Megalencephalic leukodystrophy with subcortical cysts panel [2 genes]

Some hereditary leukodystrophies and leukoencephalopathies have special MRI features that differentiate them from other disorders and have a high diagnostic value. Some of these features include white matter rarefaction and the presence of cystic lesions, which represent degenerative changes in myelin, with increased content of interstitial fluid and astrogliosis, and which can be visualized best by fluid-attenuated inversion recovery (FLAIR) imaging. Rarefied white matter shows an intermediate signal on FLAIR imaging, while cystic lesions show a very low signal, similar to that of cerebrospinal fluid.

One of the most frequent disorders within this group of diseases is childhood ataxia with central nervous system hypomyelination (CACH), or vanishing white matter (VWM), an autosomal recessive disease characterized by progressive cerebellar ataxia, spasticity, and cognitive decline, where white matter rarefaction and cystic degeneration occur in a diffuse, melting-away fashion, leaving behind a cobweb of better preserved tissue where well-delimited isolated cysts occur rarely. Age of onset varies from early childhood to adulthood, and febrile infections or cranial trauma can lead to rapid neurological decline. This disease is caused by biallelic pathogenic variants in the five genes that encode subunits of eukaryotic translation initiation factor 2B: EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5.