Frequency of spinocerebellar ataxia types 1, 2, 3, 6, 7 and dentatorubral pallidoluysian atrophy mutations in Korean patients with spinocerebellar ataxia

Autosomal dominant cerebellar ataxias (ADCAs) are a heterogeneous group of disorders characterized by degenerative symptoms in the cerebellum, spinal cord, and brain stem. Six different genes have been reported to be associated with ADCA, and the length of trinucleotide repeats of these genes is correlated with the age at onset and severity of symptoms. Although there are strong hereditary effects in these disorders, most of the studies carried out in heterogeneous populations and in small groups obscure the true incidence of these diseases. We examined the frequency of six types of ADCAs in 87 unrelated Korean patients with progressive ataxia and compared the results to the frequencies in other ethnic groups. Spinocerebellar ataxia (SCA) type 2 was the most frequent hereditary ataxia (12.6%) and types 3 and 6 accounted for 4.6% and 6.9% of ataxia patients, respectively. Dentatorubral pallidoluysian atrophy was also found in three patients (3.4%). No instances of SCA types 1 or 7 were detected. These findings show the striking contrast to the white population and a difference from Japanese findings. Our results demonstrate that dentatorubral pallidoluysian atrophy should be included in the differential diagnosis of Korean patients with spinocerebellar ataxia, and that there are strong hereditary effects in patients with ADCAs. Received: 6 March 1998 Received in revised form: 8 July 1998 Accepted: 18 August 1998     

Molecular genetics of hereditary spinocerebellar ataxia: mutation analysis of spinocerebellar ataxia genes and CAG/CTG repeat expansion detection in 225 Italian families

BACKGROUND: Autosomal dominant cerebellar ataxias are a clinical and genetically heterogeneous group of progressive neurodegenerative diseases, at present associated with 22 loci (spinocerebellar ataxia [SCA] 1-SCA8, SCA10-SCA19, SCA21, SCA22, fibroblast growth factor 14 [FGF14]-SCA, and dentatorubral-pallidoluysian atrophy [DRPLA]). The relevant gene has been identified in 12 cases (SCA1-3, SCA6-8, SCA10, SCA12, FGF14, and DRPLA), and in all but the recently identified SCA14, SCA17, PRKCG and FGF14 genes, the defect consists of the expansion of a short nucleotide repeat. OBJECTIVES: To investigate the relative prevalence of SCA1-3, SCA6-8, SCA10, SCA12, and SCA17 gene expansions in Italian families with hereditary ataxia, specifically to verify the occurrence of SCA10, SCA12, and SCA17 in Italy; and to analyze samples from probands with negative test results at the initial screening by means of the repeat expansion detection technique to identify CAG/CTG expansions in novel loci.Patients Two hundred twenty-five unrelated Italian index cases with hereditary ataxia, most (n = 183) of whom presented with a clear dominantly transmitted trait. RESULTS: We found that SCA1 and SCA2 gene mutations accounted for most cases (21% and 24%, respectively). We found SCA3, SCA6, SCA7, SCA8, and SCA17 to be very rare (approximately 1% each), and no case of SCA10 or SCA12 was identified. Half of the index cases (113/225) were negative for expansions in the known SCA genes. Repeat expansion detection analysis performed on 111 of these cases showed a CAG/CTG repeat expansion of at least 50 triplets in 22 (20%). Twenty-one of 22 expansions could be attributed to length variation at 2 polymorphic loci (expanded repeat domain CAG/CTG 1 [ERDA1] or CTG repeat on chromosome 18q21.1 [CTG18.1]). In 1 patient, the expansion was assigned to the DRPLA gene. CONCLUSIONS: The distribution of SCA1-3 and SCA6-7 gene mutations is peculiar in Italy. We found a relatively high frequency of SCA1 and SCA2 gene expansions; SCA3, SCA6, and SCA7 mutations were rare, compared with other European countries. No SCA10 or SCA12 and only a few SCA8 (2/225) and SCA17 (2/225) families were detected. In patients negative for defects in known SCA genes, repeat expansion detection data strongly suggest that, at least in our population, CAG/CTG expansions in novel genes should be considered an unlikely cause of the SCA phenotype.     

