• Clinical and Experimental Pediatrics
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• v.48 no.4
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• pp.425-432
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• 2005

Purpose : Polyglutamine diseases are a group of diseases caused by the expansion of a polyglutamine tract in the protein. The present study was performed to verify if polyglutamine disease transgenic Drosophila models show similar dysfunctions as are seen in human patients. Methods : Polyglutamine disease transgenic Drosophila were tested for their climbing ability. And using genetic methods, the effects of anti-apoptotic gene bcl-2 and chemical chaperones on neurodegeneration were observed. Also, spinocerebellar ataxia 2 (SCA2) transgenic Drosophila lines were generated for future studies. Results : Expanded forms of spinocerebellar ataxia 3 (SCA3) transgenic protein causes characteristic locomotor dysfunction when expressed in the nervous system of Drosophila but the anti-apoptotic gene bcl-2 shows no evidence of ameliorating the deleterious effect of the expanded protein. However, Glycerol, a chemical chaperone, seemed to reduce the toxicity, at least in the eyes of the transgenic flies. The level SCA2 expression is too weak in the transgenic SCA2 Drosophila for evaluation. Conclusion : SCA3 transgenic Drosophila show ataxic behavior as observed in human patients. Chemical chaperones such as glycerol may prove beneficial in this class of genetic disease, which has no current method of cure.

• Journal of Genetic Medicine
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• v.4 no.1
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• pp.22-37
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• 2007

The autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases, clinically and genetically heterogeneous, characterized by degeneration of spinocerebellar pathways with variable involvement of other neural systems. At present, 27 distinct genetic forms of SCAs are known: SCA1-8, SCA10-21, SCA23, SCA25-28, DRPLA (dentatorubral-pallidoluysian atrophy), and 16q-liked ADCA (autosomal dominant cerebellar ataxia). Epidemiological data about the prevalence of SCAs are restricted to a few studies of isolated geographical regions, and most do not reflect the real occurrence of the disease. In general a prevalence of about 0.3-2 cases per 100,000 people is assumed. As SCA are highly heterogeneous, the prevalence of specific subtypes varies between different ethnic and continental populations. Most recent data suggest that SCA3 is the commonest subtype worldwide; SCA1, SCA2, SCA6, SCA7, and SCA8 have a prevalence of over 2%, and the remaining SCAs are thought to be rare (prevalence <1%). In this review, we highlight and discuss the SCA7. The hallmark of SCA7 is the association of hereditary ataxia and visual loss caused by pigmentary macular degeneration. Visual failure is progressive, bilateral and symmetrical, and leads irreversibly to blindness. This association represents a distinct disease entity classified as autosomal dominant cerebellar ataxia (ADCA) type II by Harding. The disease affectsprimarily the cerebellum and the retina by the moderate to severe neuronal loss and gliosis, but also many other central nervous system structures as the disease progresses. SCA7 is caused by expansion of an unstable trinucleotide CAG repeat in the ATXN7 gene encoding a polyglutamine (polyQ) tract in the corresponding protein, ataxin-7. Normal ATXN7 alleles contain 4-35 CAG repeats, whereas pathological alleles contain from 36->450 CAG repeats. Immunoblott analysis demonstrated that ataxin-7 is widely expressed but that expression levels vary among tissues. Instability of expanded repeats is more pronounced in SCA7 than in other SCA subtypes and can cause substantial lowering of age at onset in successive generations termed ‘anticipation’ so that children may become diseased even before their parents develop symptoms. The strong anticipation in SCA7 and the rarity of contractions should have led to its extinction within a few generations. There is no specific drug therapy for this neurodegenerative disorder. Currently, therapy remains purely symptomatic. Cellular models and SCA7 transgenic mice have been generated which constitute valuable resources for studying the disease mechanism. Understanding the pathogenetic mechanisms of neurodegeneration in SCAs should lead to the identification of potential therapeutic targets and ultimately facilitate drug discovery. Here we summarize the clinical, pathological, and genetic aspects of SCA7, and review the current understanding of the pathogenesis of this disorder. Further, we also review the potential therapeutic strategies that are currently being explored in polyglutamine diseases.

