Clinical Domain Working Groups

Leukodystrophies (LDs) are heritable disorders affecting the glial-axonal unit and resulting in differences in the genesis and maintenance of myelin. Despite many recent advances, the genetics of LDs remain incompletely characterized. With the recent emergence of broad use next-generation sequencing, over 240 genes affecting myelin have recently been identified.

As the community prepares for additional clinical trials, advocacy partners, clinicians and scientists have consolidated clinical trial readiness efforts in a Rare Disease Clinical Research Network (RDCRN) funded consortium, the Global LD Initiative (GLIA). GLIA has established a case description, using a modified Delphi approach, for the LDs. The expert consensus established that “LDs are heritable disorders affecting the white matter of the CNS with or without peripheral nervous system involvement. These disorders have in common glial cell or myelin sheath abnormalities…[and] neuropathology is primarily characterized by involvement of oligodendrocytes, astrocytes and other non-neuronal cell types,…, including significant axonal pathology.” In this definition, LDs were distinguished from other, secondary causes of white matter injury, including acquired and infectious etiologies, as well as primary epilepsies and developmental disorders. Based on this definition and exclusions, we have identified a list of all genes historically and recently associated with the LD phenotype via literature review and expert consensus. For more exact classification and organization, we have further divided the leukodystrophies into several subtypes: Demyelinating, Hypomyelinating, Myelin Vasculoization, Astrocytopathies, Leukoaxonopathies, Microgliopathies, Leukovasculopathies, and Unclassified.