Leukodystrophy or genetic leukoencephalopathy? Nature does not make leaps.

Abstract

The importance of classification was first recognized by Aristotle of caused by mutations in the ABCD1 gene that is variably expressed in Stagira, the great Greek philosopher who proposed rigorous classifications in literally every area of human knowledge. Classifications are indispensable for language and convenient for our ordinary mental operations [1], but—as Aristotle also suggested—every classification presents pitfalls and limitations. Nature does not make leaps (natura non facit saltus), and it does not conform to rigorous divisions. Pragmatically speaking, however, one classification may be, if not more correct, at least more useful than another one. 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. This esoteric work—as defined by the authors—was largely performed for epidemiological purposes, including the assessment of the frequency and burden of these diseases as a group, but it also led to a very comprehensive list of inherited disorders characterized by brain WM involvement. What is a “leukodystrophy”? 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. Therefore, we should use the term “leukodystrophy” only when the pathology of the disease is (well-)known, and we could admit that subjects with late onset Alexander Disease (AxD), SPG2, or adrenomyeloneuropathy (AMN) meet the criterion for being classified as having a “leukodystrophy.” The pathology of late onset AxD shows the abundant presence of Rosenthal fibers, i.e., the astrocytic inclusions containing a mixture of glial fibrillary acidic protein, ubiquitin and heat shock proteins, which are the key diagnostic feature of the neuropathology in AxD [4]. The pathology of SPG2, which is caused by mutations in the PLP1 gene encoding for the predominant CNS myelin protein, shows diffuse hypomyelination/dysmyelination with some WM tracts preferentially affected [5]. The pathology in AMN, which is