We searched PubMed for articles published in English, German, and French between Jan 1, 2013, and March 1, 2019, using the terms “leukodystrophy”, “leukoencephalopathy”, and assorted combinations of the following terms: “MRI”, “mutation”, “genetic”, “pathophysiology”, “management”, “metabolic”, “biomarker”, “diagnosis”, “treatment”, “therapy”, and “transplantation”. We reviewed reference lists within original research and review articles for additional references. We finalised the reference
ReviewDiagnosis, prognosis, and treatment of leukodystrophies
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.
Section snippets
Definition and categorisation
The definition of leukodystrophy has evolved over time, first focused only on myelin and oligodendrocytes, and subsequently including astrocytes.1 The latest definition includes all genetically determined disorders with selective and primary involvement of CNS white matter, irrespective of the structural white-matter component involved and molecular process affected.2, 8 By contrast, leukoencephalopathies comprise all primary CNS white-matter disorders, both genetic and acquired.2 This Review
Whole-exome sequencing
The introduction of WES has had a major effect on the diagnosis of rare diseases, including leukodystrophies. Many previously undetermined cases have been given a specific diagnosis and numerous new leukodystrophy genetic defects have been identified. The percentage of leukodystrophy cases without specific diagnosis has decreased from about 50% in 2010 to 20–30% in 2016,3, 4 and this percentage is still decreasing. WES is cheaper15 and delivers a much faster diagnosis (which takes a few months)
Prognosis
Leukodystrophies can present at any age. Age of onset typically correlates inversely with disease severity and rate of progression.37, 38 Leukodystrophies have a reputation of being relentlessly progressive and fatal.7 Although this concept is true for many leukodystrophies, more variable and more benign disease phenotypes with long episodes of stability, permanent improvement, or complete recovery are now apparent.9, 12 For example, megalencephalic leukodystrophy with subcortical cysts (MLC)
Management and treatment
Currently, many interventions are available to manage disease manifestations, improve the quality of life of patients,57 reduce the use of medical resources, and reduce expenses.58 Some clinical manifestations are disease-specific, while others are general (panel 2). Anticipation and monitoring of manifestations allow initiation of treatment (eg, hydrocortisone replacement for adrenal failure in adrenoleukodystrophy59 and cholecystectomy for gallbladder involvement in metachromatic
Pathophysiological mechanisms
Increasing insights into the variety of gene defects underlying leukodystrophies has also greatly improved the understanding of the pathological mechanisms. Leukodystrophies are not only caused by myelin defects (either scarcity of myelin deposition [eg, in Pelizaeus-Merzbacher disease] or myelin loss [eg, in MLD]), but also by defects affecting astrocytes (eg, in Alexander disease and MLC), microglia (eg, ALSP), and small blood vessels.2, 8, 10, 11 At the molecular level, as opposed to the
Conclusions and future directions
Substantial progress has occurred in many aspects of leukodystrophies, in particular regarding diagnosis, number of diseases known, insight into variability of clinical disease and prognosis, and options for therapy and management. The cumulative change is immense, demanding review and discussion of the implications for the clinical approach of leukodystrophies. The number of disorders and gene defects known has steeply increased, and with the introduction of next-generation sequencing, the
Search strategy and selection criteria
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