Secondary Logo

Journal Logo

Original Contribution

Two Patients With Spinocerebellar Ataxia Type 7 Presenting With Profound Binocular Visual Loss Yet Minimal Ophthalmoscopic Findings

Thurtell, Matthew J MBBS, FRACP; Fraser, J Alexander MD; Bala, Elisa MD; Tomsak, Robert L MD, PhD; Biousse, Valérie MD; Leigh, R John MD; Newman, Nancy J MD

Author Information
Journal of Neuro-Ophthalmology: September 2009 - Volume 29 - Issue 3 - p 187-191
doi: 10.1097/WNO.0b013e3181b41764

Abstract

Spinocerebellar ataxia type 7 (SCA7) is a rare neurodegenerative disease caused by a CAG triplet repeat expansion in the SCA7 gene on chromosome 3 (1-3), encoding for a protein called ataxin 7 (4). It is inherited in an autosomal dominant fashion, and sporadic cases are reported rarely (5). SCA7 characteristically produces progressive ataxia. Its common ophthalmologic manifestations include visual loss from photoreceptor degeneration and ophthalmoplegia (6,7).

We describe two unrelated patients with SCA7 who had visual loss with only subtle ophthalmoscopic signs. Electroretinography (ERG) disclosed photoreceptor dysfunction. Both patients had slow saccades and partial limitation of ocular ductions. We emphasize the importance of assessing eye movements and obtaining ERG for timely diagnosis of this disorder.

CASE REPORTS

Case 1

A 12-year-old African-American boy presented with progressive painless bilateral visual loss over several years. His family had also noticed that his eyes became “crossed” when he looked laterally, but he denied diplopia or any other neurologic symptoms. His mother and twin sister had similar manifestations.

Best-corrected visual acuity was 20/200 in the right eye and 20/300 in the left eye. He could identify only the control Ishihara plate bilaterally. Confrontation visual fields revealed bilateral central scotomas. Results of external and anterior segment examinations were normal. Ophthalmoscopy revealed equivocally pale discs and attenuated retinal arteries. The foveal light reflexes were absent, and there was subtle pigmentary mottling in the foveal region (Fig. 1). Pupil examination was normal. Ocular motor examination revealed normal alignment in primary gaze position, slow horizontal saccades, and limited abduction of each eye that could be partially overcome with the doll's head maneuver. (Video, Supplemental Digital Content 1, http://links.lww.com/WNO/A3). Tandem gait was unsteady, and results of the remainder of the neurologic examination were unremarkable.

FIG. 1
FIG. 1:
Case 1. Retinal artery attenuation, subtle pigmentary mottling in the foveal region, and equivocal temporal optic disc pallor are evident.

Humphrey visual fields confirmed bilateral central scotomas. Brain MRI revealed cerebellar atrophy (Fig. 2). Multifocal ERG showed severely attenuated foveal responses (Fig. 3). Genetic testing revealed an increased CAG repeat number of 65 (normal <18, borderline 19-36) in one SCA7 allele, confirming the diagnosis of SCA7.

FIG. 2
FIG. 2:
Case 1. Precontrast T1 axial (A), sagittal (B), and coronal (C) MRI shows cerebellar atrophy, most apparent in the vermis, and minimal brainstem atrophy.
FIG. 3
FIG. 3:
Case 1. Multifocal electroretinogram from the right eye (left panel) and left eye (right panel). Trace arrays (top) and field plots (bottom) demonstrate severely attenuated central responses with an absent foveal peak.

Case 2

A 21-year-old Caucasian woman presented with bilateral visual loss and gait ataxia, both progressive since age 14 years. By age 18 years, she had developed a wide-based gait and, over the following 3 years, increasing clumsiness of her upper limbs. She took no regular medications and denied alcohol consumption. Similar manifestations were present in her mother, in whom multiple sclerosis had been diagnosed, and in her mother's male cousin.

