Spinocerebellar ataxia type 6 in relation to CAG repeat length

The purpose of the present study was to assess the relationship between clinical characteristics of spinocerebellar ataxia type 6 (SCA6) and CAG repeat length. MATERIALS AND METHODS: We examined clinical symptoms of 54 patients with SCA6. CAG repeat length was compared among subgroups divided by clinical manifestations. RESULTS: The major symptom was progressive cerebellar ataxia. Truncal or limb ataxia, dysarthria, and nystagmus were observed in more than 80% of the patients. In analysis of CAG repeat length in patients with different types of nystagmus, CAG repeat length was the longest when both upbeat and downbeat nystagmus existed (P < 0.01). In addition, CAG repeat length was longer when the initial symptom was ataxic gait and was shorter when the initial symptom was dysarthria or ocular symptom (P < 0.05). CONCLUSION: Clinical features of SCA6 might be influenced by the length of abnormal CAG repeat.     

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.     

The P/Q-type voltage-dependent calcium channel: a therapeutic target in spinocerebellar ataxia type 6

BACKGROUND: Voltage-dependent calcium channels (VDCCs) are heteromultimeric complexes that mediate calcium influx into cells; the alpha 1A subunit is the pore-forming subunit specific to the neuronal P/Q-type VDCCs. Spinocerebellar ataxia type 6 (SCA 6) is caused by an abnormal expansion of a CAG repeat in CACNA1A, which encodes the alpha 1A subunit. Heterologous expression of mutated alpha 1A subunits resulted in increased channel inactivation in electrophysiological tests. Gabapentin and pregabalin interact with the alpha 2 delta subunit of the VDCCs and improved ataxia in cases of cortical cerebellar atrophy (CCA) and ataxia-telangiectasia. MATERIALS AND METHODS: A bibliographical review was performed in order to find out if gabapentin and pregabalin could prove useful in the treatment of SCA 6. RESULTS: Gabapentin and pregabalin slowed the rate of inactivation in recombinant P/Q-type VDCCs. SCA 6 shares neuropathological findings with CCA. CONCLUSIONS: On the basis of the neuropathological identity of SCA 6 with CCA, and of the effect of gabapentin and pregabalin on recombinant VDCCs the authors put forward the hypothesis that these drugs might prove beneficial in SCA 6, as the ataxia would be expected to improve. The authors hope that researchers working with this illness will be encouraged to undertake the appropriate clinical and experimental work.     

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     

Spinocerebellar ataxia type 1: clinical and neurophysiological characteristics in German kindreds

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of an unstable (CAG)_n repeat on chromosome 6p. We investigated 36 German families suffering from hereditary ataxias for the SCA1 mutation and elaborated clinical and neurophysiological characteristics. SCA1 accounts for 10 - 15% of dominant cerebellar ataxias in German kindreds. The clinical presentation is characterized by broad, even intrafamilial variability and multiple system involvement already in early stages. Slowed saccades, ptosis and facial weakness are more prevalent in SCA1 but were unspecific differences compared to non-SCAl ataxias. Two electrophysiological parameters characterize SCA1: markedly prolonged central motor conduction time in motor evoked potentials and predominantly demyelinating polyneuropathy. Molecular genetic analyses are indispensable to diagnose SCA patients precisely. Extensive neurophysiological studies are recommendable in the clinical approach as they are suitable to discover subclinical damage of the nervous system. In contrast to the enormous variability of clinical signs in SCA1 neurophysiological findings are rather constant.     

Spinocerebellar ataxia type 10 (SCA10): a disease caused by a novel pentanucleotide repeat expansion]

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant progressive disorder characterized by ataxia, seizures and anticipation, mapped to chromosome 22q13.3. We have found that the mutation of SCA10 is an unstable and massive expansion (800-4,500 repeats) of the ATTCT pentanucleotide repeat in intron 9 of SCA 10 (also known as E46L), a novel gene of unknown function. The mutation, so far, has only been found in the population of the Mexican descent with a founder effect supported by haplotype data. The expansion size of the repeat inversely correlates with age of disease onset and SCA10 is highly expressed throughout the central nervous system. Expanded ATTCT repeats in SCA10 patients show repeat size instability in their somatic and germline cells as well as time-dependent instability in blood. This novel type of microsatellite repeat expansion is the largest found to date in human diseases. Its epidemiological, clinical, genetic and pathophysiological features need to be further investigated.     