三核苷酸重复的检测在脊髓小脑型共济失调的应用研究

目的建立中国人遗传性脊髓小脑型共济失调（ＳＣＡ）患者的ＳＣＡ１、ＳＣＡ２、ＳＣＡ３／ＭＪＤ、ＳＣＡ６型的ＣＡＧ三核苷酸重复（ＣＡＧ）ｎ频率的检测方法并探讨其诊断意义。方法应用聚合酶链式反应（ＰＣＲ）和６％变性聚丙烯酰胺凝胶电泳技术,检测了３０例正常人和６例临床诊断为ＳＣＡ患者上述４型的（ＣＡＧ）ｎ重复数。结果３０例正常人（ＣＡＧ）ｎ的重复数目分别为ＳＣＡ１６～４０次,ＳＣＡ２２２～２９次,ＳＣＡ３１３～３６次,ＳＣＡ６４～１６次。６例ＳＣＡ患者中２例有ＳＣＡ３异常,（ＣＡＧ）ｎ重复数分别为６７和７５,而ＳＣＡ１、ＳＣＡ２、ＳＣＡ６型（ＣＡＧ）ｎ重复数均在正常范围内。结论研究三核苷酸重复频率的检测为ＳＣＡ患者提供了准确可靠的诊断方法和标准。     

遗传性脊髓小脑型共济失调患者SCA1基因突变检测分析

检测中国人遗传性脊髓小脑型共济失调（ＳＣＡ）患者的ＳＣＡ１基因突变［（ＣＡＧ）ｎ］。方法应用聚合酶链（ＰＣＲ）技术，检测了２７个ＳＣＡ家系中４４例ＳＣＡ患者的ＳＣＡ１（ＣＡＧ）ｎ。结果首次发现１个家系２例患者及１位“正常者”均有１个ＳＣＡ１异常等位基因扩增片段。患者Ⅲ５与其１位兄弟（“正常者”）的异常等位基因扩增片段，长度为２７２ｂｐ，三核苷酸ＣＡＧ重复数为５３次，患者Ⅲ２的异常等位基因扩增片段，长度为２９９ｂｐ，ＣＡＧ重复数为６２次，均超出正常范围。另２６个家系４２例患者的等位基因扩增片段长度范围在１６４～２１８ｂｐ之间，ＣＡＧ重复数在１７～３５次间，属于正常范围。结论来自１家系２例ＳＣＡ患者的基因分型为ＳＣＡ１型，“正常者”可能是未到发病年龄的无症状ＳＣＡ１患者，余２６个家系４２例患者不是ＳＣＡ１型。     

Age related axonal neuropathy in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD)

To identify determinants of peripheral involvement in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) the influence of CAG repeat length, age of onset, disease duration and age on the results of nerve conduction studies was analysed in 58 patients with SCA3/MJD. Patients with SCA3/MJD showed marked reduction of compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes indicating axonal neuropathy of both motor and sensory fibres. In addition, there was moderate slowing of nerve conduction suggestive of mild peripheral demyelination. Multivariate regression showed that CMAP and SNAP amplitudes decreased with age, but were not affected by CAG repeat length, age of onset, or disease duration. The age related decline of CMAP and SNAP amplitudes in SCA3/MJD was greater than in normal subjects. The data suggest that the degree of peripheral damage in SCA3/MJD does not depend on CAG repeat length, age of onset, or disease duration, but is mainly related to the time period over which the SCA3/MJD mutation exerts its effect.     