Best-corrected visual acuity was 20/100 in both eyes. She could identify only the control Ishihara plate with each eye. Confrontation visual fields revealed bilateral central scotomas. Results of external and anterior segment examinations were unremarkable. Ophthalmoscopic examination revealed normal optic discs and slightly attenuated retinal arteries. The foveal light reflexes were absent, but there were no pigmentary changes (Fig. 4). Pupillary examination was normal. Ocular alignment was normal in primary gaze position. Horizontal and vertical saccades were slow, and there was reduced abduction and supraduction that could be partially overcome with the doll's eye maneuver (Video, Supplemental Digital Content 2, http://links.lww.com/WNO/A4). She had mild bilateral ptosis, facial weakness, head titubation, and appendicular, truncal, and gait ataxia. Deep tendon reflexes were symmetrically brisk, but plantar responses were flexor.

FIG. 4
FIG. 4:
Case 2. Subtle retinal artery attenuation is the only evident abnormality.

Fundus autofluorescence was normal (Fig. 5). Humphrey and Goldmann visual fields showed bilateral central scotomas. Brain MRI showed brainstem and cerebellar atrophy (Fig. 6). Full-field ERG showed abnormalities consistent with severe cone dysfunction and moderate rod dysfunction. Genetic testing revealed an increased CAG repeat number of 56 in one SCA7 allele, confirming the diagnosis of SCA7.

FIG. 5
FIG. 5:
Case 2. Ocular fundus autofluorescence is normal.
FIG. 6
FIG. 6:
Precontrast T1 axial (A) and sagittal (B) and coronal FLAIR (C) MRI show marked cerebellar and brainstem atrophy.

DISCUSSION

In contrast with the other autosomal dominant spinocerebellar ataxias, SCA7 is characterized by progressive irreversible bilateral visual loss due to a degenerative retinopathy that initially affects cone photoreceptors but progresses toward a cone-rod dystrophy phenotype (8,9). Early in the disease, visual acuity is decreased and there are central scotomas. Peripheral vision and night vision are relatively preserved (6,10). Dyschromatopsia is usually severe and may be detected years before symptom onset in affected individuals (6). The retinopathy classically results in granular pigmentary changes in the foveal region (6,10), occasionally producing a “bull's eye” appearance (11), often with associated secondary optic disc pallor (6,10). However, these ophthalmoscopic abnormalities are not usually present until late in the course of the disease. Indeed, it has been noted that the fundus may initially appear normal, even after substantial visual acuity loss has occurred (6), potentially causing a diagnostic delay. Despite noting visual loss for several years, our 2 patients had only subtle retinal artery attenuation and absent foveal light reflexes (Fig. 1 and 4). In our Case 1, who had more severe visual loss, there was very subtle pigmentary mottling in the foveal regions and equivocal temporal optic disc pallor. Our review of fundus photographs from previously reported patients with SCA7, in whom the ocular fundi were considered normal, suggests that subtle abnormalities, such as retinal arterial attenuation, were actually present (12). A prospective study of individuals with the SCA7 mutation is required to further delineate the sequence of ophthalmoscopic changes in relation to symptom onset and visual function.

Pigmentary changes in the foveal region may be more evident on fluorescein angiography (11). Retinal thinning that is more extensive than suggested by ophthalmoscopy can be detected with optical coherence tomography (OCT) (11).

The role of fundus autofluorescence photography (13), a noninvasive imaging technique for topographical mapping of lipofuscin in the retinal pigment epithelium, has not been evaluated in SCA7. Lipofuscin is a fluorescent pigment that accumulates in the retinal pigment epithelium cells as a consequence of photoreceptor degradation (13). Although lipofuscin accumulation can be seen with a variety of inherited and acquired retinal diseases, fundus autofluorescence was normal in our Case 2, suggesting that it might not be a useful tool for detecting retinal degeneration in the early stages of SCA7.

The presence of photoreceptor disease can be confirmed with ERG. Although full-field ERG is widely available and is abnormal once ophthalmoscopic changes have become apparent (10), multifocal ERG may be more sensitive for detecting foveal dysfunction in the early stages of the disease (11,12). Indeed, the multifocal ERG can be grossly abnormal even when ophthalmoscopic changes are absent or subtle (12), as in our Case 1.

