Miller, Randee C BS; Tewari, Aash MD; Miller, Joel A MD; Garbern, James MD; Van Stavern, Gregory P MD
Spinocerebellar ataxia type 7 (SCA7) is a rare autosomal dominant, slowly progressive neurodegenerative disorder associated with abnormal expansion of a CAG trinucleotide repeat within the ATXN7 gene on chromosome 3p12-13 (1). Normal alleles have less than 20 CAG repeats; approximately 75% of normal alleles have 10 repeats. Disease-causing alleles have greater than 36 CAG repeats (1).
SCA7 is the only inherited ataxia invariably associated with a cone-rod dystrophy (1,2). Patients with cone-rod dystrophy present with reduced visual acuity, dyschromatopsia, and photosensitivity, followed by progressive loss in peripheral vision and night blindness (2). On ophthalmoscopic evaluation, such patients may initially have a normal-appearing macula. Eventually retinal pigment epithelial mottling occurs in the macular area, finally developing into a “bull's-eye” maculopathy. Full-field electroretinography (ERG) usually shows loss of photopic function, reflecting loss of cone photoreceptors. In the early stages of the disease, multifocal ERG may be more sensitive than full-field ERG. Slow saccadic eye movements are common but not specific for SCA7. The cerebellar ataxia manifests first as gait imbalance, later joined by appendicular ataxia, and eventually leading to wheelchair confinement. Other neurologic findings in SCA7 include hyperreflexia, spasticity, dysarthria, and dysphagia (3).
SCA7 exhibits genetic anticipation caused by expansion of the CAG repeats in offspring of affected males. The anticipation applies to the age of onset and rate of progression of disease, so that affected offspring experience symptoms at an earlier age and the disease progresses at a much faster rate than in the affected parent. A patient may become symptomatic before the transmitting parent, and thus there may be an apparent absence of a family history of the disorder (1).
The clinical course of SCA7 is variable with regard to age of onset and rate of progression. Patients may present with symptoms of ataxia, symptoms of visual loss, or both (3,4). The initial manifestations of SCA7 may be subtle, and affected patients may be misdiagnosed until their symptoms are advanced, resulting in unnecessary testing, incorrect treatment, and inaccurate prognosis.
Previous studies of SCA7 are limited and lack detail regarding the visual manifestations (including macular changes) and how these manifestations correlate with the neurologic features. In evaluating 26 patients with SCA7, Martin et al (3) provided detailed information regarding the number of triplet repeats and electrophysiologic data but did not report visual acuity or detailed visual and neurologic examination features. In a study of only 3 patients with SCA7, Ahn et al (4) formally evaluated visual function, fundus findings, and visual electrophysiology but did not evaluation neurologic function and the relationship between the two sets of symptoms. Our study was designed to provide more information on the neuro-ophthalmologic manifestations of SCA7, particularly their relationship to neurologic dysfunction.
The medical records of 10 consecutive patients with SCA7 seen in the Neuro-Ophthalmology Clinic of the Kresge Eye Institute, Wayne State University, Detroit, Michigan, between 2000 and 2008 were retrospectively reviewed. All patients were referred for unexplained visual loss, and none of the patients had a specific genetic diagnosis. Most of the patients had had a recent ophthalmologic examination without an explanation for complaints of visual loss.
All patients underwent a standardized evaluation at time of presentation, including measurement of visual acuity, color vision, and ocular motility, together with dilated ophthalmoscopy and a full neurologic examination. Ancillary tests, including perimetry, full-field ERG, and optical coherence tomography (OCT), were performed in some patients. Eight patients ultimately had genetically confirmed disease; 2 patients had presumptive SCA7 based on clinical presentation and a suggestive family history. Patients who returned for follow-up examinations were re-evaluated at each follow-up appointment. Patients were excluded if they had visual loss or ataxia due to other causes.
We determined the age of disease onset, initial symptoms, and duration of illness based on the patient's recollection. All patients with noncoincident visual and neurologic symptoms were asked to specify the estimated gap. The best they could offer was “several years,” and we could not verify the accuracy of this information.
All patients were assigned a disease stage corresponding to their degree of disability at presentation. Disease stages were defined as follows: stage 0, no gait difficulties; stage 1, self-reported difficulty with gait; stage 2, loss of independent gait as defined by permanent use of a walking aid or reliance on a supporting arm; and stage 3, confinement to a wheelchair (5).
Color vision testing was assessed using Ishihara color plates. Patients who were unable to identify the control plate were not included in color vision analysis. Snellen visual acuity was obtained using best optical correction. Macular changes were graded based on the ophthalmoscopic examination by the neuro-ophthalmologist (GPV).
Family history was considered positive if there was at least one first-degree relative with ataxia, not necessarily confirmed genetically as SCA7.
The initial symptoms experienced by patients included visual dysfunction, neurologic dysfunction, or a combination of the two. Nine patients had visual symptoms at presentation, either alone or in combination with neurologic symptoms (Table 1).
