Diagnosis, prognosis, and treatment of leukodystrophies

Summary

Leukodystrophies comprise a large group of rare genetic disorders primarily affecting CNS white matter. Historically, the diagnostic process was slow and patient prognosis regarded as poor because curative treatment was only available for very few leukodystrophies in early stages of the disease. Whole-exome sequencing has both greatly increased the number of known leukodystrophies and improved diagnosis. Whether MRI keeps its central place in diagnosis and what the role is of whole-exome sequencing are relevant questions for neurologists. Improved diagnosis has revealed the phenotypic variability of leukodystrophies, requiring adaptation of prognostication. Technological advance in molecular techniques and improved insight into the pathophysiology of individual leukodystrophies have led to therapeutic developments, including drug design and gene therapy. Despite this progress, therapies are only beneficial early in the disease course, emphasising the need for a speedy diagnosis and for research on regenerative approaches to repair the damage already present.

Introduction

Leukodystrophies constitute a large, highly heterogeneous group of rare genetic disorders, characterised by selective and primary involvement of the CNS white matter.1, 2 Such disorders can manifest in people of all ages. Various underlying gene defects are known, each defining a specific leukodystrophy.1, 2 Advances in molecular techniques have had a fundamental effect on the diagnosis, understanding, and treatment of leukodystrophies.3, 4, 5, 6 Diagnosis of leukodystrophy used to be time-consuming and cumbersome, but whole-exome sequencing (WES; mostly used in clinical settings) and whole-genome sequencing (WGS; currently mostly used for research) now allow rapid identification of the underlying gene defect. WES and WGS have led to the identification of the molecular basis of many leukodystrophies, solving the persistent problem of a high proportion of leukodystrophy cases without molecular diagnosis, increasing the number of diagnosable disorders,3, 4 and adding knoweldge about clinical variability and prognosis.⁵ Therapy for leukodystrophies has lagged, but prospects are improving.⁶ Gene-editing techniques are rapidly advancing, facilitating in-vivo and in-vitro gene correction, necessary for gene therapy. Other treatment options include drugs that modulate disease pathways, antisense oligonucleotide therapy, and therapy based on stem cells.⁶

The almost overwhelming increase in the number of known leukodystrophies necessitates an updated categorisation system to facilitate diagnosis. WES availability requires reconsideration of the traditional step-by-step approaches to achieve definitive diagnoses. The role of MRI as a primary diagnostic tool needs be also reconsidered, and perhaps redefined. For the leukodystrophies with improving therapeutic prospects, a speedy diagnosis is particularly important, as such therapies are only relevant in early disease stages, when the brain is not yet irreparably damaged. New knowledge on wide clinical variation and benign disease variants requires modification of the traditional view on leukodystrophies as disorders with an invariably poor prognosis.⁷ New insights into the molecular and cellular bases of the disorders have changed the concept of leukodystrophies and have led to recognition that all structural white-matter components (including myelin, oligodendrocytes, astrocytes, microglia, axons, and blood vessels) can be primary disease targets.2, 8 This new view affects the understanding of disease mechanisms and directs therapy development. This Review provides an update on these advances in diagnosis, prognosis, and treatment of leukodystrophies.