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Clinicopathologic Reports, Case Reports, and Small Case Series
May 2002

Ocular Findings in Spinocerebellar Ataxia 7

Arch Ophthalmol. 2002;120(5):655-659. doi:

Spinocerebellar ataxia (SCA) 7, also known as autosomal dominant cerebellar ataxia (ADCA) type II or olivopontocerebellar atrophy with retinal degeneration, is one of at least 14 genetically distinct forms of hereditary SCA. All of these forms are characterized by variable degeneration of the cerebellar cortex, the basal ganglia, the brainstem, the spinal cord, and the peripheral nerves. Prior to the identification of the causative genes, ADCAs were divided into 3 subtypes.1 In ADCA type I, cerebellar ataxia is associated with ophthalmoplegia, optic atrophy, extrapyramidal signs, and dementia. Patients with ADCA type II develop retinal degeneration and cerebellar ataxia. Ophthalmoplegia, extrapyramidal signs, and dementia are variably present. Autosomal dominant cerebellar ataxia type III is described as a "pure" cerebellar syndrome. All 3 ADCA types are genetically heterogeneous. Almost all of ADCA type II cases are due to mutations in the SCA7 locus; thus, SCA7 is unique in that it is the only SCA invariably associated with retinal degeneration. Here, we describe the ocular findings in a patient diagnosed after postmortem examination as having had SCA7.

Report of a Case

A 17-year-old black male died of aspiration pneumonia and a urinary tract infection. No notable developmental or medical problems were evident until the age of 8 years when he was noted to have poor vision. He was diagnosed with retinitis pigmentosa at age 9.5 years and was legally blind (20/300 OD and 20/400 OS) by age 11 years (Figure 1). At age 10 years, he started to have difficulty walking. He had full muscle strength but poor coordination and dysmetric finger-to-nose and knee-to-chin movements. Speech was slow and dysarthric. There was limited upward gaze, limited adduction, dysconjugate gaze, and bilateral ptosis. There was no family history of relevant ocular or neurologic diseases.

Figure 1.
Fundus photograph of the right
eye at age 11 years shows attenuated retinal vessels, diffuse areas of hypopigmentation
of the retinal pigment epithelium, and severe atrophy of the retinal pigment
epithelium in the macula.

Fundus photograph of the right eye at age 11 years shows attenuated retinal vessels, diffuse areas of hypopigmentation of the retinal pigment epithelium, and severe atrophy of the retinal pigment epithelium in the macula.

Electrocardiogram results showed no evidence of cardiac conduction block. Electroencephalogram findings were normal. Magnetic resonance imaging of the head revealed cerebellar atrophy, a dilated fourth ventricle, and thin but otherwise normal-appearing optic nerves. At age 12 years, a muscle biopsy specimen showed no ragged red fibers with the Masson trichrome stain and no abnormal mitochondria by electron microscopy. Electron transport chain (ETC) analysis revealed a partial defect in ETC complex I and normal ETC complexes II, III, and IV. No deletions of mitochondrial DNA were detected by Southern blot analysis; no sequence analysis was performed to search for point mutations in the mitochondrial genome. Nevertheless, the patient carried the diagnosis of an atypical form of mitochondrial disease, such as a variant of Kearns-Sayre syndrome or myoclonic epilepsy and ragged red fiber disease/progressive external ophthalmoplegia.

By age 13 years, the patient was confined to a wheelchair. He began to have myoclonic seizures. A percutaneous gastrostomy tube was placed for feeding. At age 16 years, the patient had respiratory failure requiring assisted ventilation, especially at night. He had 15 hospital admissions in the last year of life for respiratory distress, aspiration pneumonia, and episodes of lethargy and unresponsiveness. One month prior to death, the patient was admitted to the hospital with seizure activity characterized by jerking of the head, both arms, and right leg. A head computed tomography scan revealed no focal lesions. He was treated for presumed status epilepticus, after which an electroencephalogram showed findings suggestive of diffuse cortical dysfunction but no evidence of seizure activity. He developed a left lower lobe pulmonary infiltrate and a urinary tract infection. Given the patient's poor neurologic and pulmonary status, mechanical respiratory support was discontinued and the patient died the following day.