• Journal of Genetic Medicine
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• v.12 no.1
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• pp.38-43
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• 2015

Purpose: Spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders with diverse modes of inheritance. There are several subtypes of SCAs. SCA 8, SCA 12, and SCA 17 are the less common forms of SCAs with limited information available on their epidemiological profiles in Korea. The purpose of this study was to investigate the prevalence of SCA8, SCA12, and SCA17 in Korea. Materials and Methods: Ninety-six unrelated Korean patients were enrolled and showed normal trinucleotide repeats through polymerase-chain reaction (PCR) for the genes ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7, which correspond to SCA1, SCA2, SCA3, SCA6, and SCA7, respectively. PCR products from patients were further analyzed by capillary electrophoresis using fluorescence labeled primers for the genes ATXN8OS, PPP2R2B, and TBP, which correspond to SCA8, SCA12, and SCA17. Results: Three patients had 104, 97, and 75 abnormal expanded repeats in the ATXN8OS gene, the causative gene for SCA8. None of the patients exhibited abnormal repeats in SCA12 and SCA17. Normal trinucleotide repeat ranges of the cohort in this study were estimated to be 17-34 copies (average, $24{\pm}4copies$) for SCA8, 7-18 copies (average, $13{\pm}3copies$) for SCA12, and 26-43 copies (average, $35{\pm}2copies$) for SCA17. Conclusion: This study demonstrated that SCA8, SCA12, and SCA17 are rare in Korean patients with SCA, and further genetic studies are warranted to enhance the mutation detection rate in the Korean SCA population.

• Molecules and Cells
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• v.19 no.1
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• pp.23-30
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• 2005

Spinocerebellar ataxia type 1 (SCA1) is an autosomal-dominant neurodegenerative disorder caused by expansion of the polyglutamine tract in the SCA1 gene product, ataxin-1. Using d2EGFP, a short-lived enhanced green fluorescent protein, we investigated whether polyglutamine-expanded ataxin-1 affects the function of the proteasome, a cellular multicatalytic protease that degrades most misfolded proteins and regulatory proteins. In Western blot analysis and immunofluorescence experiments, d2EGFP was less degraded in HEK 293T cells transfected with ataxin-1(82Q) than in cells transfected with lacZ or empty vector controls. To test whether the stability of the d2EGFP protein was due to aggregation of ataxin-1, we constructed a plasmid carrying $ataxin-1-{\Delta}114$, lacking the self-association region (SAR), and examined degradation of the d2EGFP. Both the level of $ataxin-1-{\Delta}114$ aggregates and the amount of d2EGFP were drastically reduced in cells containing $ataxin-1-{\Delta}114$. Furthermore, d2EGFP localization experiments showed that polyglutamine-expanded ataxin-1 inhibited the general function of the proteasome activity. Taken together, these results demonstrate that polyglutamine-expanded ataxin-1 decreases the activity of the proteasome, implying that a disturbance in the ubiquitin-proteasome pathway is directly involved in the development of spinocerebellar ataxia type1.

• Journal of Genetic Medicine
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• v.11 no.2
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• pp.69-73
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• 2014

Purpose: Spinocerebellar ataxia (SCA) is a genetically heterogeneous disease for which more than 30 subtypes have been identified. However, 5 subtypes, SCA1, SCA2, SCA3, SCA6, and SCA7, account for more than 60% of cases. In this study, we report the distribution of these 5 subtypes in Korean patients. Materials and Methods: Six hundred and thirty-eight unrelated patients with a presumptive diagnosis of SCA were included in this study. Trinucleotide (CAG) repeat number (TNR) repeat number was determined using fluorescently labeled primers and fragment analysis. Results: A total of 128 unrelated patients (20.1% of all individuals tested) tested positive for SCA subtypes, including SCA1 (5 patients, 3.9% of those testing positive), SCA2 (38 patients, 29.7%), SCA3 (30 patients, 23.4%), SCA6 (39 patients, 30.5%), and SCA7 (16 patients, 12.5%). The mean copy number of pathogenic TNR alleles was $45{\pm}8.5$ for SCA1, $42{\pm}3.1$ for SCA2, $72{\pm}5.4$ for SCA3, $23{\pm}1.5$ for SCA6, and $50{\pm}11.4$ for SCA7. TNR copy number was inversely correlated with onset age in SCA2, SCA6, and SCA7. Conclusion: SCA2, SCA3, and SCA6 are common SCA subtypes in Korean patients and could be screened as a first-line test. Expanded pathogenic allele size was associated with early onset age.

