Revisiting genotype–phenotype overlap in neurogenetics: Triplet-repeat expansions mimicking spastic paraplegias

Authors

  • Conceição Bettencourt,

    Corresponding author
    1. Laboratorio de Biología Molecular, Instituto de Enfermedades Neurológicas, Fundación Socio-Sanitaria de Castilla la Mancha, Guadalajara, Spain
    2. Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal
    3. Center of Research in Natural Resources (CIRN) and Department of Biology, University of the Azores, Ponta Delgada, Portugal
    • Laboratorio de Biología Molecular, Instituto de Enfermedades Neurológicas, Fundación Sociosanitaria de Castilla-La Mancha, Paseo de la Estación, 2–1a Planta, 19001 Guadalajara, Spain.
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  • Beatriz Quintáns,

    1. University Clinical Hospital of Santiago de Compostela-SERGAS, Santiago de Compostela, Spain
    2. Grupo de Medicina Xenómica, University of Santiago de Compostela, Galicia, Spain
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  • Raquel Ros,

    1. Laboratorio de Biología Molecular, Instituto de Enfermedades Neurológicas, Fundación Socio-Sanitaria de Castilla la Mancha, Guadalajara, Spain
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  • Israel Ampuero,

    1. Laboratorio de Biología Molecular, Instituto de Enfermedades Neurológicas, Fundación Socio-Sanitaria de Castilla la Mancha, Guadalajara, Spain
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  • Zuleima Yáñez,

    1. Grupo de Medicina Xenómica, University of Santiago de Compostela, Galicia, Spain
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  • Samuel Ignacio Pascual,

    1. Servicio de Neuropediatría, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain
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  • Justo García de Yébenes,

    1. Laboratorio de Biología Molecular, Instituto de Enfermedades Neurológicas, Fundación Socio-Sanitaria de Castilla la Mancha, Guadalajara, Spain
    2. Department of Neurology, Hospital Ramón y Cajal, Madrid, Spain
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  • María-Jesús Sobrido

    1. Grupo de Medicina Xenómica, University of Santiago de Compostela, Galicia, Spain
    2. Fundación Publica Galega de Medicina Xenómica, Santiago de Compostela, SERGAS, Spain
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  • For the Databases in Neurogenetics Special Issue

Abstract

Hereditary spastic paraplegias (HSPs) constitute a heterogeneous group of neurological disorders, characterized primarily by progressive spasticity and weakness of the lower limbs. HSPs are caused by mutations in multiple genes (at least 48 loci and 28 causative genes). The clinical spectrum of HSPs is wide and important differences have been reported between patients with distinct mutations in the same gene, or even between different family members bearing the same mutation. Many patients with HSP present clinical deficits related to the involvement of neuronal systems other than corticospinal tracts, namely, peripheral nerves, sensory, or cerebellar pathways. These cases may be difficult to differentiate from other neurological diseases (e.g., hereditary ataxias), also genetically and clinically heterogeneous. As an illustration of how overlapping this genotype–phenotype relationship is, and the difficulties that it brings upon the development of neurogenetic algorithms and databases, we review the main clinical and genetic features of HSPs, and summarize reports on cases of triplet-repeat spinocerebellar ataxias that can mimic HSP phenotypes. This complex scenario makes the necessity of high-quality, curated mutation databases even more urgent, in order to develop adequate diagnostic guidelines, correct interpretation of genetic testing, and appropriate genetic counseling. Hum Mutat 33:1315–1323, 2012. © 2012 Wiley Periodicals, Inc.

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