22 van der Knaap MS, Naidu S, Pouwels PJ, et al.A new leukoencephalopathy with vanishing white matter. 21 van der Knaap MS, Barth PG, Gabreëls FJ, et al.Childhood ataxia with diffuse central nervous system hypomyelination. 20 Schiffmann R, Moller JR, Trapp BD, et al.Diffuse white matter disease in three children: an encephalopathy with unique features on magnetic resonance imaging and proton magnetic resonance spectroscopy. 19 Hanefeld F, Holzbach U, Kruse B, Wilichowski E, Christen HJ, Frahm J.Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. 18 van der Knaap MS, Barth PG, Stroink H, et al.Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach. 17 van der Knaap MS, Breiter SN, Naidu S, Hart AA, Valk J.Magnetic Resonance of Myelin, Myelination and Myelin Disorders. Pattern recognition in magnetic resonance imaging of white matter disorders in children and young adults. 15 van der Knaap MS, Valk J, de Neeling N, Nauta JJ.Autosomal dominant diffuse leukoencephalopathy with neuroaxonal spheroids. 13 van der Knaap MS, Naidu S, Kleinschmidt-Demasters BK, Kamphorst W, Weinstein HC.Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant. New York, NY: The McGraw-Hill Companies 2016. The Online Metabolic and Molecular Bases of Inherited Disease.

11 Valle D, Beaudet AL, Vogelstein B, et al.

10 Demaerel P, Faubert C, Wilms G, Casaer P, Piepgras U, Baert AL.

Myelin disorders of childhood: correlation of MR findings and severity of neurological impairment.

9 Dietrich RB, Vining EP, Taira RK, Hall TR, Phillipart M.

Nuclear magnetic resonance imaging of the brain in multiple sclerosis.

8 Young IR, Hall AS, Pallis CA, Legg NJ, Bydder GM, Steiner RE.

The evolution of white matter disease as seen on computed tomography. Structural manifestations of leukodystrophies. A correlative synopsis of the leukodystrophies. Über familiäre diffuse sklerose (Leukodystrophia cerebri progressiva hereditaria). London, United Kingdom: Longman, Orme, Brown, Green and Longman 1838 Illustrations of the Elementary Forms of Disease. 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. Based on the original definition of the leukodystrophies, numerous defects in proteins important in myelin structure, maintenance, and function were expected.

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. Since 2011, whole-exome sequencing has resulted in an exponential increase in numbers of known, distinct, genetically determined, ultrarare leukodystrophies. As recently as 2010, 50% of the leukodystrophy patients remained unclassified. This process required substantial numbers of cases and many rare disorders remained unclarified. Their genetic defects were usually identified through genetic linkage studies.

In the following two decades, magnetic resonance imaging pattern recognition revolutionized the field, allowing the definition of numerous novel leukodystrophies. The majority of the leukodystrophy patients remained without a specific diagnosis. At that time, a limited number of such disorders and no associated gene defects were known. Leukodystrophies were defined in the 1980s as progressive genetic disorders primarily affecting myelin of the central nervous system. Buy Article Permissions and Reprints Abstract

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