A sporadic case of spinocerebellar ataxia 6 (SCA 6) with large CAG expansion of the CACNL1A4 gene]

We reported a 73-year-old woman of spinocerebellar ataxia 6 (SCA 6). There was no family history of neurological diseases. She demonstrated cerebellar ataxia and scanning speech at the age of 48. These symptoms gradually developed. Brain MRI showed severe cerebellar atrophy and no abnormality in the brain stem. Her neurological symptoms and MRI findings were compatible with cerebellocortical atrophy (CCA). Analysis of the CACNL1A4 gene on chromosome 19p 13 demonstrated she had an expanded allele with 27 CAG repeats. Therefore, she was diagnosed with SCA 6. In spite of her large CAG expansion, there was no family history of SCA 6 in this case. SCA 6 needs to be ruled out in cases of clinical CCA.     

Frequency analysis and clinical characterization of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Korean patients

BACKGROUND: By genetic analysis, the CAG repeat expansion has been established in spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7. Despite the genetic differentiation of SCA, the characterization of the phenotypes of various SCAs has been challenging for better clinical diagnosis. OBJECTIVE: To analyze the frequencies and the clinical manifestations of SCA1, SCA2, SCA3, SCA6, and SCA7 in Korean patients. PATIENTS AND METHODS: We performed genetic analysis in 253 unrelated Korean patients with progressive cerebellar ataxia. We compared the frequencies, inheritance patterns, and various clinical manifestations of patients with genetically confirmed SCA. RESULTS: Among the 52 patients with expanded CAG repeat, the most frequent SCA type was SCA2, followed by SCA3, SCA6, SCA1, and SCA7. Nine patients (17%) had a negative family history of ataxia, mostly in SCA6. There were characteristic clinical features such as hypotonia and optic atrophy for SCA1; hyporeflexia for SCA2; nystagmus, bulging eye, and dystonia for SCA3; and macular degeneration for SCA7. Interestingly, 4 patients (1 with SCA2, 1 with SCA3, and 2 with SCA6) were misdiagnosed as having multiple-system atrophy because of the absence of family history and the presence of parkinsonism and urinary incontinence. CONCLUSIONS: This study provides a detailed analysis of the clinical characteristics of the genetically defined CAG-repeat SCAs in Korean patients. Although phenotypes were heterogeneous, some clinical features may be helpful for clinical diagnosis. However, genetic studies for SCA are needed despite uncertain family history or the presence of atypical clinical features causing misdiagnosis as atypical parkinsonism.     

Spinocerebellar ataxia type 6: CAG trinucleotide expansion, clinical characteristics and sperm analysis

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant spinocerebellar degeneration caused by CAG repeat expansions in the human α1A voltage-dependent calcium channel subunit gene. We analyzed 16 SCA6 patients in 14 unrelated Japanese families, and documented the clinical and molecular properties correlating with the CAG repeat expansion. Three of them were sporadic. The CAG repeat number of the expanded and normal alleles was 22.7 ± 2.0 (mean ± SD, n = 15) and 13.8 ± 2.0 (n = 15), respectively, and the repeat size of the expanded alleles correlated inversely with age at onset. The patients presented here were clinically characterized by a slowly progressive cerebellar ataxia and nystagmus. In leukocytes, the strict pattern of the peak in the expanded allele on polyacrylamide gel electrophoresis did not show the presence of cell mosaicism in SCA6, in contrast to other trinucleotide disorders. Moreover, in each patient, the number of CAG repeats in sperm was the same as in leukocytes, and the expanded alleles in sperm indicated uniform peaks as well. In our geographic area, the frequency of SCA6 was as high as MJD, in contrast to the low frequency of other autosomal dominant cerebellar ataxias. Thus, a geographic difference in the frequency of autosomal dominant spinocerebellar ataxias may be present in Japan.     

