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

S. Parikh, G. Bernard, R.J. Leventer, M.S. van der Knaap, J. ten Hove, A. Pizzino, N.H. McNeill, G. Helman, C. Simons, J.L. Schmidt, W.B. Rizzo, M.C. Patterson, R.J. Taft, A. Vanderver

    Research output: Contribution to JournalArticleAcademicpeer-review

    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
    Pages (from-to)501-515
    JournalMolecular Genetics and Metabolism
    Volume114
    Issue number4
    DOIs
    Publication statusPublished - 2015

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    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

    Cite this

    Parikh, S. ; Bernard, G. ; Leventer, R.J. ; van der Knaap, M.S. ; ten Hove, J. ; Pizzino, A. ; McNeill, N.H. ; Helman, G. ; Simons, C. ; Schmidt, J.L. ; Rizzo, W.B. ; Patterson, M.C. ; Taft, R.J. ; Vanderver, A. / 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.
    @article{7f4dad401ca64ba0a0607ca80cd91601,
    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.",
    author = "S. Parikh and G. Bernard and R.J. Leventer and {van der Knaap}, M.S. and {ten Hove}, J. and A. Pizzino and N.H. McNeill and G. Helman and C. Simons and J.L. Schmidt and W.B. Rizzo and M.C. Patterson and R.J. Taft and A. Vanderver",
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    language = "English",
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    journal = "Molecular Genetics and Metabolism",
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    Parikh, S, Bernard, G, Leventer, RJ, van der Knaap, MS, ten 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

    A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies. / Parikh, S.; Bernard, G.; Leventer, R.J.; van der Knaap, M.S.; ten Hove, J.; Pizzino, A.; McNeill, N.H.; Helman, G.; Simons, C.; Schmidt, J.L.; Rizzo, W.B.; Patterson, M.C.; Taft, R.J.; Vanderver, A.

    In: Molecular Genetics and Metabolism, Vol. 114, No. 4, 2015, p. 501-515.

    Research output: Contribution to JournalArticleAcademicpeer-review

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    AU - Parikh, S.

    AU - Bernard, G.

    AU - Leventer, R.J.

    AU - van der Knaap, M.S.

    AU - ten Hove, J.

    AU - Pizzino, A.

    AU - McNeill, N.H.

    AU - Helman, G.

    AU - Simons, C.

    AU - Schmidt, J.L.

    AU - Rizzo, W.B.

    AU - Patterson, M.C.

    AU - Taft, R.J.

    AU - Vanderver, A.

    PY - 2015

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    N2 - 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.

    AB - 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.

    U2 - 10.1016/j.ymgme.2014.12.434

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    JF - Molecular Genetics and Metabolism

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