The right globe and central nervous system were obtained at autopsy. On gross examination, the retinal pigment epithelium (RPE) had a mottled appearance throughout the fundus (Figure 2). Ciliary epithelial cysts containing acellular eosinophilic material were present on microscopic examination (Figure 3) but were not appreciated grossly. The ganglion cell layer of the retina appeared normal. There was diffuse photoreceptor degeneration that appeared more severe in the posterior pole than in the periphery. There were very rare intraretinal pigment deposits and areas with subretinal proteinaceous material. Patches of atrophic RPE were intermixed with hyperpigmented and hypertrophic RPE cells (Figure 4).

Figure 2.
Postmortem gross examination of
the left eye showing a mottled retinal pigment epithelium.

Postmortem gross examination of the left eye showing a mottled retinal pigment epithelium.

Figure 3.
Ciliary epithelial cysts contain
acellular eosinophilic material (hematoxylin-eosin; original magnification
×40).

Ciliary epithelial cysts contain acellular eosinophilic material (hematoxylin-eosin; original magnification ×40).

Figure 4.
Severe photoreceptor degeneration
in the posterior pole of the retina (A) with very rare intraretinal pigment
deposits (A and B). Patches of atrophic retinal pigment epithelium (RPE) are
intermixed with hyperpigmented and hypertrophic RPE cells (A and B) (hematoxylin-eosin;
original magnifications ×100 and ×400, respectively).

Severe photoreceptor degeneration in the posterior pole of the retina (A) with very rare intraretinal pigment deposits (A and B). Patches of atrophic retinal pigment epithelium (RPE) are intermixed with hyperpigmented and hypertrophic RPE cells (A and B) (hematoxylin-eosin; original magnifications ×100 and ×400, respectively).

Immunohistochemical staining with an antibody against ubiquitin, a component of many types of inclusions, revealed rare intranuclear inclusions in the inner and outer nuclear layers and the ganglion cell layer (Figure 5). The ubiquitin-positive inclusions were either round and compact or diffuse. We were unable to convincingly detect these inclusions with an antibody against expanded polyglutamine repeats. However, electron microscopy of the retina confirmed the presence of 2 distinct types of intranuclear inclusions (Figure 6). The first type of inclusion was round, compact, and predominantly filamentous, while the second type was larger and more diffuse with granular and filamentous structures.

Figure 5.
Retinal intranuclear inclusions
containing ubiquitin. Immunohistochemical staining with an antibody against
ubiquitin reveals a round, compact, intranuclear inclusion in the inner nuclear
layer (A) and a more diffuse, intranuclear inclusion in the ganglion cell
layer (B). Intranuclear inclusions are designated by arrows. Immunohistochemistry
was performed on formalin-fixed tissue (original magnification ×1000).

Retinal intranuclear inclusions containing ubiquitin. Immunohistochemical staining with an antibody against ubiquitin reveals a round, compact, intranuclear inclusion in the inner nuclear layer (A) and a more diffuse, intranuclear inclusion in the ganglion cell layer (B). Intranuclear inclusions are designated by arrows. Immunohistochemistry was performed on formalin-fixed tissue (original magnification ×1000).

Figure 6.
An electron micrograph shows 2
intranuclear inclusions in a retinal cell. One is compact and predominantly
filamentous (arrow). The second is larger and more diffuse with granular and
filamentous structures (surrounded by arrowheads). n indicates the nucleus;
c, cytoplasm. Electron microscopy was performed on glutaraldehyde-fixed tissue
stained with lead citrate. Scale bar = 1 µm.

An electron micrograph shows 2 intranuclear inclusions in a retinal cell. One is compact and predominantly filamentous (arrow). The second is larger and more diffuse with granular and filamentous structures (surrounded by arrowheads). n indicates the nucleus; c, cytoplasm. Electron microscopy was performed on glutaraldehyde-fixed tissue stained with lead citrate. Scale bar = 1 µm.

