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Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA)

Authors

  • Michael C. Kruer MD,

    1. Divisions of Developmental Pediatrics and Pediatric Neurology, Child Development and Rehabilitation Center, Oregon Health & Science University, Portland, OR
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    • M.C.K., C.P-R, and N.B. contributed equally to this manuscript.

  • Coro Paisán-Ruiz PhD,

    1. Department of Molecular Neuroscience and Reta Lila Weston Institute, UCL Institute of Neurology, Queen Square, London, UK
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    • M.C.K., C.P-R, and N.B. contributed equally to this manuscript.

  • Nathalie Boddaert MD, PhD,

    1. INSERM U781, Département de Radiologie Pédiatrique, Université Paris Descartes, Hôpital Necker-Enfants Malades, Paris, France
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    • M.C.K., C.P-R, and N.B. contributed equally to this manuscript.

  • Moon Y. Yoon BS,

    1. Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR
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  • Hiroko Hama PhD,

    1. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC
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  • Allison Gregory MS,

    1. Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR
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  • Alessandro Malandrini MD,

    1. Unit of Neurometabolic Diseases, Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Siena, Italy
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  • Randall L. Woltjer MD, PhD,

    1. Division of Neuropathology, Department of Pathology, Oregon Health & Science University, Portland, OR
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  • Arnold Munnich MD,

    1. INSERM U781, Département de Génétique, Université Paris Descartes, Hôpital Necker-Enfants Malades, Paris, France
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  • Stephanie Gobin MD,

    1. INSERM U781, Département de Génétique, Université Paris Descartes, Hôpital Necker-Enfants Malades, Paris, France
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  • Brenda J. Polster PhD,

    1. Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR
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  • Silvia Palmeri MD,

    1. Unit of Neurometabolic Diseases, Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Siena, Italy
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  • Simon Edvardson MD,

    1. Pediatric Neurology Unit, Hadassah, Hebrew University Medical Center, Jerusalem, Israel
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  • John Hardy PhD,

    1. Department of Molecular Neuroscience and Reta Lila Weston Institute, UCL Institute of Neurology, Queen Square, London, UK
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  • Henry Houlden MD, PhD,

    1. Department of Molecular Neuroscience and Reta Lila Weston Institute, UCL Institute of Neurology, Queen Square, London, UK
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  • Susan J. Hayflick MD

    Corresponding author
    1. Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR
    2. Departments of Pediatrics and Neurology, Oregon Health & Science University, Portland, OR
    • Department of Pediatrics and Neurology, Oregon Health & Science University, Portland, OR 97239
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Abstract

Objective

Neurodegeneration with brain iron accumulation (NBIA) represents a distinctive phenotype of neurodegenerative disease for which several causative genes have been identified. The spectrum of neurologic disease associated with mutations in NBIA genes is broad, with phenotypes that range from infantile neurodegeneration and death in childhood to adult-onset parkinsonism-dystonia. Here we report the discovery of a novel gene that leads to a distinct form of NBIA.

Methods

Using autozygosity mapping and candidate gene sequencing, we identified mutations in the fatty acid hydroxylase gene FA2H, newly implicating abnormalities of ceramide metabolism in the pathogenesis of NBIA.

Results

Neuroimaging demonstrated T2 hypointensity in the globus pallidus, confluent T2 white matter hyperintensities, and profound pontocerebellar atrophy in affected members of two families. Phenotypically, affected family members exhibited spastic quadriparesis, ataxia, and dystonia with onset in childhood and episodic neurological decline. Analogous to what has been reported previously for PLA2G6, the phenotypic spectrum of FA2H mutations is diverse based on our findings and those of prior investigators, because FA2H mutations have been identified in both a form of hereditary spastic paraplegia (SPG35) and a progressive familial leukodystrophy.

Interpretation

These findings link white matter degeneration and NBIA for the first time and implicate new signaling pathways in the genesis of NBIA. ANN NEUROL 2010

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