title: A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies.
abstract: 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.
authors: Department of Neurogenetics/Neurometabolism, Neuroscience Institute, Cleveland Clinic Children's Hospital, Cleveland, OH, USA.
authors: Sumit
authors: S
authors: Parikh
authors: Departments of Pediatrics, Neurology and Neurosurgery, Montreal Children's Hospital, McGill University Health Center, Montreal, Canada.
authors: Geneviève
authors: G
authors: Bernard
authors: Royal Children's Hospital Department of Neurology, Murdoch Children's Research Institute and University of Melbourne Department of Pediatrics, Melbourne, Australia.
authors: Richard J
authors: RJ
authors: Leventer
authors: Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Marjo S
authors: MS
authors: van der Knaap
authors: Section of Genetics, Department of Pediatrics, University of Colorado, Aurora, CO, USA.
authors: Johan
authors: J
authors: van Hove
authors: Department of Neurology, Children's National Health System, Washington, DC, USA.
authors: Amy
authors: A
authors: Pizzino
authors: Institute of Metabolic Disease, Baylor University Medical Center, Dallas, TX, USA.
authors: Nathan H
authors: NH
authors: McNeill
authors: Department of Neurology, Children's National Health System, Washington, DC, USA.
authors: Guy
authors: G
authors: Helman
authors: Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
authors: Cas
authors: C
authors: Simons
authors: Department of Neurology, Children's National Health System, Washington, DC, USA.
authors: Johanna L
authors: JL
authors: Schmidt
authors: Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA.
authors: William B
authors: WB
authors: Rizzo
authors: Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA.
authors: Marc C
authors: MC
authors: Patterson
authors: Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.|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.
authors: Ryan J
authors: RJ
authors: Taft
authors: Department of Neurology, Children's National Health System, Washington, DC, USA.|Departments of Neurology, Pediatrics and Medical Genetics, Mayo Clinic, Rochester, MN, USA.|School of Medicine and Health Services, Departments of Integrated Systems Biology and of Pediatrics, George Washington University, Washington, DC, USA.
authors: Adeline
authors: A
authors: Vanderver
mesh_terms: D000326:Adrenoleukodystrophy / Q000175:diagnosis; D000848:Anodontia / Q000175:diagnosis; D003711:Demyelinating Diseases / Q000175:diagnosis*; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000175:diagnosis*; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000175:diagnosis*; D008279:Magnetic Resonance Imaging
keywords: Glia; Leukodystrophy; Myelin
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