Update on Leukodystrophies: A Historical Perspective and Adapted Definition

Sietske H. Kevelam; Marjan E. Steenweg; Siddharth Srivastava; Guy Helman; Sakkubai Naidu; Raphael Schiffmann; Susan Blaser; Adeline Vanderver; Nicole I. Wolf; Marjo S. van der Knaap

doi:10.1055/s-0036-1588020

Neuropediatrics, Table of Contents

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

Authors

Sietske H. Kevelam

¹Department of Child Neurology, VU University Medical Centre, Amsterdam, The Netherlands

²Amsterdam Neuroscience, VU University, Amsterdam, The Netherlands
Marjan E. Steenweg

¹Department of Child Neurology, VU University Medical Centre, Amsterdam, The Netherlands

²Amsterdam Neuroscience, VU University, Amsterdam, The Netherlands
Siddharth Srivastava

³Department of Neurogenetics, Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
Guy Helman

⁴Department of Neurology, Children's National Health System, Washington, District of Columbia, United States
Sakkubai Naidu

³Department of Neurogenetics, Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
Raphael Schiffmann

⁵Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, United States
Susan Blaser

⁶Division of Neuroradiology, The Hospital for Sick Children, Toronto, Ontario, Canada
Adeline Vanderver

⁴Department of Neurology, Children's National Health System, Washington, District of Columbia, United States
Nicole I. Wolf

¹Department of Child Neurology, VU University Medical Centre, Amsterdam, The Netherlands

²Amsterdam Neuroscience, VU University, Amsterdam, The Netherlands
Marjo S. van der Knaap

¹Department of Child Neurology, VU University Medical Centre, Amsterdam, The Netherlands

²Amsterdam Neuroscience, VU University, Amsterdam, The Netherlands

⁷Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands

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

Full Text

References

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