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February 2004

Spinocerebellar Ataxia Type 17: Latest Member of Polyglutamine Disease Group Highlights Unanswered Questions

Arch Neurol. 2004;61(2):183-184. doi:10.1001/archneur.61.2.183

Expansion of CAG repeat units coding for polyglutamine stretches has been identified in at least 9 hereditary neurodegenerative diseases, including spinal and bulbar muscular atrophy; Huntington disease; spinocerebellar ataxia (SCA) types 1, 2, 6, 7, and 17; Machado-Joseph disease (also called SCA3); and dentatorubral-pallidoluysian atrophy. Among these, SCA17, which is caused by expansion of a CAG/CAA repeat coding for a polyglutamine stretch of the TATA-binding protein (TBP) gene, is the latest polyglutamine disease.

Heterogeneity of clinical presentations of sca17

Expansion of the CAG repeat of the TBP gene was first described by Koide et al1 in a 14-year-old Japanese patient with a de novo partial duplication of the CAG/CAA repeat in the TBP gene. The patient had an expanded CAG/CAA repeat gene coding for 63 glutamines, exceeding the range of CAG/CAA repeats in healthy individuals (25-42 repeat units). The initial symptoms at age 6 years were ataxic gait and intellectual deterioration. The patient showed severely impaired intellectual performance, cerebellar ataxia of the limbs and trunk, dysarthria, dysphagia, and hyperreflexia with extensor plantar responses.

Subsequently, familial cases with expansion of the CAG repeats of the TBP gene have been reported. Nakamura et al2 identified 4 Japanese pedigrees. The CAG/CAA repeats of the TBP gene were expanded to 47 to 55 repeat units. The mode of inheritance was autosomal dominant, with incomplete penetrance. Age at onset ranged from 19 to 48 years (mean, 33.2 years). Including the patient with de novo expansion of the CAG/CAA repeat, a strong inverse correlation between age at onset and the size of expanded CAG/CAA repeats was observed. The clinical presentations include gait ataxia, dementia, hyperreflexia, and parkinsonism. Dystonia, chorea, and epilepsy were present in some patients. Zuhlke et al3 identified expansions of CAG/CAA repeats (50 and 55 repeat units) in the TBP gene in 4 patients from 2 families with autosomal dominant inheritance of ataxia, dystonia, and intellectual decline. Stevanin et al4 screened a group of patients with a Huntington disease–like phenotype and identified 2 patients with expansions of CAG repeats (44 and 46 repeat units) in the TBP gene. The patient with 46 repeat units showed behavioral changes, chorea, ataxic gait, dysarthria, increased tendon reflexes, and parkinsonism. The other patient had gait instability, behavioral abnormality, dementia, and increased tendon reflexes with extensor plantar responses. Silveira et al5 described a 66-year-old Portuguese patient with mild ataxia and dementia who had a mildly expanded CAG/CAA repeat (43 repeat units) of the TBP gene. Zuhlke et al6 described a German kindred with 4 siblings with cerebellar ataxia, chorea, and dementia. In this pedigree, the mother and 2 of the siblings carrying the 48 repeat allele were asymptomatic, indicating that even the 48 repeat allele is not fully penetrant.

Oda et al,7 in this issue of the ARCHIVES, report the results of a large-scale screening for CAG/CAA repeat expansions of the TBP gene. By screening 734 patients with SCA, 216 with Parkinson disease, and 195 with Alzheimer disease, they identified 8 patients with SCA with alleles exceeding 43 CAG/CAA repeat units. Alleles with 43 to 45 repeat units were seen in 3 healthy individuals and in 2 patients with Parkinson disease. They further identified a 34-year-old patient carrying 47 and 44 repeat units who had developed progressive cerebellar ataxia and myoclonus at age 25 years and who exhibited dementia and pyramidal signs; his father and mother were asymptomatic but carried 44 and 47 repeat units, respectively, as a heterozygous state, strongly supporting a gene dosage effect of expanded alleles.

