Spinocerebellar ataxia type 7: clinical course, phenotype-genotype correlations, and neuropathology.
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.
Ataxia Unit, Cognitive and Behavioral Neurology Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Suite 340, Charles River Plaza South, 175 Cambridge Street, Boston, MA 02114, USA.
Laura C
LC
Horton
Matthew P
MP
Frosch
Mark G
MG
Vangel
Carol
C
Weigel-DiFranco
Eliot L
EL
Berson
Jeremy D
JD
Schmahmann
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000067719:Ataxin-7; D001921:Brain / Q000473:pathology*; D003933:Diagnosis; D004596:Electroretinography; D005192:Family Health; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000473:pathology; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000473:pathology; D010775:Photic Stimulation; D012189:Retrospective Studies; D012720:Severity of Illness Index; D020754:Spinocerebellar Ataxias / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D018911:Trinucleotide Repeats / Q000235:genetics; D055815:Young Adult
C000593829:ATXN7 protein, human; D000067719:Ataxin-7; D009419:Nerve Tissue Proteins