Clinical features and ATTCT repeat expansion in spinocerebellar ataxia type 10

BACKGROUND: Spinocerebellar ataxia type 10, an autosomal dominant disease characterized by ataxia and seizures, is caused by a large expansion of an unstable ATTCT pentanucleotide repeat. OBJECTIVES: To characterize the phenotypic expression of spinocerebellar ataxia type 10 and to examine the genotype-phenotype correlations in 2 large families. DESIGN: Clinical characterization and genotype-phenotype correlation. SETTING: Studies at 2 medical schools with private practice referral. PATIENTS: Twenty-two affected individuals from 2 large Mexican American pedigrees. RESULTS: Of the 22 individuals, ataxia was the initial symptom in 21; seizure disorders developed in 11, mostly within several years following the onset of ataxia. The seizure frequency was different in the 2 families: 3 (25%) of 12 had seizures in family 1, and 8 (80%) of 10 had seizures in family 2 (P =.01). A brain magnetic resonance imaging or computed tomographic scan showed cerebellar atrophy in all patients examined. An electroencephalogram demonstrated epileptiform discharges in 4 of 8 patients studied. Although anticipation was apparent in both families, only family 1 showed a strong inverse correlation between age of onset and repeat number (r(2) = 0.79, P =.001). In family 1, 8 transmissions, of which 7 were paternal, resulted in an average gain of 1940 repeats. In contrast, despite anticipation, 2 affected male subjects transmitted their expanded alleles to 8 progenies, with an average loss of 755 repeats, in family 2. CONCLUSIONS: Seizure is an integral part of the spinocerebellar ataxia type 10 phenotype, with documented morbidity and mortality. Family-dependent factors may alter the frequency of the seizure phenotype and the pattern of intergenerational repeat size changes, making the genotype-phenotype correlation complex.     

Genetic and clinical analyses of spinocerebellar ataxia type 8 in mainland China

Journal of Neurology - Spinocerebellar ataxia type 8 (SCA8) is a rare autosomal dominant neurodegenerative disease caused by CTA/CTG repeat expansion in the ATXN8/ATXN8OS gene. To analyze the...     

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.     

A family with spinocerebellar ataxia type 8 expansion and vitamin E deficiency ataxia

BACKGROUND: Ataxia with vitamin E deficiency is a recessive autosomal neurodegenerative disorder resembling the Friedreich ataxia phenotype but is due to mutations in the alpha-tocopherol transfer protein (TTPA) gene. In a recent article, we described a patient with ataxia carrying reduced serum vitamin E levels and showing CTA/CTG expansions of 320 triplet repeats in the SCA8 gene. OBJECTIVES: To perform a screening of the TTPA gene in the patient and to evaluate the effects of treatment with vitamin E on the patient's neurologic disturbances. PATIENT AND METHODS: We performed a single-strand conformation polymorphism and nucleotide sequence analysis of the 5 exons of the TTPA gene in the patient's family members. RESULTS: The results indicated the patient to be a compound heterozygote for 2 mutations (in exon 3), each transmitted by one of the 2 parents, yielding a nonfunctional protein. CONCLUSIONS: We describe for the first time, to our knowledge, a mutated form of the TTPA gene in a patient also carrying an expansion in the SCA8 gene. The lack of improvement in the patient's symptoms on supplementation with alpha-tocopherol suggests that the SCA8 mutations may act in the neurodegeneration process, worsening the neurologic signs caused by the vitamin E deficit, and it could be speculated that the co-occurrence of mutant alleles for 2 distinct loci may influence the clinical course of the disease.     

