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Mol Genet Metab. 2015 Apr;114(4):501-515. doi: 10.1016/j.ymgme.2014.12.434. Epub 2014 Dec 29.

A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies.

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Department of Neurogenetics/Neurometabolism, Neuroscience Institute, Cleveland Clinic Children's Hospital, Cleveland, OH, USA.
Departments of Pediatrics, Neurology and Neurosurgery, Montreal Children's Hospital, McGill University Health Center, Montreal, Canada.
Royal Children's Hospital Department of Neurology, Murdoch Children's Research Institute and University of Melbourne Department of Pediatrics, Melbourne, Australia.
Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands.
Section of Genetics, Department of Pediatrics, University of Colorado, Aurora, CO, USA.
Department of Neurology, Children's National Health System, Washington, DC, USA.
Institute of Metabolic Disease, Baylor University Medical Center, Dallas, TX, USA.
Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA.
School of Medicine and Health Services, Departments of Integrated Systems Biology and of Pediatrics, George Washington University, Washington, DC, USA.
Illumina, Inc., San Diego, CA, USA.
Departments of Neurology, Pediatrics and Medical Genetics, Mayo Clinic, Rochester, MN, USA.
Contributed equally


Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison's disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive--many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroimaging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders.


Glia; Leukodystrophy; Myelin

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