The brain weighed 950 g (normal for an adult male is 1350-1450 g). The cerebrum was mildly atrophic and microscopically showed reactive gliosis. There was severe atrophy of the cerebellum with gliosis and only rare Purkinje cells (Figure 7). Severe gliosis and neuronal loss were also found in the brainstem and the spinal cord in a pattern consistent with SCA.

Figure 7.
A normal cerebellar cortex (A)
compared with the cerebellar cortex in the patient in this report with spinocerebellar
ataxia (SCA) 7 (B). There is severe atrophy of the cerebellar cortex in the
patient with SCA7, with loss of Purkinje cells (p) and internal granule cells
(ig). There are no identifiable Purkinje cells in most sections of the cerebellum;
this section is one of the few with a remaining Purkinje cell (seen in the
center of the field) (hematoxylin-eosin; original magnification ×40).

A normal cerebellar cortex (A) compared with the cerebellar cortex in the patient in this report with spinocerebellar ataxia (SCA) 7 (B). There is severe atrophy of the cerebellar cortex in the patient with SCA7, with loss of Purkinje cells (p) and internal granule cells (ig). There are no identifiable Purkinje cells in most sections of the cerebellum; this section is one of the few with a remaining Purkinje cell (seen in the center of the field) (hematoxylin-eosin; original magnification ×40).

Molecular analysis of the SCA7 gene showed that the patient was a heterozygote, with 1 allele having approximately 12 CAG repeats and the other having 70 to 87 repeats (normal, ≤36 repeats) (Figure 8). DNA from the patient's parents was not available.

Figure 8.
Molecular genetic analysis of
the patient's DNA purified from a fragment of unfixed, frozen liver. The portion
of the SCA7 gene containing the polyglutamine region
was amplified by polymerase chain reaction (PCR). The PCR-amplified DNA products
were separated by denaturing gel electrophoresis. Size was determined by comparing
the migration of the PCR-amplified DNA products with a DNA sequence ladder
of known size (not shown). DNA from a patient known to have spinocerebellar
ataxia (SCA) 7 is the positive control (+). DNA from an unaffected individual
is the negative control (−). DNA from our patient is in the middle lane
(pt). One allele of the SCA7 gene in our patient
contains expanded CAG repeats (70-87 repeats). The second allele is wild type
with approximately 12 repeats. Multiple bands are due to "stuttering" of the
polymerase as it replicates the polyglutamine region. Numbers along the right
side of the gel indicate the number of CAG repeats.

Molecular genetic analysis of the patient's DNA purified from a fragment of unfixed, frozen liver. The portion of the SCA7 gene containing the polyglutamine region was amplified by polymerase chain reaction (PCR). The PCR-amplified DNA products were separated by denaturing gel electrophoresis. Size was determined by comparing the migration of the PCR-amplified DNA products with a DNA sequence ladder of known size (not shown). DNA from a patient known to have spinocerebellar ataxia (SCA) 7 is the positive control (+). DNA from an unaffected individual is the negative control (−). DNA from our patient is in the middle lane (pt). One allele of the SCA7 gene in our patient contains expanded CAG repeats (70-87 repeats). The second allele is wild type with approximately 12 repeats. Multiple bands are due to "stuttering" of the polymerase as it replicates the polyglutamine region. Numbers along the right side of the gel indicate the number of CAG repeats.

Comment

This case is noteworthy because the diagnosis of SCA7 was made only after postmortem examination. The patient had a prior diagnosis of an atypical mitochondrial disorder because the clinical symptoms overlapped with those found in mitochondrial myopathies and because of an abnormal ETC complex I analysis. The significance of the abnormal ETC complex I analysis is uncertain.

