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

Sumit Parikh, Geneviève Bernard, Richard J. Leventer, Marjo S. van der Knaap, Johan van Hove, Amy Pizzino, Nathan H. McNeill, Guy Helman, Cas Simons, Johanna L. Schmidt, William B. Rizzo, Marc C. Patterson, Ryan J. Taft, Adeline Vanderver

Research output: Contribution to journalArticle

74 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)501-515
Number of pages15
JournalMolecular Genetics and Metabolism
Volume114
Issue number4
DOIs
StatePublished - Apr 1 2015
Externally publishedYes

Fingerprint

Leukoencephalopathies
Testing
Genes
Anodontia
Adrenoleukodystrophy
Neuroimaging
Addison Disease
Inborn Genetic Diseases
Workflow
Medical imaging
Genetic Testing
Neurology
Magnetic resonance imaging
Molecular Biology
Central Nervous System
Magnetic Resonance Imaging
Genome
Imaging techniques
White Matter

Keywords

  • Glia
  • Leukodystrophy
  • Myelin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Parikh, S., Bernard, G., Leventer, R. J., van der Knaap, M. S., van Hove, J., Pizzino, A., ... Vanderver, A. (2015). A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies. Molecular Genetics and Metabolism, 114(4), 501-515. https://doi.org/10.1016/j.ymgme.2014.12.434

A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies. / Parikh, Sumit; Bernard, Geneviève; Leventer, Richard J.; van der Knaap, Marjo S.; van Hove, Johan; Pizzino, Amy; McNeill, Nathan H.; Helman, Guy; Simons, Cas; Schmidt, Johanna L.; Rizzo, William B.; Patterson, Marc C.; Taft, Ryan J.; Vanderver, Adeline.

In: Molecular Genetics and Metabolism, Vol. 114, No. 4, 01.04.2015, p. 501-515.

Research output: Contribution to journalArticle

Parikh, S, Bernard, G, Leventer, RJ, van der Knaap, MS, van Hove, J, Pizzino, A, McNeill, NH, Helman, G, Simons, C, Schmidt, JL, Rizzo, WB, Patterson, MC, Taft, RJ & Vanderver, A 2015, 'A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies', Molecular Genetics and Metabolism, vol. 114, no. 4, pp. 501-515. https://doi.org/10.1016/j.ymgme.2014.12.434
Parikh, Sumit ; Bernard, Geneviève ; Leventer, Richard J. ; van der Knaap, Marjo S. ; van Hove, Johan ; Pizzino, Amy ; McNeill, Nathan H. ; Helman, Guy ; Simons, Cas ; Schmidt, Johanna L. ; Rizzo, William B. ; Patterson, Marc C. ; Taft, Ryan J. ; Vanderver, Adeline. / A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies. In: Molecular Genetics and Metabolism. 2015 ; Vol. 114, No. 4. pp. 501-515.
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