Brain MRI Abnormalities, Epilepsy and Intellectual Disability in LAMA2 Related Dystrophy – a Genotype/Phenotype Correlation

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.

Exploring Splice-Site Mutations in LAMA2-Related Muscular Dystrophies: A Comprehensive Analysis of Genotypic and Phenotypic Patterns

“…Therefore, the suspicion of LAMA2-RDs in patients of this origin should prompt a search for this specific mutation. The c.5234+1G>A mutation was identified in five patients from Portugal and seven from Brazil [25][26][27]. The c.5562+5G>C variant was predominantly observed in patients from the UK [6,28,29].…”

“…Besides, 10 patients were identified as LGMD-like phenotype cases. Among individuals with severe MDC1A (n=68), 16 patients had a homozygous genotype, 50 patients exhibited a compound heterozygous genotype characterized by a splice-site mutation combined with another loss-of-function mutation (splicing/frameshift/nonsense), and only two patients had a splice-site mutation associated with a missense mutation [6,7,11,17,18,[24][25][26][30][31][32][33][34][35][36][37][38][39][40][41]. Of the 68 severe MDC1A cases, 32 patients had documented results regarding the level of laminin-α2 expression.…”

“…Concerning the patients with LGMD-like phenotype (n=10), their genotype was primarily made of splice-site mutations with missense mutations (7/10) [17,26,27,[44][45][46][47]. Genotypes with missense mutations, especially those in the N-terminal region with a preserved C-terminal expression (G domain of laminin-α2), are linked to partial expression of laminin-α2 and less severe clinical manifestations [5,9], which could explain these…”

“…The c.5562+5G>C variant was predominantly observed in patients from the UK [ 6 , 28 , 29 ]. Lastly, the mutation c.8244+1G>A (n=9) was detected in five Brazilian patients, two from Tunisia, two from Morocco, and two others with unspecified origins [ 6 , 11 , 18 , 26 , 30 ]. This suggests the possibility of it being a recurrent mutation, particularly in the Maghreb region.…”

The Interaction of LAMA2 and Duration of Illness Affects the Thickness of the Right Transverse Temporal Gyrus in Major Depressive Disorder

“…LAMA2 gene is the most common cause of MDC1A, 53 Nevertheless, the condition has a widespread impact and affects not just the muscles but can also cause brain malformations, mental retardation, and other alterations. 54 Moreover, it is frequently accompanied by seizures. Electroencephalogram (EEG) showed that temporal and occipital epilepsy was the most common, further proving that the right transverse temporal might be the primary brain region affected by the LAMA2 gene.…”