Research Article: Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms

Date Published: June 21, 2017

Publisher: Springer Berlin Heidelberg

Author(s): Marjo S. van der Knaap, Marianna Bugiani.


Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic resonance imaging pattern recognition and next generation sequencing. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin- or oligodendrocyte-specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels. We here propose a novel classification of leukodystrophies that takes into account the primary involvement of any white matter component. Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin (hypomyelinating and demyelinating leukodystrophies, leukodystrophies with myelin vacuolization); astrocytopathies; leuko-axonopathies; microgliopathies; and leuko-vasculopathies. Following this classification, we illustrate the neuropathology and disease mechanisms of some leukodystrophies taken as example for each category. Some leukodystrophies fall into more than one category. Given the complex molecular and cellular interplay underlying white matter pathology, recognition of the cellular pathology behind a disease becomes crucial in addressing possible treatment strategies.

Partial Text

Leukodystrophies are heritable, mostly progressive encephalopathies characterized by the selective involvement of the central nervous system (CNS) white matter. The first report of a familial white matter disorder dates back over a century, when Pelizaeus and Merzbacher separately described the familial occurrence of a chronic progressive ‘diffuse sclerosis’ (as opposed to the already recognized ‘multiple sclerosis’) with lack of myelin and sclerotic hardening of the white matter [138, 169]. The term “leukodystrophy” (leuko, white and dystrophy, wasting) was used for the first time in 1928 in the context of metachromatic leukodystrophy and coined to define hereditary, progressive diseases characterized by white matter degeneration [16]. In the 1980s [145], leukodystrophies were considered genetic, progressive disorders primarily affecting myelin, either directly or through oligodendrocytes. At that time, the diseases were pathogenetically poorly characterized with an unknown molecular basis; data were available from pathology, biochemical analyses of brain tissue and knowledge of some metabolic and enzymatic defects, but no gene defects. Soon after, MRI came into use as primary tool to diagnose leukodystrophies, while no pathological data were available to confirm the primary myelin involvement. In the last two decades many gene defects have been identified, first by genetic linkage and more recently by whole exome and genome sequencing. Because many of these disorders prove to be caused by defects in housekeeping processes, the myelin-focused definition of term leukodystrophy has been recently considered too narrow [103].

The white matter comprises half of the human brain. It has expanded more than gray matter during evolution [274], and constitutes an indispensable component of the neural networks that subserve motor and cognitive operations. White matter tracts mediate the essential connectivity by which brain function is organized, working in concert with gray matter to enable the extraordinary repertoire of human neurobehavioral capacities [60].

Every classification reflects the knowledge of its time. The current classification of white matter disorders recognizes four categories: hypomyelinating (i.e., lack of myelin deposition), demyelinating (i.e., loss of previously deposited myelin), dysmyelinating (i.e., deposition of structurally or biochemically abnormal myelin) and myelinolytic diseases [147] (i.e. myelin vacuolization). This classification has the major value of categorizing white matter disorders according to main mechanism of white matter injury and recognizing the possibility that different pathomechanisms may contribute to a single disease. One could, however, question the choice of terms arguing that, also in the light of more recent insights on white matter integrity and function, their reflection of the different disease categories is no longer tenable and that more pathomechanisms may play a primary role in white matter pathology than those four alone.

The diagnostic approach combining MRI pattern recognition with next generation sequencing has remarkably increased the number of diagnosable genetic white matter disorders, and confirmed that many are due to defects in gene products specifically or also expressed in cell types other than the oligodendrocyte. The last decades have also witnessed a tremendous increase in the knowledge of the white matter demonstrating that all cell types inhabiting it are involved in its development, maintenance, function and repair. This has challenged the traditional myelin-centric view of leukodystrophies that is now proved surpassed. We support a novel definition of leukodystrophy that reflects the current knowledge: leukodystrophies are all genetically determined disorders primarily affecting the CNS white matter, irrespective of the structural white matter component involved, the molecular process affected and the disease course [103]. In the wake of this definition, we here propose a new classification of leukodystrophies based on a cellular pathology approach that takes into account the contribution of cell types other than oligodendrocytes and structures other than myelin driving white matter pathology, including astrocytes, axons, microglia and blood vessels. In reviewing the neuropathology and disease mechanisms of some leukodystrophies, we show that this classification also provides systematic additional information regarding the pathogenesis. The complicated interplay between the different white matter components in the healthy CNS necessarily implies that the diseases mechanisms underlying leukodystrophies are also complex. Our classification therefore also recognizes the possibility that a specific disease does not primarily affect only one cell type or structure and with that belongs to more than one category. Giant axonal neuropathy, for example, is due to defects in gigaxonin that maintains neuroaxonal cytoskeletal integrity and transport, but is also responsible for proper intermediate filament degradation in astrocytes. In other disorders, the neuropathology may be characterized by prominent secondary involvement of selected white matter components. MLC, for example, is due to a defective function of the astrocyte-specific protein MLC1, which is involved in astrocytic control of ion–water homeostasis. Although MLC is pathologically characterized by intramyelinic edema, this is a secondary phenomenon and MLC is thus categorized under the astrocytopathies. The implications of such information are important. We face a time in which new treatments are being explored, including cell-based replacement treatments, new drugs and small molecules, and therapies aiming at enhancing endogenous repair. It is conceivable that none of the leukodystrophies will be cured by a single treatment, but that they will rather benefit from a combined therapeutic approach. Knowledge on which cells types are involved in the pathophysiology of the single disorder and their disease mechanisms and interactions becomes thus crucial to develop a successful therapeutic strategy for these deleterious and often fatal diseases.