Cobblestone Malformation in LAMA2 Congenital Muscular Dystrophy (MDC1A)

Abstract

Congenital muscular dystrophy type 1A (MDC1A) is caused by recessive variants in laminin α2 (LAMA2). Patients have been found to have white matter signal abnormalities on magnetic resonance imaging (MRI) but rarely structural brain abnormalities. We describe the autopsy neuropathology in a 17-year-old with white matter signal abnormalities on brain MRI. Dystrophic pathology was observed in skeletal muscle, and the sural nerve manifested a mild degree of segmental demyelination and remyelination. A diffuse, bilateral cobblestone appearance, and numerous points of fusion between adjacent gyri were apparent on gross examination of the cerebrum. Brain histopathology included focal disruptions of the glia limitans associated with abnormal cerebral cortical lamination or arrested cerebellar granule cell migration. Subcortical nodular heterotopia was present within the cerebellar hemispheres. Sampling of the centrum semiovale revealed no light microscopic evidence of leukoencephalopathy. Three additional MDC1A patients were diagnosed with cobblestone malformation on brain MRI. Unlike the autopsied patient whose brain had a symmetric distribution of cobblestone pathology, the latter patients had asymmetric involvement, most severe in the occipital lobes. These cases demonstrate that cobblestone malformation may be an important manifestation of the brain pathology in MDC1A and can be present even when patients have a structurally normal brain MRI.

Cobblestone‐like brain malformation with a new bi‐allelic ADGRG1 (GPR‐56) mutation: Fetal imaging‐pathology correlation

“…The biallelic mutations in COL3A1, encoding collagen III (the ligand to ADGRG1/GPR56), may mimic the ADRG1/GPR56 cobblestone‐like cortical malformation phenotype, without muscular or ocular abnormalities 4,28 . Similarly, some biallelic mutations in LAMA2, encoding laminin alpha 2 (the ligand to alpha‐dystroglycan), mimic the CMD phenotype with cobblestone lissencephaly but without retinal involvement 29 . Furthermore, biallelic ADGRG1/GPR56‐mutations share with CMD the presence of pontine and cerebellar hypoplasia, especially at the level of the vermis or cerebellar dysplasia with the presence of hemispheric cysts 6 .…”

“…Pontine and cerebellar hypoplasia with cerebellar extrapial neuronal heterotopy was demonstrated at neuropathology in our cases. Biallelic mutations in COL3A1 and biallelic mutations in LAMA2 cause similar cerebellar abnormalities 28,29 . Nevertheless, in CMD, brainstem and cerebellar hypoplasia/dysplasia may present a more severe appearance (pontine midline cleft and deformity of the mid‐hindbrain junction, also called pontomedullary “kinking”), due to an unusual appearance of the corticospinal tracts 14 …”

“…Biallelic mutations in COL3A1 and biallelic mutations in LAMA2 cause similar cerebellar abnormalities. 28,29 Nevertheless, in CMD, brainstem and cerebellar hypoplasia/dysplasia may present a more severe appearance (pontine midline cleft and deformity of the mid-hindbrain junction, also called pontomedullary "kinking"), due to an unusual appearance of the corticospinal tracts. 14 Biallelic ADGRG1/GPR56 pathogenic mutations were initially reported as a cause of BFPP.…”

Widening the spectrum of LAMA 2 congenital muscular dystrophy (MDC1A): cobblestone malformation

“…A 4-year-old boy with LAMA2 -related congenital muscular dystrophy had two pathogenic variants (NM_000426): c.1255delA and c.2461A>C. Magnetic resonance imaging (MRI) of the brain showed signal abnormalities in supratentorial white matter (WM), which are conspicuous findings in this disease 1 . Interestingly, MRI also depicted malformations of cortical development -symmetric bilateral parieto-occipital bumpy or pebbly cortical surface (cobblestone malformation) 2 ( Figure 1 ).…”

Sequenciamento completo do exoma no diagnóstico de defeitos do desenvolvimento cerebelar e da migração neuronal cerebral

“…Variantes nos genes que regulam esses processos resultam em um amplo espectro de malformações do desenvolvimento cortical (MCDs), incluindo as lissencefalias (Di Donato et al, 2017). Por outro lado, uma migração cortical maciça para as leptomeninges pode levar a defeitos na superfície pial do córtex, resultando em um espectro variável de polimicrogiria ou malformações em pedra de calçamento (cobblestone), como notado nas distroglicanopatias (Taniguchi-Ikeda et al, 2021), laminopatias (Jayakody et al, 2020) e doenças relacionadas ao GPR56 (Bahi-Buisson et al, 2010;Vandervore et al, 2017). Uma hipótese é que, dependendo do tamanho do defeito nesta membrana, o córtex resultante pode ser polimicrogírico, se houver pequenos espaços entre os giros, ou em pedras de calçamento, se houver grandes espaços (Barkovich et al, 2015;Desikan e Barkovich, 2016).…”