TY - JOUR
T1 - Update on leukodystrophies
T2 - A historical perspective and adapted definition
AU - Kevelam, Sietske H.
AU - Steenweg, Marjan E.
AU - Srivastava, Siddharth
AU - Helman, Guy
AU - Naidu, Sakkubai
AU - Schiffmann, Raphael
AU - Blaser, Susan
AU - Vanderver, Adeline
AU - Wolf, Nicole I.
AU - Van Der Knaap, Marjo S.
N1 - Funding Information:
The study received financial support from ZonMw TOP grant 91211005. G. H. and A. V. are supported by the Myelin Disorders Bioregistry Project.
Publisher Copyright:
© 2016 Georg Thieme Verlag KG Stuttgart. New York.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
KW - genetics
KW - leukodystrophy
KW - myelin
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U2 - 10.1055/s-0036-1588020
DO - 10.1055/s-0036-1588020
M3 - Article
C2 - 27564080
AN - SCOPUS:84984626781
SN - 0174-304X
VL - 47
SP - 349
EP - 354
JO - Neuropediatrics
JF - Neuropediatrics
IS - 6
ER -