellectual disability are more frequent among LAMA2-RD patients than previously reported and correlate with motor function severity and the presence of variants affecting the laminin-α2 LG domain. This brings more insight fore phenotype-genotype correlations, shows the importance of reviewing the brain MRI of patients with LAMA2-RD and allows greater attention to the risk of brain malformation, epilepsy, and intellectual disability in those patients with variants that affect the LG domain.