• Journal of Genetic Medicine
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• v.15 no.2
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• pp.110-114
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• 2018

Ataxia-telangiectasia (AT; OMIM 208900) is a rare autosomal recessive inherited progressive neurodegenerative disorder, with onset in early childhood. AT is caused by homozygous or compound heterozygous mutations in ATM (OMIM 607585) on chromosome 11q22. The average prevalence of the disease is estimated at 1 of 100,000 children worldwide. The prevalence of AT in the Republic of Korea is suggested to be extremely low, with only a few cases genetically confirmed thus far. Herein, we report a 5-year-old Korean boy with clinical features such as progressive gait and truncal ataxia, both ankle spasticity, dysarthria, and mild intellectual disability. The patient was identified as a compound heterozygote with two novel genetic variants: a paternally derived c.5288_5289insGA p.(Tyr1763*) nonsense variant and a maternally derived c.8363A>C p.(His2788Pro) missense variant, as revealed by next-generation sequencing and confirmed by Sanger sequencing. Based on claims data from the Health Insurance Review and Assessment Service Republic of Korea, we calculated the prevalence of AT in the Republic of Korea to be about 0.9 per million individuals, which is similar to the worldwide average. Therefore, we suggest that multi-gene panel sequencing including ATM should be considered early diagnosis.

• Molecules and Cells
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• v.24 no.3
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• pp.338-342
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• 2007

Spinocerebellar ataxias (SCAs) are caused by expansion of (CAG)n triplet repeats. These repeats occur as polymorphic forms in general population; however, beyond a threshold size they become pathogenic. The sizes and distributions of repeats at the SCA1, SCA2, SCA3, SCA7 and DRPLA loci were assessed by molecular analysis of 124 unrelated ataxia patients and 44 controls, and the association of larger normal (LN) alleles with disease prevalence was evaluated. Triplet repeat expansions in the disease range were detected in 8% (10/124) of the cases, with the majority having expansion at the SCA1 locus. Normal allele ranges in the cohort studied were similar to the Caucasian and North Indian populations but differed from the Korean and Japanese populations at various loci. The percentage of individuals with LN alleles at the SCA1 and SCA2 loci was higher than reported in Indians, Japanese and Caucasians. LN alleles showed a good correlation with the incidence of SCA1, indicating that SCA1 is the most prevalent ataxia in our population. The majority of cases with clinical symptoms of SCA could not be diagnosed by established CAG repeat criteria, suggesting that there may be an alternative basis for disease pathogenesis: (i) Repeats lower than the normal range may also result in abnormal phenotypes (ii) LN alleles at different loci in the same individual may contribute to symptoms (iii) Exogenous factors may play a role in triggering disease symptoms in individuals with LN alleles (iv) Triplet repeats may reach the disease range in the brain but not in the blood.

• Journal of Genetic Medicine
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• v.4 no.1
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• pp.84-87
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• 2007

Spinocerebellar Ataxia Type 3 (SCA 3) is a rare autosomal dominative disorder in which one of the neurodegenerative disorders is caused by a CAG repeat expansion on chromosome 14q32.1. The age at onset of disease is related to the size of the expanded CAG repeat. We present the prenatal diagnosis of SCA3 in a woman whose husband was known to carry an unstable CAG repeat expansion in the MJD gene. The diagnosis was made using PCR with a fluorescent probe for an expanded MJD allele. The normal ranges of (CAG)n of SCA3 are 14~38 repeats. The husband, who had a family history of SCA 3, has an expanded allele of 69 CAG repeats with a normal allele of 27 repeats. His wife had two normal alleles with 26 and 32 CAG repeats. The fetus had two normal alleles with 26 and 27 CAG repeats; consequently, the baby w as healthy. We report a case of prenatal diagnosis of SCA3 using a fluorescent PCR which is rapid and accurate.

• 대한생식의학회:학술대회논문집
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• 2007.06a
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• pp.132-132
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• 2007

• The Journal of the Korea Contents Association
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• v.18 no.11
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• pp.634-642
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• 2018

People with spinocerebellar ataxia, a hereditary and progressive neurogenic disorder, suffer from ataxic dysarthria due to cerebellar dystrophy. This study was designed to examine if intensive motor speech treatment yields improvement in progressive ataxic dysarthria and if then, to investigate magnitude of therapeutic effect. SPEAK $OUT!^{(R)}$ was provided to a 55-year old female diagnosed with SCA for improving motor speech functions. Magnitude of therapeutic effect was large in changes of MPT and vocal intensity across speech tasks. Small effect size was found in changes of fundamental frequency, however, large therapeutic effect was observed in changes of frequency range. In addition, improvement of vocal quality based on jitter, shimmer, and HNR was observed with large therapeutic effect size and vowel space was expanded, particularly, due to F1. Lastly, VHI scores were decreased. Intensive motor speech treatment, called as SPEAK $OUT!^{(R)}$ was effective enough to observe improvement in vocal intensity, frequency range, and vocal quality, expanding vowel space and lowering VHI scores. Based on the results of this case study, further efficacy evaluation of SPEAK $OUT!^{(R)}$ for improving progressive ataxic dysarthria in people with SCA is required.