Given the results of extensive molecular analyses on CAG/CAG repeats of the TBP gene, the whole spectrum of the clinical and molecular genetic features of SCA17 can now be summarized as follows: (1) There is a threshold length for the development of disease conditions. Although the smallest CAG/CAA repeat associated with the disease phenotype reported to date is 43 repeat units,5 alleles of 43 to 48 repeat units are not fully penetrant. (2) There is an inverse correlation between the size of expanded CAG repeats and age at onset. (3) The cardinal clinical features of SCA17 include ataxia, dementia, and extrapyramidal symptoms, including chorea, dystonia, and parkinsonism. However, some patients exhibit clinical presentations indistinguishable from those of Huntington disease, indicating the broad spectrum of the clinical presentations of SCA17. (4) The presence of intranuclear inclusions containing mutant proteins with expanded polyglutamine stretches that have also been in most polyglutamine diseases strongly supports the hypothesis that common mechanisms underlie the molecular pathophysiologic mechanisms of neurodegeneration in polyglutamine diseases. (5) The age at onset of patients carrying expansions of CAG/CAA repeats in both alleles is earlier than that of patients carrying 1 expanded allele. Such a gene dosage effect has also been described in other polyglutamine diseases.8-10 (6) Patients with expansion of CAG/CAA repeats of the TBP gene come from a variety of ethnic backgrounds, but the frequency of such cases seems to be substantially low.

Unanswered questions on polyglutamine diseases

The latest member of the polyglutamine disease group is SCA17. As described previously herein, SCA17 shares many characteristic features that have been established in polyglutamine diseases. Despite the fact that 9 diseases caused by expanded polyglutamine stretches have been identified, unanswered questions remain: What are the common pathophysiologic mechanisms caused by expanded CAG repeats? What are the specific mechanisms determining the regional specificities of neurodegeneration and the spectrum of clinical presentations of each disease?

Of the 9 polyglutamine diseases, the physiologic functions of the gene products are known for SCA6, spinal and bulbar muscular atrophy, and SCA17 only. Thus, SCA17 is a good target for investigating the pathophysiologic mechanisms of neurodegeneration. TATA-binding protein is an important general transcription initiation factor and is the DNA-binding subunit of RNA polymerase II transcription factor D, the multisubunit complex crucial for the expression of most genes.11 Intranuclear accumulation of mutant proteins carrying expanded polyglutamine stretches and subsequent nuclear dysfunction through association of mutant proteins with various transcriptional factors have been considered to play essential roles in the pathogenesis of polyglutamine diseases. Intranuclear inclusions identified in autopsied brains of patients with SCA17 support this hypothesis.2 In contrast to the "gain of toxic function" hypothesis, interference with the physiologic functions of the TBP gene may also be involved in the pathophysiologic mechanisms. In spinal and bulbar muscular atrophy, another form of polyglutamine disease, the gynecomastia and hypogonadism commonly observed are clearly attributable to the loss of function of androgen receptor with expanded polyglutamine stretches. Thus, we need to pay attention not only to the gain of toxic function but also to the loss of function mechanisms.

Little is known about the mechanisms that determine the regional specificity of neurodegeneration. Several possibilities can be raised; for example, regional differences in the expression of messenger RNA and proteins, intracellular processing of the mutant proteins, nuclear transport of the mutant proteins, distribution of proteins interacting with the wild type of mutant proteins, and vulnerability of neuronal cells may be involved in determining the regional specificity of neurodegeneration. It is, therefore, important to answer these questions to fully understand the pathophysiologic mechanisms of polyglutamine diseases.

The ultimate goal of studies on polyglutamine diseases is the development of efficacious treatment. To accomplish this, the answers to the 2 questions posed earlier herein will be the keys to future success.

Correspondence and reprints are available from Dr Tsuji.

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