Update on Leukodystrophies: A Historical Perspective and Adapted Definition

Neuropediatrics. 2016 Dec;47(6):349-354. doi: 10.1055/s-0036-1588020. Epub 2016 Aug 26.


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.

Publication types

  • Historical Article
  • Review

MeSH terms

  • Hereditary Central Nervous System Demyelinating Diseases* / diagnosis
  • Hereditary Central Nervous System Demyelinating Diseases* / genetics
  • Hereditary Central Nervous System Demyelinating Diseases* / history
  • History, 19th Century
  • History, 20th Century
  • History, 21st Century
  • Humans
  • RNA Polymerase III / genetics
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / genetics


  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • POLR3A protein, human
  • RNA Polymerase III