Dados do Trabalho

Título

CENTRAL NERVOUS SYSTEM INVOLVEMENT AND THE GENOTYPE-PHENOTYPE CORRELATION IN CMD-LAMA2

Introdução

Patients with LAMA2-congenital muscular dystrophy (CMD) usually present with a severe phenotype characterized by inability to achieve walking capacity, multiple joint deformities, and respiratory insufficiency. However, there is a gravity spectrum, and some patients can walk unassisted. Characteristically, the patients have white matter changes in T2-WI and FLAIR in brain magnetic ressonance. More rarely, cortical changes like polymicrogyria in the temporo-occipital regions can be observed and some of these patients can manifest epilepsy and intellectual disabilities.

Objetivo

The aim of this study was to characterize central nervous system manifestations in a large cohort of CMD-LAMA2 and correlate them to genotype and motor function.

Métodos

In this observational study, 52 patients with genetically confirmed CMD-LAMA2 were included. All patients had brain MRI, and the presence of cortical malformations, epilepsy, intellectual disability was correlated to the motor function. The type and location of the LAMA2 variants were correlated to the motor function and central nervous system manifestations.

Resultados

All patients had white matter abnormalities in brain MRI, and ten of them (19,2%) presented cortical malformations (i.e. polymicrogyria, lissencephaly-pachygyria, cobblestone), seven had cerebellar cysts and white matter changes and three had temporal cysts. In addition, ten patients (19,2%) presented epilepsy and six (11,5%) had intellectual disability. Central nervous system manifestations correlated with motor function severity, and to the variants located at LG-domain (p=0.029). The presence of cortical malformations correlated to the occurrence of epilepsy and intellectual disability (p=0.016 and p=0.0017). A higher frequency of missense, in comparison to null variants, was observed in patients able to walk (p=0.037) and null variants in both alleles were observed in 90% of the patients with cortical malformations.

Conclusões

Central nervous system manifestations are frequent among the CMD-LAMA2 patients and correlate with motor function severity and the presence of LG-domain variants in LAMA2.

Palavras chave

CMD-LAMA2, congenital muscular dystrophy, brain malformation, clinical-genetical correlation, LG-domain

Referências (se houver)

1- Sarkozy Anna, Foley A. Reghan, Zambon Alberto A., Bönnemann Carsten G., Muntoni Francesco. LAMA2-Related Dystrophies: Clinical Phenotypes, Disease Biomarkers, and Clinical Trial Readiness. Frontiers in Molecular Neuroscience, 13, 2020.
2- Leite CC, Reed UC, Otaduy MC, Lacerda MT, Costa MO, Ferreira LG, Carvalho MS, Resende MB, Marie SK, Cerri GG. Congenital muscular dystrophy with merosin deficiency: 1H MR spectroscopy and diffusion-weighted MR imaging. Radiology. 2005;235:190–6
3- Menezes M; McClenahan F; Leiton C; et al. The extracellular matrix protein laminin alpha2 regulates the maturation and function of the blood-brain barrier. J Neurosci, 2014. 12;34(46):15260-80.
4- Arreguin Andrea J., Colognato Holly. Brain Dysfunction in LAMA2-Related Congenital Muscular Dystrophy: Lessons From Human Case Reports and Mouse Models. Frontiers in Molecular Neuroscience, 2020, 13.
5- Carsten G. Bönnemann, Ching H. Wang, Susana Quijano-Roy, Nicolas Deconinck, Enrico Bertini, Ana Ferreiro, Francesco Muntoni, Caroline Sewry, Christophe Béroud, Katherine D. Mathews, Steven A. Moore, Jonathan Bellini, Anne Rutkowski, Kathryn N. North, Diagnostic approach to the congenital muscular dystrophies, Neuromuscular Disorders, Volume 24, Issue 4, 2014, 289-311.
6- Salvati A, Bonaventura E, Sesso G, Pasquariello R, Sicca F. Epilepsy in LAMA2-related muscular dystrophy: A systematic review of the literature. Seizure. 2021 Oct;91:425-436.

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Área

Doenças neuromusculares