Ocular motor abnormalities are common in SCA7. Slowing of saccades is an early sign, suggesting involvement of the brainstem reticular formation (10,14), and is later followed by progressive ophthalmoplegia. The ophthalmoplegia is often partially overcome with vestibular stimulation in the earlier stages of the disease, but later becomes consistent with an external ophthalmoplegia (10). In both of our patients, there were no symptoms, such as diplopia, to suggest ocular motor dysfunction. Ocular motor abnormalities that are commonly seen in association with spinocerebellar degeneration, such as downbeat, gaze-evoked, and rebound nystagmus, dysmetric saccades, and impaired smooth pursuit (15), were not present in either of our patients, consistent with previous reports (6,7,10). Unfortunately, there are few reports of quantitative eye movement recordings in SCA7 (10,14).

Signs of cerebellar dysfunction can be found in almost all patients with SCA7 as the disease progresses (7), but may be subtle or absent in the early stages, as in our Case 1. Cerebellar and brainstem atrophy is often seen on MRI (10,14) but can also be subtle and easily overlooked.

REFERENCES

1. Gouw LG, Kaplan CD, Haines JH, et al. Retinal degeneration characterizes a spinocerebellar ataxia mapping to chromosome 3p. Nat Genet 1995;10:89-93.
2. Benomar A, Krols L, Stevanin G, et al. The gene for autosomal dominant cerebellar ataxia with pigmentary macular dystrophy maps to chromosome 3p12-p21.1. Nat Genet 1995;10:84-8.
3. Holmberg M, Johansson J, Forsgren L, et al. Localization of autosomal dominant cerebellar ataxia associated with retinal degeneration and anticipation to chromosome 3p12-p21.1. Hum Mol Genet 1995;4:1441-5.
4. Kaytor MD, Duvick LA, Skinner PJ, et al. Nuclear localization of the spinocerebellar ataxia type 7 protein, ataxin-7. Hum Mol Genet 1999;8:1657-64.
5. Stevanin G, Giunti P, Belal GD, et al. De novo expansion of intermediate alleles in spinocerebellar ataxia 7. Hum Mol Genet 1998;7:1809-13.
6. Gouw LG, Digre KB, Harris CP, et al. Autosomal dominant cerebellar ataxia with retinal degeneration: clinical, neuropathologic, and genetic analysis of a large kindred. Neurology 1994;44:1441-47.
7. David G, Durr A, Stevanin G, et al. Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7). Hum Mol Genet 1998;7:165-70.
8. Aleman TS, Cideciyan AV, Volpe NJ, et al. Spinocerebellar ataxia type 7 (SCA7) shows a cone-rod dystrophy phenotype. Exp Eye Res 2002;74:737-45.
9. Michalik A, Martin JJ, Van Broeckhoven C. Spinocerebellar ataxia type 7 associated with pigmentary retinal dystrophy. Eur J Hum Genet 2004;12:2-15.
10. Enevoldson TP, Sanders MD, Harding AE. Autosomal dominant cerebellar ataxia with pigmentary macular dystrophy: a clinical and genetic study of eight families. Brain 1994;117:445-60.
11. Ahn JK, Seo JM, Chung H, et al. Anatomical and functional characteristics in atrophic maculopathy associated with spinocerebellar ataxia type 7. Am J Ophthalmol 2005;139:923-25.
12. Hugosson T, Granse L, Ponjavic V, et al. Macular dysfunction and morphology in spinocerebellar ataxia type 7 (SCA 7). Ophthalmic Genet 2009;30:1-6.
13. Schmitz-Valckenberg S, Holz FG, Bird AC, et al. Fundus autofluorescence imaging: review and perspectives. Retina 2008;28:385-409.
14. Oh AK, Jacobson KM, Jen JC, et al. Slowing of voluntary and involuntary saccades: an early sign in spinocerebellar ataxia type 7. Ann Neurol 2001;49:801-4.
15. Leigh RJ, Zee DS. The Neurology of Eye Movement. 4th ed. New York: Oxford University Press; 2006.

Supplemental Digital Content

© 2009 Lippincott Williams & Wilkins, Inc.