Spinocerebellar ataxia type 7 presenting as Stargardt's disease

Abstract

Sirs: Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disorder characterised by progressive retinal and cerebellar degeneration [1]. Stargardt’s disease (STD) represents the most common hereditary (autosomal recessive) macular dystrophy manifesting with juvenile central visual impairment and progressive bilateral atrophy of the macula and the retinal pigmental epithelium (RPE) [2]. We report a case of juvenile SCA7 caused by de novo expansion of polyglutamine repeats, whose clinical presentation (isolated progressive visual impairment) simulated STD. A 12-year-old girl, with no family history of neurological or retinal disease, presented for ophthalmologic evaluation due to over six months of progressing bilateral visual loss. Based on the findings of the ophthalmologic examination (visual acuity of 0.2 was homozygote for a normal allele (< 19 repeats). The length of the SCA7 CAG repeat is inversely correlated with age of onset and dictates the initial symptom presentation. Longer CAG repeats lead to earlier onset of the disease, more rapid progression and increased chance of visual failure preceding cerebellar ataxia [1]. Interestingly, Johansson et al., after investigating the effect of repeat length on clinical manifestation in four Swedish SCA7 families, reported that in 80% of SCA7 cases with 59 repeats or more the disease started with visual impairment and visual symptoms preceded ataxia over a period of 1–6 years [4]. The retinal degeneration in SCA7 consists of a progressive cone-rod dystrophy causing substantial impairment of central visual acuity [1, 5]. The same phenotypic features may be shared by STD, which represents one of the most common causes of macular degeneration during the first two decades of life and is caused by homozygous mutations in the gene ABCA4 that encodes the photoreceptor-specific, ATP-binding transporter ABCA4 [6, 7]. The same gene, which has been mapped to the short arm of chromosome 1, is also associated with the phenotypic manifestation of fundus flavimaculatus (FFM) (Fig. 1D) [6, 7]. Recent, genotypephenotype correlation studies have highlighted the wide allelic heterogeneity of this gene. The spectrum of disease severity, associated with specific mutations in the ABCA4 gene, may vary from a mild phenotypic manifestation of STD (with absent dark choroid and normal electroretinographic amplitudes) to a severe and diffuse atrophy of the retinal pigmental epithelium and the choriocapillaris (present dark choroid) [6, 7]. Thus, in the absence of neurological manifestations and positive family history the differential diagnosis between bilaterally, impairment of color vision in the blue-yellow axis and subtle pigment mottling of the RPE; Fig. 1A), the visual field testing (central scotoma bilaterally), the unremarkable Ganzfeld electroretinography and the findings of fluorescein angiography (perifoveal flecks and absence of dark choroid), STD was diagnosed. Neurological examination and brain MRI were normal. Three years later she developed progressive truncal ataxia and poor motor coordination. The patient was admitted for further evaluation at our institution. Neurological examination revealed severe brainstem (bilateral pyramidal symptoms, dysphagia, tongue atrophy, markedly slowed ocular saccades) and cerebellar involvement (truncal ataxia, dysmetria, dysdiadochokinesia, gaze-evoked nystagmus and dysarthria). Repeat ophthalmologic examination disclosed pigmentary degeneration and accumulation, fundus atrophy with “bull’s eye configuration” (Fig. 1B). Substantial brainstem and cerebellar atrophy was noted on repeat brain MRI (Fig. 1C). Other systemic disorders with retinal and cerebellar degeneration (juvenile neuronal ceroid lipofuscinosis, abetalipoproteinemia, mitochondriopathies) were excluded on the basis of diagnostic work-up (negative skin punch biopsy, unremarkable muscle biopsy, negative DNA testing for Leber hereditary optic neuropathy, normal serum lipid electrophoresis). Molecular genetic testing identified one allele with abnormal CAG expansion (70 repeats, normal < 36) in the ataxin 7 gene and confirmed the diagnosis of SCA7. The patient’s father (asymptomatic with unremarkable neurological and ophthalmologic evaluations) was heterozygote for a mutable normal allele (intermediate allele, 34 repeats) [3]. The patient’s mother G. Tsivgoulis, MD ( ) · S. Vassilopoulou, MD · K. Spengos, MD Dept. of Neurology University of Athens School of Medicine Iras 39, Gerakas 15344 Athens, Greece Tel.: +306937178635 Fax: +302106742604 E-Mail: tsivgoulisgiorg@yahoo.gr