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

Abstract

INTRODUCTION 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. METHODS 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 5, and autopsy in 4 cases. RESULTS We identified 4 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. 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. DISCUSSION Spinocerebellar ataxia type 7 evolves through 4 clinical stages; neuropathological findings underlie the clinical presentation; electroretinograms are a potential biomarker of disease progression.

Spinocerebellar Ataxia Type 7: A Neurodegenerative Disorder with Peripheral Neuropathy

“…The gene causing SCA7 is located on chromosome 3p21-p12 and encodes for a protein named ataxin-7. Although ataxin-7 is broadly expressed, the pathology is primarily localized in the cerebellum and retina [14]. It has been reported that neuropathological hallmarks of SCA7 include neuronal loss in the cerebellar cortex, deep cerebellar nuclei, inferior olive, and anterior horns of the spinal cord, as well as axonal loss in spinocerebellar tracts [14].…”

Phenotype variability and early onset ataxia symptoms in spinocerebellar ataxia type 7: comparison and correlation with other spinocerebellar ataxias

“…SCA7 accounts for approximately 2 to 5 percent of all SCA and has a variable clinical expression, particularly depending on age at onset and CAG repeat 7 . Thus, the higher the number of repetitions, the more severe the disease, and the earlier the onset of symptoms 7 . Extremely long CAG repeats (.…”

“…Normal alleles contain 4-35 CAG repeats, whereas pathological alleles for SCA7 contain from 36-306 CAG repeats 7 . Besides cerebellar signs, the main neurological manifestations of SCA7 include visual loss, due to macular changes, cone dysfunction, retinal pigmentary dystrophy and ophthalmoplegia 8,9,10 .…”

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

“…The gene has 13 exons with the polyQ repeat region in exon 3, the first coding exon of the gene. The healthy repeat range in SCA7 is 7-19, with an incomplete penetrance of 19-35, while a wide disease range of 36 to >400 repeats has been reported ( Table 2) [172]. Although all SCA diseases have a tendency for genetic anticipation, ATXN7 is particularly known to be highly unstable, resulting in extreme anticipation and expansion during paternal transmission [38].…”