Molecular and clinical study of spinocerebellar ataxia type 7 in Chinese kindreds

OBJECTIVE: To investigate the clinical and molecular characteristics of spinocerebellar ataxia type 7 (SCA7) in Chinese kindreds. BACKGROUND: Spinocerebellar ataxia type 7 is caused by the expansion of an unstable CAG repeat in the first exon of the SCA7 gene. METHODS: Clinical and related examinations were performed in all affected or at-risk individuals from 4 Chinese families presenting with autosomal dominant cerebellar ataxia and decreased visual acuity. The size of the (CAG)(n) array of the SCA7 gene was detected by polymerase chain reaction, polyacrylamide gel electrophoresis, and related techniques in the 4 families and 67 healthy controls. The relationship between expanded repeat number and age of onset was statistically analyzed. RESULTS: The SCA7 mutation was identified in 2 families. Clinical study revealed that great variation occurred in the age of onset, initial symptoms, and associated signs. Meanwhile, the analysis of 11 parent-child couples demonstrated the existence of marked anticipation. Some distinct retinal changes were noted in 2 affected patients. All SCA7 patients in our series exhibited expanded CAG repeats, ranging from 44 to 85 repeats, with a strong negative correlation between repeat size and age of onset. Repeat lengths of expanded alleles showed somatic mosaicism in leukocyte DNA. There were some subtle clinical differences between the SCA7-positive and -negative cases. CONCLUSIONS: Clinical variation occurred not only among the SCA7 families but also within the same kindred. Meiotic and mitotic instability of the CAG repeat in the SCA7 gene were demonstrated, and intergenerational instability of the array was associated with the clinical phenomenon of anticipation. Arch Neurol. 2000;57:1513-1518     

Coincident trinucleotide repeat expansions in a patient with myotonic dystrophy type 1 and spinocerebellar ataxia

This is a case report of a patient with confirmed myotonic dystrophy type 1 and spinocerebellar ataxia type 6. The coexistence of two trinucleotide repeat expansions in this family illustrates the importance of continued and vigilant diagnostic inquiry when a patient with a confirmed genetic abnormality has an atypical presentation. The coincidence of two trinucleotide repeat expansions in this patient may suggest an underlying error in DNA metabolism.     

Searching for modulating effects of SCA2, SCA6 and DRPLA CAG tracts on the Machado-Joseph disease (SCA3) phenotype

CONTEXT: Machado-Joseph disease (MJD/SCA3) is an autosomal dominant cerebellar ataxia of adult onset. The variability in age at onset and the complex and heterogeneous neurologic findings indicate that MJD, caused by a major gene, is modulated by modifier factors. OBJECTIVE: To study if the polymorphic CAG repeats at other loci (namely, SCA2, SCA6 and DRPLA) thus acted as modifier factors of this disease. DESIGN: Case-control. SETTING: Ambulatory care in a referral center. PATIENTS: A convenience sample of 39 unrelated, Brazilian patients with MJD. Main outcome measures: age of onset, anticipation, clinical subtypes and neurological findings. RESULTS: Fasciculations were associated with CAG repeat length of the long SCA2 allele (Mann-Whitney U-test, P < 0.03, after Bonferroni procedure). Other measures (age of onset, anticipation, clinical types and other neurological signs) were not associated with CAG repeat length of SCA2, SCA6 and DRPLA genes. CONCLUSIONS: The present results show that the CAG tract of SCA2 gene interferes with MJD phenotype. Further studies, with patients of other origins and with typing of other (CAG)n loci, are necessary.     