Spinocerebellar ataxia type 8: clinical features in a large family

OBJECTIVE: To compare the clinical and genetic features of the seven-generation family (MN-A) used to define the spinocerebellar ataxia 8 (SCA8) locus. BACKGROUND: The authors recently described an untranslated CTG expansion that causes a novel form of SCA (SCA8) characterized by reduced penetrance and complex patterns of repeat instability. METHODS: Clinical and molecular features of 82 members of the MN-A family were evaluated by neurologic examination, quantitative dexterity testing, and, in some individuals, MRI and sperm analyses. RESULTS: SCA8 is a slowly progressive, predominantly cerebellar ataxia with marked cerebellar atrophy, affecting gait, swallowing, speech, and limb and eye movements. CTG tracts are longer in affected (mean = 116 CTG repeats) than in unaffected expansion carriers (mean = 90, p < 10-8). Quantitative dexterity testing did not detect even subtle signs of ataxia in unaffected expansion carriers. Surprisingly, all 21 affected MN-A family members inherited an expansion from their mothers. The maternal penetrance bias is consistent with maternal repeat expansions yielding alleles above the pathogenic threshold in the family (>107 CTG) and paternal contractions resulting in shorter alleles. Consistent with the reduced penetrance of paternal transmissions, CTG tracts in all or nearly all sperm (84 to 99) are significantly shorter than in the blood (116) of an affected man. CONCLUSIONS: The biologic relationship between repeat length and ataxia indicates that the CTG repeat is directly involved in SCA8 pathogenesis. Diagnostic testing and genetic counseling are complicated by the reduced penetrance, which often makes the inheritance appear recessive or sporadic, and by interfamilial differences in the length of a stable (CTA)n tract preceding the CTG repeat.     

中国汉族人群CACNA1A基因CAG重复数目分布特点及其在脊髓小脑性共济失调6型基因诊断中的应用

目的 探讨我国汉族人群CACNA1A基因CAG重复数目分布特点及其在脊髓小脑性共济失调6型(spinocerebellar ataxias type 6,SCA6)基因诊断中的应用.方法 应用"两步PCR法"、变性聚丙烯酰胺凝胶电泳(DPAGE)和测序等方法对300名健康对照及109例无血缘关系的SCA患者进行CACNA1A基因CAG三核苷酸重复数目分析.结果 300名健康对照的CAG重复次数范围为3～18次,以13次最常见.在109例SCA患者中,发现1例SCA6患者,其CAG异常重复次数为24次,该患者的母亲和哥哥亦为SCA6患者,临床上均表现为缓慢进展的小脑性共济失调、构音障碍、眼震、轻度的振动及本体觉减退,遗传早现现象较明显.结论 SCA6病例在我国较少见,进行CACNA1A基因突变分析有助于临床诊断."两步PCR法"可提高CACNA1A基因突变分析的效率.     

中国汉族人群CACNA1A基因CAG重复数目分布特点及其在脊髓小脑性共济失调6型基因诊断中的应用

目的 探讨我国汉族人群CACNA1A基因CAG重复数目分布特点及其在脊髓小脑性共济失调6型(spinocerebellar ataxias type 6,SCA6)基因诊断中的应用.方法 应用"两步PCR法"、变性聚丙烯酰胺凝胶电泳(DPAGE)和测序等方法对300名健康对照及109例无血缘关系的SCA患者进行CACNA1A基因CAG三核苷酸重复数目分析.结果 300名健康对照的CAG重复次数范围为3～18次,以13次最常见.在109例SCA患者中,发现1例SCA6患者,其CAG异常重复次数为24次,该患者的母亲和哥哥亦为SCA6患者,临床上均表现为缓慢进展的小脑性共济失调、构音障碍、眼震、轻度的振动及本体觉减退,遗传早现现象较明显.结论 SCA6病例在我国较少见,进行CACNA1A基因突变分析有助于临床诊断."两步PCR法"可提高CACNA1A基因突变分析的效率.     

