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Neuropediatrics 2016; 47(06): 349-354
DOI: 10.1055/s-0036-1588020
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Update on Leukodystrophies: A Historical Perspective and Adapted Definition

Sietske H. Kevelam  
1   Department of Child Neurology, VU University Medical Centre, Amsterdam, The Netherlands
2   Amsterdam Neuroscience, VU University, Amsterdam, The Netherlands
,
Marjan E. Steenweg  
1   Department of Child Neurology, VU University Medical Centre, Amsterdam, The Netherlands
2   Amsterdam Neuroscience, VU University, Amsterdam, The Netherlands
,
Siddharth Srivastava
3   Department of Neurogenetics, Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
,
Guy Helman
4   Department of Neurology, Children's National Health System, Washington, District of Columbia, United States
,
Sakkubai Naidu
3   Department of Neurogenetics, Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
,
Raphael Schiffmann
5   Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, United States
,
Susan Blaser
6   Division of Neuroradiology, The Hospital for Sick Children, Toronto, Ontario, Canada
,
Adeline Vanderver
4   Department of Neurology, Children's National Health System, Washington, District of Columbia, United States
,
Nicole I. Wolf
1   Department of Child Neurology, VU University Medical Centre, Amsterdam, The Netherlands
2   Amsterdam Neuroscience, VU University, Amsterdam, The Netherlands
,
Marjo S. van der Knaap
1   Department of Child Neurology, VU University Medical Centre, Amsterdam, The Netherlands
2   Amsterdam Neuroscience, VU University, Amsterdam, The Netherlands
7   Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands
› Author Affiliations
Further Information

Publication History

09 July 2016

13 July 2016

Publication Date:
26 August 2016 (online)

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Abstract

Leukodystrophies were defined in the 1980s as progressive genetic disorders primarily affecting myelin of the central nervous system. At that time, a limited number of such disorders and no associated gene defects were known. The majority of the leukodystrophy patients remained without a specific diagnosis. In the following two decades, magnetic resonance imaging pattern recognition revolutionized the field, allowing the definition of numerous novel leukodystrophies. Their genetic defects were usually identified through genetic linkage studies. This process required substantial numbers of cases and many rare disorders remained unclarified. As recently as 2010, 50% of the leukodystrophy patients remained unclassified. Since 2011, whole-exome sequencing has resulted in an exponential increase in numbers of known, distinct, genetically determined, ultrarare leukodystrophies. We performed a retrospective study concerning three historical cohorts of unclassified leukodystrophy patients and found that currently at least 80% of the patients can be molecularly classified. Based on the original definition of the leukodystrophies, numerous defects in proteins important in myelin structure, maintenance, and function were expected. By contrast, a high percentage of the newly identified gene defects affect the housekeeping process of mRNA translation, shedding new light on white matter pathobiology and requiring adaptation of the leukodystrophy definition.

Keywords

leukodystrophy - genetics - myelin

Funding

The study received financial support from ZonMw TOP grant 91211005. G. H. and A. V. are supported by the Myelin Disorders Bioregistry Project.


* These authors contributed equally to the study.


 

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