Molecular and clinical analyses of spinocerebellar ataxia type 8 in Japan

OBJECTIVE: To clarify the molecular and clinical features of the newly identified spinocerebellar ataxia type 8 (SCA8). METHODS: We analyzed the CTG repeat region of the SCA8 gene in a series of Japanese patients with cerebellar ataxia. We also investigated the frequency of the CTG repeat length in Japanese normal elderly subjects older than age 79. Morphometric measurements on the cerebral MRI were compared between patients with SCA8 and SCA6. RESULTS: The number of the combined CTA/CTG repeats of six affected SCA8 alleles was 106.3+/-24.4 (mean +/- SD) ranging from 89 to 155 and that of normal elderly subjects was 24.3+/-4.4 (n = 104 alleles) ranging from 15 to 34. The mean age at onset of the SCA8 cases was 53.8+/-19.7 years, with a range from 20 to 73 years. One father and daughter from an SCA8 family showed remarkable paternal anticipation. The number increase from father to daughter was + 16 CTG repeats, with a 31-year acceleration of onset. The six identified SCA8 patients were clinically characterized by high frequencies of incoordination of trunk and limbs, ataxic dysarthria, impaired smooth pursuit, and horizontal nystagmus, and the MRI showed significant atrophy of the cerebellar vermis and hemispheres compared with that of normal controls. There was no significant difference between SCA8 and SCA6 on the morphometric MRI study. CONCLUSIONS: The CTG repeat expansions in the SCA8 alleles were much greater than the range of repeats in normal elderly subjects. The SCA8 phenotype manifested by cerebellar symptoms and atrophy corresponded to features of the autosomal dominant cerebellar ataxia type III (ADCA III).     

马查多-约瑟夫病/脊髓小脑型共济失调Ⅲ型患者(CAG)n拷贝数与临床特征

目的探讨马查多约瑟夫病基因１（ＭＪＤ１）ＣＡＧ三核苷酸动态突变及其拷贝数与ＭＪＤ／脊髓小脑型共济失调Ⅲ型（ＳＣＡ３）患者临床特征的相关关系。方法应用聚合酶链式反应、变性聚丙烯酰胺凝胶电泳和银染技术,对９个ＭＪＤ／ＳＣＡ３家系１０９名成员进行ＭＪＤ１基因（ＣＡＧ）ｎ拷贝数分析。结果发现异常扩增的（ＣＡＧ）ｎ拷贝数与发病年龄呈负相关,并在一定程度上影响病情严重程度;主要临床症状、体征与异常扩增的（ＣＡＧ）ｎ拷贝数无关,而是受病程影响。同时发现１７例症状前患者。结论异常扩增的（ＣＡＧ）ｎ拷贝数对疾病表型有影响,但不能完全作为临床特征的预测指标     

Cognitive impairment in spinocerebellar ataxia type 8

OBJECTIVES: Only a limited number of studies have investigated the cognitive performances of spinocerebellar ataxia (SCA) patients. In none of the SCA8 studies have the neuropsychological test performances been the primary measures. The objective of the current study was to investigate the characteristics of cognitive deficits in SCA8. METHODS: Ten SCA8 patients and ten case-by-case matched control subjects underwent a comprehensive neuropsychological examination evaluating attention and information processing, concept formation, reasoning and executive functions, verbal production, memory and learning and visuoperceptual and -constructive functions. RESULTS: SCA8 patients demonstrated deficits primarily in attention and information processing, as well as in concept formation, reasoning, executive functions and verbal production. Visuoperceptual and -constructive functions, as well as most of the performances of memory were unaffected. CONCLUSIONS: Cognitive impairments, especially those related to attention, information processing and executive functions, seem to be a clinical feature of SCA8 disease.     

Anticipation and intergenerational repeat instability in spinocerebellar ataxia type 17

Spinocerebellar ataxia type 17 (SCA17) is caused by expansion of a CAG/CAA repeat in the TBP gene. Most pathogenic alleles are interrupted and are stably transmitted from parent to offspring without anticipation. We identified three SCA17 families with expansion of uninterrupted alleles, thus greatly increasing the number of known intergenerational transmissions of such alleles. We found that uninterrupted SCA17 alleles are unstable, associated with anticipation, and show a paternal expansion bias that increases with age. Even small increments in repeat length resulted in inordinate increases in anticipation. Anticipation was also associated with childhood presentation. Sequencing of all SCA17 alleles is required for effective genetic counseling.     

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.     

