Case definition and classification of leukodystrophies and leukoencephalopathies

Abstract

Objective An approved definition of the term leukodystrophy does not currently exist. The lack of a precise case definition hampers efforts to study the epidemiology and the relevance of genetic white matter disorders to public health. Method Thirteen experts at multiple institutions participated in iterative consensus building surveys to achieve definition and classification of disorders as leukodystrophies using a modified Delphi approach. Results A case definition for the leukodystrophies was achieved, and a total of 30 disorders were classified under this definition. In addition, a separate set of disorders with heritable white matter abnormalities but not meeting criteria for leukodystrophy, due to presumed primary neuronal involvement and prominent systemic manifestations, was classified as genetic leukoencephalopathies (gLE). Interpretation A case definition of leukodystrophies and classification of heritable white matter disorders will permit more detailed epidemiologic studies of these disorders.

Loss-of-Function Alanyl-tRNA Synthetase Mutations Cause an Autosomal-Recessive Early-Onset Epileptic Encephalopathy with Persistent Myelination Defect

“…At this point, it is unclear whether AARS mutations result in a primary defect of myelin development or whether the delay in myelination can be attributed to primary neuronal dysfunction. 25 It is intriguing to note that two previously reported AARS missense mutations 20,21 cause Charcot-Marie-Tooth type 2N (CMT2N), a dominant axonal peripheral neuropathy characterized by muscle weakness, wasting, and impaired sensation in the extremities. These mutations have catastrophic effects on AARS activity (50-fold and 4,130-fold decreases in k cat /K m ).…”

Leukodystrophy or genetic leukoencephalopathy? Nature does not make leaps

“…In this issue of Molecular Genetics and Metabolism, Vanderver et al [2] first address an important and controversial topic in neurology, i.e., the definition of the term "leukodystrophy," and make a conceptual distinction between "leukodystrophies" and "genetic leukoencephalopathies." Subsequently, they propose a classification of all the inherited white matter (WM) diseases under one of these two groups.…”

“…It is true that this question has been rarely discussed in a scholarly way and an approved definition did not exist [2], but this is probably because the answer was assumed to be self-evident. The term "leukodystrophy," introduced by Bielschowski and Henneberg in 1928 [3], is in its essence a neuropathological term, which reflects the presence of abnormalities in central nervous system (CNS) glial cell types as the primary or fundamental pathological abnormality.…”

“…The pathology in AMN, which is caused by mutations in the ABCD1 gene that is variably expressed in glial cells, but not in neurons [6], shows microscopic dysmyelinative lesions of the cerebral WM [7]. In contrast, as also discussed by Vanderver et al [2], it is questionable to consider the disease hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) as "leukodystrophy," given that no autopsy study is available, lesions in the basal ganglia and cerebellum are a characteristic imaging finding, and the disease-causing gene TUBB4A is expressed in neurons. Nature, however, does make leaps, and the individual contributions by neurons and glial cells to the pathology over time can be hard to be determined, thus complicating the matter of nomenclature.…”

“…To classify a disease as "leukoencephalopathy," I believe that it should have WM abnormalities on neuroimaging so prominent or characteristic to be considered as a fundamental hint for the diagnosis. For instance, Vanderver et al [2] have classified diseases like NOTCH3-related cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) or COL4A1-related brain small vessel disease as "genetic leukoencephalopathies," and not as "leukodystrophies." This is an excellent point, as in these inherited diseases the primary dysfunction is not in glial cells, but in the brain vessels, and extensive WM abnormalities are by far the most prominent feature on neuroimaging.…”