Clinical and genetic findings in Finnish ataxia patients with the spinocerebellar ataxia 8 repeat expansion

Spinocerebellar ataxia 8 (SCA8) is caused by a CTG repeat expansion in an untranslated region of a recently cloned gene on 13q21. The pathogenic role of this trinucleotide repeat was evaluated by examining 154 Finnish ataxia patients and 448 controls. Expansions ranging from 100 to 675 repeats were present in 9 (6%) unrelated patients and in 13 (3%) controls. There was a threefold excess of shorter expansions (<204 repeats) in the ataxia series, and the expansions tended to cluster in patients with a family history for the disease. Clinical and genetic data were subsequently collected from 15 patients. Common initial symptoms included gait instability, dysarthria, and tremor. A marked cerebellar atrophy in magnetic resonance imaging or computed tomography was found in all patients. Pyramidal affection was often seen, and various kinds of cognitive impairment were evident in 40% of patients. Disease progression was slow, and fluctuation of symptoms was commonly observed. A maternal penetrance bias was not seen, nor was there any clear-cut negative correlation between age of onset and repeat number. Meiotic but not mitotic instability of the repeat expansion was evident. Haplotype analysis suggests multiple origins for the Finnish spinocerebellar ataxia 8 repeat expansions.     

Intermediate CAG repeat lengths (53,54) for MJD/SCA3 are associated with an abnormal phenotype.

We report on a Dutch family in which 4 members in 2 generations have intermediate repeat lengths (53 and 54) for Machado-Joseph Disease/Spinocerebellar Ataxia (MJD/SCA3). All but the youngest have a restless legs syndrome with fasciculations and a sensorimotor axonal polyneuropathy. Central neurological abnormalities are only present in 2. This family shows that intermediate repeat lengths can be pathogenic and may predispose for restless legs and peripheral nerve disorder.     

Brain regional differences in the expansion of a CAG repeat in the spinocerebellar ataxias: Dentatorubral-pallidoluysian atrophy,machado-joseph disease,and spinocerebellar ataxia type 1

Three autosomal dominant spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD), and spinocerebellar ataxia type 1 (SCA1), are associated with the expansion of a CAG repeat in the respective genes. To investigate the association between CAG repeat expansion and neuropathological findings, we analyzed several brain regions from 9 cases of DRPLA, 3 cases of MJD, and 1 case of SCA1. We found that the expanded alleles were smaller in the cerebellar cortex than in other brain regions, such as the frontal cortex, in these three diseases. The discrepancy in the expanded CAG repeat length between cerebellar cortex and other tissues was most prominent in DRPLA, and especially in cases of adult-onset DRPLA. A significant correlation was found between the age at onset of DRPLA and the size of the CAG repeat expansion. Cerebella of DRPLA patients were microscopically dissected into three layers, the molecular and granularlayers and the white matter, which were analyzed separately. The lower level of CAG repeat expansion in DRPLA cerebella was representative of CAG repeat expansion in the granule cells. The microdissected samples of the granular layer of the hippocampal formation, which is densely packed with neuronal cells, revealed that the degree of CAG repeat expansion in this layer was similar to that in the cerebellum. These observations suggest that granule cells in the cerebellum and hippocampus have low levels of CAG repeat expansion, and that other types of cells exhibit a higher level of CAG repeat expansion, in spinocerebellar ataxias.     

Regional differences in genetic subgroup frequency in hereditary cerebellar ataxia, and a morphometrical study of brain MR images in SCA1, MJD and SCA6.

Molecular genetic assessments of 69 individuals in 44 families with hereditary cerebellar ataxia (HCA) were made to determine the relative frequencies of subtypes of HCA in Yamagata, Japan. Fifteen families (34%) had SCA1, none had SCA2, nine (20%) had MJD, five (11%) had SCA6 and nine (20%) had DRPLA. These findings differ markedly from those in other regions of Japan and the rest of the world. A morphometrical study of the brain MR images also was made on 38 individuals with SCA1 (n = 14), MJD (n = 8) or SCA6 (n = 16). In SCA1, the ventral pons was atrophic in proportion to the amount of cerebellar atrophy. In MJD, both the pons and the cerebellum were atrophic, cerebellar atrophy being less pronounced than that in SCA1 and SCA6. While both the major and minor axes of the ventral pons were proportionally decreased in SCA1, the minor axis was more decreased than the major axis in MJD. In SCA6, a mild reduction in the ratio of the ventral pontine area to the posterior fossa area (Pv/PF) was observed as well as obvious cerebellar atrophy. These findings indicate that in MR images SCA1, MJD and SCA6 show different atrophic features of the cerebellum and brainstem.     