Meiotic CAG repeat instability in spinocerebellar ataxia type 6: maternally transmitted elongation in a presumed sporadic case

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominantly inherited disorder characterized by cerebellar ataxia, dysarthria and nystagmus. The molecular background for the disorder is a CAG repeat expansion in the CACNA1A gene located on chromosome 19. The size of SCA6 expanded alleles is usually stable, and variation in repeat size over successive generations is rare. We report a Danish family with one case of SCA6 resembling a sporadic case of spinocerebellar ataxia. Analysis of the CACNA1A gene showed meiotic CAG repeat instability in the transmission from a 70-year-old woman with no subjective symptoms to her symptomatic son. The CAG repeat size expanded from 22 repeats in the mother to 23 repeats in the proband. This case demonstrates maternal repeat instability and clinical anticipation in a family with SCA6.     

Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds

OBJECTIVE—Spinocerebellar ataxia type 6 (SCA6) isan autosomal dominant cerebellar ataxia (ADCA) of which the mutationcausing the disease has recently been characterised as an expanded CAGtrinucleotide repeat in the gene coding for theα_1A-subunit of the voltage dependent calcium channel. Theaim was to further characterise the SCA6 phenotype
METHODS—The SCA6 mutation was investigated in 69 German families with ADCA and 61 patients with idiopathic sporadiccerebellar ataxia and the CAG repeat length of the expanded allele wascorrelated with the disease phenotype.
RESULTS—Expanded alleles were found in nine of 69 families as well as in four patients with sporadic disease. Diseaseonset ranged from 30 to 71 years of age and was significantlylater than in other forms of ADCA. Age at onset correlated inverselywith repeat length. The SCA6 phenotype comprises predominantlycerebellar signs in concordance with isolated cerebellar atrophy onMRI. Non-cerebellar systems were only mildly affected with external ophthalmoplegia, spasticity, peripheral neuropathy, and parkinsonism. Neither these clinical signs nor progression rate correlated with CAGrepeat length.
CONCLUSIONS—This study provides the first detailedcharacterisation of the SCA6 phenotype. Clinical features apart fromcerebellar signs were highly variable in patients with SCA6. Bycomparison with SCA1, SCA2, and SCA3 no clinical orelectrophysiological finding was specific for SCA6. Therefore, themolecular defect cannot be predicted from clinical investigations. InGermany, SCA6 accounts for about 13% of families with ADCA. However,up to 30% of SCA6 kindreds may be misdiagnosed clinically as sporadicdisease due to late manifestation in apparently healthy parents.Genetic testing is therefore recommended for the SCA6 mutation also inpatients with putative sporadic ataxia.

     

Spinocerebellar ataxia type 2 (SCA2) in an Egyptian family presenting with polyphagia and marked CAG expansion in infancy

We describe an Egyptian family having SCA2 affecting three generations with marked molecular and clinical anticipation observed in the index case. Our proband was a male child starting as early as 2 years old with progressive extrapyramidal manifestations, slow eye movements and cognitive impairment. A history of nonspecific mild developmental delay was recorded. The patient lost all cognitive functions, had persistent dystonic posture, trophic changes, vasomotor instability, dysphagia and died at the age of 7 years. The age at presentation among other affected family members varied between 11 and 45 years old across three generations. The early common neurological symptoms were choreoathetotic movements, myoclonic jerk, gait difficulty, expressionless face and emotional liability. Later, overt ataxia, incoordination, dysarthria, mild dementia and slow eye saccades predominated. Brisk tendon reflexes were detected in three cases. Peripheral nerve affection was a late manifestation. Interestingly, polyphagia and obesity were striking manifestations in the middle stage of the disease; an observation that might support a previously suggested relation between the ataxin-2 gene and body weight. The proband showed an amplified allele with marked CAG expansion in the form of a smear sized 69-75 repeats resulted from maternal transmission. To our knowledge, our index case is the second report in the literature presenting with infantile onset SCA2 and intermediate repeat expansion. This family expands the phenotypic spectrum of early onset SCA2 and points out the importance of considering SCA2 gene analysis in children with progressive neurological impairment and abnormal movements with or without polyphagia.     

