Dados do Trabalho

Título

Neuroimaging, genetic and clinical correlations in LAMA2- congenital muscular dystrophy

Resumo

Introduction:LAMA2-Congenital muscular dystrophy (CMD) is the most common cause of CMD. LAMA2 gene codifies a protein named laminin alpha-2 (merosin), which binds to alpha-dystroglycan and is expressed in skeletal muscle fibers, and also in the brain.
Objective:Characterize motor, genetic and neuroimaging changes, and in a large cohort of CMD-LAMA2
Methods: Patients were divided according to motor severity, and, for each group, comparisons were made among motor, genetic and central nervous system findings.
Results:The study cohort consisted of 56 patients. (1)Three patients (5,3%) had the severe congenital form and were not able to sit without support.
(2) Forty-three (76,8%) patients had the classic congenital form and were able to sit unassisted.
(3) Five patients (8,9%) had the mild congenital form and were able to walk; among them, two patients who had acquired independent gait at four and five years of age became wheelchair dependent at age of eight years.
(4) Five patients (8,9%) had the limb girdle muscular dystrophy form and acquired gait within the expected age.
40 different mutations were found, 26 variants were novel.
All three patients with the severe congenital form had null variants in both alleles.
36 (83,7 %) patients with the classic congenital form presented null variants in both alleles and 7 (16,3 %) had one null variant with one missense or inframe variant.
Among 5 patients with mild congenital form, 3 had one missense variant plus one null or CNV variant, and two had two null variants. The patients with 2 null variants were those who lost ambulation.
Among patients able to walk, there was a higher frequency of missense variants than null variants (p<0.05).
Among the three patients with severe congenital form, one had associated cortical malformation. Cortical malformations were also found in 8 (18,6%) patients with the classic congenital form.
Among patients who were able to acquire gait none had cortical malformation.
All patients who presented cortical malformations had null variants in both alleles.
Cortical malformations were: occipital polymicrogyria, temporal polymicrogyria, occipital lissencephaly-pachygyria and white matter changes.
They were more frequently seen in patients with mutations located in the LG domains, region that binds Laminin-211 to alpha dystroglycan (p<0.05)
Conclusion: The most severe motor presentations are related to cortical malformations and null variants, and to variants present in the LG domain of LAMA2 gene.