Cobblestone malformation in LAMA2 congenital muscular dystrophy (MDC1A)

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.