In vivo neurometabolic profiling in patients with spinocerebellar ataxia types 1, 2, 3, and 7

Spinocerebellar ataxias (SCAs) belong to polyglutamine repeat disorders and are characterized by a predominant atrophy of the cerebellum and the pons. Proton magnetic resonance spectroscopy (¹H MRS) using an optimized semiadiabatic localization by adiabatic selective refocusing (semi‐LASER) protocol was performed at 3 T to determine metabolite concentrations in the cerebellar vermis and pons of a cohort of patients with SCA1 (n = 16), SCA2 (n = 12), SCA3 (n = 21), and SCA7 (n = 12) and healthy controls (n = 33). Compared with controls, patients displayed lower total N‐acetylaspartate and, to a lesser extent, lower glutamate, reflecting neuronal loss/dysfunction, whereas the glial marker, myoinositol (myo‐Ins), was elevated. Patients also showed higher total creatine as reported in Huntington's disease, another polyglutamine repeat disorder. A strong correlation was found between the Scale for the Assessment and Rating of Ataxia and the neurometabolites in both affected regions of patients. Principal component analyses confirmed that neuronal metabolites (total N‐acetylaspartate and glutamate) were inversely correlated in the vermis and the pons to glial (myo‐Ins) and energetic (total creatine) metabolites, as well as to disease severity (motor scales). Neurochemical plots with selected metabolites also allowed the separation of SCA2 and SCA3 from controls. The neurometabolic profiles detected in patients underlie cell‐specific changes in neuronal and astrocytic compartments that cannot be assessed by other neuroimaging modalities. The inverse correlation between metabolites from these two compartments suggests a metabolic attempt to compensate for neuronal damage in SCAs. Because these biomarkers reflect dynamic aspects of cellular metabolism, they are good candidates for proof‐of‐concept therapeutic trials. © 2015 International Parkinson and Movement Disorder Society     

Involvement of the auditory brainstem system in spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3) and type 7 (SCA7)

Aims: The spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3) and type 7 (SCA7) are clinically characterized by progressive and severe ataxic symptoms, dysarthria, dysphagia, oculomotor impairments, pyramidal and extrapyramidal manifestations and sensory deficits. Although recent clinical studies reported additional disease signs suggesting involvement of the brainstem auditory system, this has never been studied in detail in SCA2, SCA3 or SCA7. Methods: We performed a detailed pathoanatomical investigation of unconventionally thick tissue sections through the auditory brainstem nuclei (that is, nucleus of the inferior colliculus, nuclei of the lateral lemniscus, superior olive, cochlear nuclei) and auditory brainstem fibre tracts (that is, lateral lemniscus, trapezoid body, dorsal acoustic stria, cochlear portion of the vestibulocochlear nerve) of clinically diagnosed and genetically confirmed SCA2, SCA3 and SCA7 patients. Results: Examination of unconventionally thick serial brainstem sections stained for lipofuscin pigment and Nissl material revealed a consistent and widespread involvement of the auditory brainstem nuclei in the SCA2, SCA3 and SCA7 patients studied. Serial brainstem tissue sections stained for myelin showed loss of myelinated fibres in two of the auditory brainstem fibre tracts (that is, lateral lemniscus, trapezoid body) in a subset of patients. Conclusions: The involvement of the auditory brainstem system offers plausible explanations for the auditory impairments detected in some of our and other SCA2, SCA3 and SCA7 patients upon bedside examination or neurophysiological investigation. However, further clinical studies are required to resolve the striking discrepancy between the consistent involvement of the brainstem auditory system observed in this study and the comparatively low frequency of reported auditory impairments in SCA2, SCA3 and SCA7 patients.