Three of 10 patients reported visual loss before the onset of ataxia, 1 reported ataxia before the onset of visual loss, 5 reported simultaneous onset of visual and neurologic symptoms, and 1 had unknown order of onset. Visual manifestations included hemeralopia (7 patients), photophobia (4 patients), dyschromatopsia (10 patients), and blurred vision (2 patients).
At presentation, all patients had measurable visual loss (average visual acuity of 20/250 right eye and 20/200 left eye) and dyschromatopsia (average number of correctly identified Ishihara color plates: 25% right eye and 27% left eye).
Macular changes ranged from mild granular retinal pigment epithelium changes to a bull's-eye maculopathy in more severely affected patients (Fig. 1). Four patients had either normal-appearing maculae or minimal macular changes, despite reduced visual acuity and evidence of cone dysfunction on ERG. The 8 patients with genetically confirmed SCA7 had a family history of visual loss and ataxia, although not always initially recognized as manifestations of SCA7. The 2 patients with suspected SCA7 had a family history of ataxia but no definite visual loss. Most patients required assistance for ambulation.
All patients had full versions but with saccadic smooth pursuit, slow saccades, and saccadic dysmetria. Convergence was normal, although this was not formally evaluated in all patients with near point of convergence and convergence amplitudes. None of the patients had nystagmus in primary gaze, but all had horizontal eccentric gaze jerk nystagmus in the direction of gaze.
Visual fields were performed in 8 patients (Humphrey automated perimetry in 7 and Goldmann kinetic perimetry in 1). One patient had a normal Humphrey visual field test, 3 had moderate generalized depression, and 4 had central scotomas (including the patient who underwent Goldmann perimetry).
Results of full-field ERG, performed in 4 patients, were always abnormal, showing reduced cone responses in 4 patients and reduced cone and rod responses in 1 patient.
At the last follow-up visit, all 10 patients had a wide-based ataxic gait with impaired balance and coordination and varying degrees of disability. Four patients needed ambulation assistance (stage 2), and two were wheelchair-bound (stage 3).
The number of abnormal CAG repeats in patients who received testing ranged from 39 to 46; the age of onset in this group ranged from the 2nd to the 5th decade. These results are similar to those of other published studies (1,6).
Our study highlights many of the key features of SCA7, including the differences in severity and time of onset of the visual loss and the ataxia, the lack of obvious visible macular changes early in the disease, the potential for misdiagnosis, and the relationship between age of onset and number of CAG repeats. Previous studies of SCA7 (Table 2) have not documented the degree of visual loss in relation to neurologic findings and have underemphasized the importance of identifying cone dystrophy.
Compared with previous reports, our study includes a relatively large number of families. Table 1 reveals that the severity of visual loss and the severity of ataxia were often discordant. Although 5 patients reported that visual and ataxic symptoms began at the same time, 3 experienced visual symptoms several years before the onset of ataxic symptoms, and 1 had ataxic symptoms for several years before experiencing visual loss. We acknowledge that our information about timing of symptom onset was based on self-recollection. Even so, we are certain that visual loss preceded ataxia by several years in 3 patients, a reminder that SCA7 may present initially with isolated cone dysfunction.
None of the patients had been genetically identified as having SCA7 when we first examined them, either for their visual or their neurologic symptoms. Some of the patients were being followed by a neurologist and an ophthalmologist, neither of whom had considered a unifying diagnosis, perhaps because the patients did not offer their visual symptoms of photosensitivity and hemeralopia without our probing. As we noted, such symptoms can be present even when the macular changes are minimal and visual loss is mild, but full-field ERG will always identify features of cone dysfunction.
Early diagnosis of SCA7 might assist patient counseling regarding disease prognosis, aid in the identification of asymptomatic family members, and result in more cost-effective diagnostic testing. A complete hereditary ataxia panel from Athena Diagnostics (www.athenadiagnostics.com) costs more than $12,000, whereas testing specifically for SCA7 costs approximately $650. Although no specific treatment is available, a correct diagnosis may prevent unnecessary diagnostic testing, allow patients access to multidisciplinary visual and neurologic rehabilitation services, and secure the diagnosis of affected family members. Indeed, the mother of one of our affected patients had a diagnosis of multiple sclerosis. Once her daughter received a confirmed diagnosis, she was reassessed by her neurologist and found to have SCA7 rather than MS and treatment for MS was discontinued. Several patients in this series were referred to a multidisciplinary visual rehabilitation service with benefit, emphasizing that the lack of specific treatment does not negate the importance of supportive and rehabilitative therapies.
SCA7 should be a diagnostic consideration when a patient presents with ataxia and evidence of a cone-rod dystrophy, especially in the setting of a positive family history. However, the absence of a family history or of ophthalmoscopically evident macular changes does not preclude the diagnosis. A strong clinical suspicion of SCA7 should prompt selective molecular genetic testing or referral to specialist familiar with such conditions.
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