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The Cerebellum

, Volume 12, Issue 2, pp 176–193 | Cite as

Spinocerebellar Ataxia Type 7: Clinical Course, Phenotype–Genotype Correlations, and Neuropathology

  • Laura C. Horton
  • Matthew P. Frosch
  • Mark G. Vangel
  • Carol Weigel-DiFranco
  • Eliot L. Berson
  • Jeremy D. SchmahmannEmail author
Original Paper

Abstract

Spinocerebellar ataxia type 7 is a neurodegenerative polyglutamine disease characterized by ataxia and retinal degeneration. The longitudinal course is unknown, and relationships between repeat expansion, clinical manifestations, and neuropathology remain uncertain. We followed 16 affected individuals of a 61-member kindred over 27 years with electroretinograms, neurological examinations including the Brief Ataxia Rating Scale, neuroimaging in five, and autopsy in four cases. We identified four stages of the illness: Stage 0, gene-positive but phenotypically silent; Stage 1, no symptoms, but hyperreflexia and/or abnormal electroretinograms; Stage 2, symptoms and signs progress modestly; and Stage 3, rapid clinical progression. CAG repeat length correlated inversely with age of onset of visual or motor signs (r = −0.74, p = 0.002). Stage 3 rate of progression did not differ between cases (p = 0.18). Electroretinograms correlated with Brief Ataxia Rating Scale score and were a biomarker of disease onset and progression. All symptomatic patients developed gait ataxia, extremity dysmetria, dysarthria, dysrhythmia, and oculomotor abnormalities. Funduscopy revealed pale optic discs and pigmentary disturbances. Visual acuity declined to blindness in those with longer CAG expansions. Hyperreflexia was present from Stage 1 onwards. Restless legs syndrome and sensory impairment were common. Neuropathological hallmarks were neuronal loss in cerebellar cortex, deep cerebellar nuclei, inferior olive, and anterior horns of the spinal cord, and axonal loss in spinocerebellar tracts, dorsal nerve roots, and posterior columns. Retinal pathology included photoreceptor degeneration and disruption of retinal pigment epithelium. Spinocerebellar ataxia type 7 evolves through four clinical stages; neuropathological findings underlie the clinical presentation; electroretinograms are a potential biomarker of disease progression.

Keywords

Trinucleotide repeat expansion Cerebellum Ataxia Pathology Electroretinography 

Notes

Acknowledgements

Our paper is dedicated to the members of this family, whose personal resolve and commitment to this study are inspirational. Dr. Katherine B. Sims performed the original genetic testing in this family. The assistance of Jason MacMore is gratefully acknowledged.

Funding

This work was supported by the MINDlink Foundation, the Birmingham Foundation, the Foundation Fighting Blindness, and the Massachusetts Alzheimer Disease Research Center [AG05134].

Conflicts of interest

None.

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Laura C. Horton
    • 1
  • Matthew P. Frosch
    • 2
  • Mark G. Vangel
    • 3
  • Carol Weigel-DiFranco
    • 4
  • Eliot L. Berson
    • 4
  • Jeremy D. Schmahmann
    • 1
    Email author
  1. 1.Ataxia Unit, Cognitive and Behavioral Neurology Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of NeurologyMassachusetts General Hospital and Harvard Medical SchoolBostonUSA
  2. 2.C.S. Kubik Laboratory for Neuropathology, Pathology ServiceMassachusetts General HospitalBostonUSA
  3. 3.Athinoula A. Martinos Center for Biomedical ImagingMassachusetts General HospitalBostonUSA
  4. 4.Berman-Gund Laboratory for the Study of Retinal Degenerations, Department of OphthalmologyHarvard Medical School, Massachusetts Eye and Ear InfirmaryBostonUSA

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