Spinocerebellar ataxia 7 was not seriously considered, possibly because of the absence of a positive family history. Like other dominant neurodegenerative disorders, such as Huntington disease, SCA7 shows strong anticipation: the age of onset and disease severity increase with each successive generation. The molecular basis for anticipation in SCA7 is the expansion of a polyglutamine tract in ataxin 7, the protein product of the SCA7 gene.2 This stretch of glutamine residues is encoded by the repetition of the sequence CAG in the coding region of the gene. The number of CAG repeats (and the encoded polyglutamine tract) varies normally from 7 to 17 repeat units. Rarely and for obscure reasons, an allele with 18 to 35 repeats will arise. Individuals with these intermediate alleles are usually asymptomatic. However, once the repeat has expanded, it is prone to expand even further during parent-to-child transmission and especially during father-to-child transmission.3 Individuals affected with SCA7 carry an allele with 37 to 200 repeat units. Thus, one possible explanation for why this patient did not have a positive family history is that one parent was an asymptomatic carrier of an intermediate allele, and the pathologic expansion of the repeat occurred between generations.

Retinal degeneration is always present in patients with SCA7. The onset of visual symptoms may precede or follow the onset of neurologic symptoms. The disease affects cone function more severely than rod function. Patients never complain of night blindness. The first visual complaint is usually reduced central visual acuity or abnormal color vision.4,5 Electroretinograms document that cone function is more severely impaired than rod function. Fundus examination early in the disease shows atrophy of the RPE in the macula; later there is attenuation of retinal vessels and a mottled RPE throughout the fundus. There is little or no intraretinal pigmentation of the sort that is ordinarily seen in retinitis pigmentosa.

Most but not all patients with ADCA type II harbor mutations in the SCA7 gene. Giunti et al6 identified one family with ADCA type II that did not have CAG expansion in the SCA7 gene and no linkage to the SCA7 locus, indicating genetic heterogeneity. Furthermore, Babovic-Vuksanovic et al7 reported a case of SCA with retinal degeneration in an infant who died with a severe form of SCA2. These rare cases emphasize the importance of molecular genetic analysis to establish the diagnosis. The ocular pathologic characteristics of 2 cases of ADCA type II described by To et al8 and Martin et al9 are now known to be from families with SCA7 gene defects determined by DNA analysis (Eliot Berson, MD, oral communication, 1999, and Mauger et al,10 respectively).

Neuronal intranuclear inclusions are a common feature of diseases related to polyglutamine expansion. In Huntington disease, SCA1, and SCA3, intranuclear inclusions develop mainly in neurons from regions affected by the disease,1113 leading to the hypothesis that the formation of intranuclear inclusions is an important step in the neurodegenerative process. However, in SCA7, intranuclear inclusions are not restricted to regions affected by the disease.14 These findings suggest that the inclusions may be necessary but not sufficient to cause cell dysfunction and death.

In this study, we described the ultrastructural appearance of 2 types of intranuclear inclusions in the retina of a patient with SCA7. The diffuse, granulofilamentous inclusions resemble the inclusions found in the retina of one patient with early-onset SCA7 described by Mauger et al.10 Similar granulofilamentous inclusions have been found in patients with Huntington disease and in mice hemizygous for a mutant form of human huntingtin (hd).11,15 The compact, filamentous inclusions in our SCA7 case differ from those described by Mauger et al10 and most closely resemble the amyloidlike structures observed in mice homozygous for the hd mutation.16 As in the SCA7 case reported by Mauger et al, the retinal intranuclear inclusions in our patient contained ubiquitin and were present in the inner and outer nuclear layers as well as the ganglion cell layer. Our data support the finding of Mauger and coworkers10 that intranuclear inclusions in the retina are not restricted to the neuronal population that degenerates.

To our knowledge, no previous report of the ocular pathology of presumed SCA7 disease mentions ciliary epithelial cysts. Such cysts containing proteinaceous material, as found in our case, are considered a specific feature of multiple myeloma and other hypergammaglobulinemic conditions,17 which were not present in this case.

This work was supported by grant EY08683 from the National Institutes of Health, Bethesda, Md.

Dr McLaughlin is a Howard Hughes Medical Institute Postdoctoral Fellow.

Corresponding author and reprints: Margaret E. McLaughlin, MD, Children's Hospital, Department of Pathology, 300 Longwood Ave, Boston, MA 02115 (e-mail: memclaughlin@partners.org).

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