Unstable triplet repeat and phenotypic variability of spinocerebellar ataxia type 1

A Siberian kindred with spinocerebellar ataxia genetically linked to the SCA1 locus on chromosome 6p has been screened for the CAG triplet expansion within the coding region of the SCA1 gene. The kindred includes 1,484 individuals, 225 affected and 656 at risk, making this collection the largest spinocerebellar ataxia type 1 (SCA1) pedigree known. Each of the studied 78 SCA1 patients carried an expanded allele containing a stretch of 39 to 72 uninterrupted CAG repeats. Normal alleles had 25 to 37 trinucleotide repeats. Expanded alleles containing 40 to 55 repeats were found in 26 atrisk relatives. The number of CAG repeats in the mutated allele was inversely correlated with age at disease onset. Cerebellar deficiency was present in each patient and its severity was moderately affected by the number of CAG repeats. In contrast, the associated signs, dysphagia, diffuse skeletal muscle atrophy with fasciculations, and tongue atrophy were absent or mild in patients with low CAG repeat numbers, but severely complicated the course of illness in patients with a larger number of repeat units. One female mutation carrier was asymptomatic at age 66, more than 2 standard deviations beyond the average age of risk, suggesting incomplete penetrance. In 2 symptomatic individuals who had an expanded number of CAG repeats on both chromosomes, age at onset, rate of progression, and clinical manifestation corresponded to the size of the larger allele.     

脊髓小脑共济失调17型临床特征和基因突变分析

目的 探讨脊髓小脑共济失调17型(spinocerebellar ataxia 17,SCA17)患者的临床特征和基因突变的特点.方法 对708个常染色体显性遗传SCA家系的先证者和另外119例临床拟诊SCA的散发患者进行常规基因检测,按照患病率不同依次筛选:SCA3、SCA1、SCA2、SCA6、SCA7、SCA8、SCA12、SCA17、齿状核-红核-苍白球-路易体萎缩致病基因三核苷酸重复动态突变分析.其中SCA17致病基因检测采用聚合酶链反应扩增TATA结合蛋白(TBP)基因CAG重复序列,琼脂糖凝胶电泳检测扩增产物;对出现2个电泳条带的样品应用毛细管电泳片段分析方法进行TBP基因CAG重复次数检测,并对其临床表型、神经影像学特征以及表型与基因型相关性进行细致分析.结果 通过上述检测及分析,发现5例患者具有TBP基因CAG重复扩展突变.片段分析显示CAG重复次数分别为37/50、36/45、38/52、38/53、36/54次,长片段重复次数已达到异常范围.5例患者的临床表型各异,以共济失调、记忆力减退为主要症状.结论 在827例共济失调病例中仅发现5例SCA17,说明该病在中国人群中较为罕见;通过对5例患者的临床表型进行分析,初步认为国人SCA17存在临床变异.     

Dystonia in spinocerebellar ataxia type 6.

Spinocerebellar ataxias are heterogeneous disorders with overlapping clinical features. Spinocerebellar ataxia-6 is a dominantly inherited condition characterized by relatively pure ataxia with a paucity of other manifestations including extrapyramidal findings. We report on two patients with genetically proven SCA-6 who had dystonia. One patient presented initially with dystonia, which remained the most disabling problem. Dystonia may occur in SCA-6 and can be disabling.     

Predictors of survival in spinocerebellar ataxia type 2 population from Southern Italy

One hundred-eighteen spinocerebellar ataxia type 2 patients from 35 distinct families personally observed between 1973 and 2016 were retrospectively reviewed. The time point of data collection was 1 January 2017. Thirty-one patients were confined to wheelchair. The median time to wheelchair was 21 years (95% CI, 17.5–24.6). Thirty-seven patients were deceased. The median time to death was 25 years (95% CI, 22.9–27.1). CAG repeat number and ataxia score at first visit influenced the time to wheelchair and death.     

脊髓小脑共济失调3型临床变异型特征及突变分析

目的 探讨脊髓小脑共济失调3型临床变异型特征.方法 应用CEQ8000核酸分析仪对1个表型为变形性肌张力障碍家系和2个表型为痉挛性截瘫家系的SCA3/MJD基因胞嘧啶-腺嘌呤-鸟嘌呤(CAG)重复序列进行基因片段分析.结果 基因学检查证实3个家系均为SCA3/MJD基因CAG重复扩增突变致病.结论 我国脊髓小脑共济失调3型存在变形性肌张力障碍和痉挛性截瘫的临床变异型.脊髓小脑共济失调3型的多种临床变异类型为调节因素假说提供了进一步的证据,并且提示在临床工作中应注意避免遗漏阳性家系.