Analysis of CAG repeat expansion in Huntington's disease gene (IT 15) in a Hungarian population

Huntington's disease (HD) is a neurodegenerative disorder with autosomal dominant inheritance. The genetic defect is a CAG trinucleotide repeat expansion at the 5' end of the IT 15 gene on chromosome 4. This gene has not been analyzed in the Hungarian population yet. To obtain data DNA from 26 HD patients, 18 members of their families and 70 normal controls was amplified in the involved region by polymerase chain reaction. The CAG repeat numbers varied from 37 to 70 (median: 43) in HD patients and asymptomatic carriers, while individuals of the normal control group had 10-36 CAG repeat numbers (median: 18). The length of CAG repeat expansion in Hungarian HD patients was similar to that reported from other countries. The group of normal controls had the same CAG repeat expansion as populations reported from Western European countries. It is a useful piece of data for population genetics to prove that the population of Hungary is a mélange of different nations that influenced the history of the country in the last 11 centuries. As opposed to this, the only closely related nation, the Finnish, was genetically more isolated during this time, so the frequency of HD (and also the number of CAG repeats in normal individuals) proved to be exceptionally low.     

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.     

Cerebellar α-Ketoglutarate dehydrogenase activity is reduced in spinocerebellar ataxia type 1

We measured the activity of the thiamine pyrophosphate–dependent enzyme α-ketoglutarate dehydrogenase complex in postmortem brain of 12 patients with the spinocerebellar ataxia type 1 form of olivopontocerebellar atrophy. α-Ketoglutarate dehydrogenase complex activity measured in the absence of thiamine pyrophosphate was markedly reduced (?72%) in olivopontocerebellar atrophy cerebellar cortex. Decreased activity of this key rate-limiting Krebs cycle enzyme could compromise cerebellar energy metabolism and excitatory amino acid synthesis and thereby contribute to the brain dysfunction of olivopontocerebellar atrophy.     

Genetic and clinical analysis of spinocerebellar ataxia type 8 repeat expansion in Italy.

BACKGROUND: The spinocerebellar ataxias (SCAs) are clinically heterogeneous disorders caused by triplet repeat expansions in the sequence of specific disease genes. Spinocerebellar ataxia type 8 (SCA8), originally described in a family characterized by pure cerebellar ataxia with slow disease progression, presents with expansion of combined CTA/CTG repeats. OBJECTIVE: To perform SCA8 repeat expansion analysis in a heterogeneous group of ataxic patients, to determine the prevalence of this mutation in our patients and establish the frequency of expanded CTA/CTG repeats in a large group of control subjects. PATIENTS: One hundred sixty-seven patients affected by sporadic, autosomal dominant and recessive hereditary ataxia were clinically examined and analyzed for SCA8 expansion. We further studied 161 control subjects and 125 patients with psychiatric disorders. RESULTS: We found abnormally expanded CTA/CTG repeats in 5 ataxic patients, 3 of them characterized by pure cerebellar ataxia. One patient had vitamin E deficiency and 1 patient with a sporadic case was affected by gluten ataxia. No evidence of expanded alleles was found in healthy control subjects and in patients with psychiatric disorders. CONCLUSIONS: Our data support the evidence that CTG expansions may be linked to SCA8, since the pathogenic expansions have been found only among patients with genetically unidentified forms of hereditary and sporadic ataxia. Patients carrying expanded alleles present peculiar phenotypic features, thus suggesting that unknown additional factors could probably predispose to the disease.     

17β‐estradiol regulation of the mRNA expression of t‐type calcium channel subunits: Role of estrogen receptor α and estrogen receptor β

Low‐voltage‐activated (T‐type) calcium channels are responsible for burst firing and transmitter release in neurons and are important for exocytosis and hormone secretion in pituitary cells. T‐type channels contain an α1 subunit, of which there are three subtypes, Cav3.1, ‐3.2, and ‐3.3, and each subtype has distinct kinetic characteristics. Although 17β‐estradiol (E2) modulates T‐type calcium channel expression and function, little is known about the molecular mechanisms involved. We used real‐time PCR quantification of RNA extracted from hypothalamic nuclei and pituitary in vehicle and E2‐treated C57BL/6 mice to elucidate E2‐mediated regulation of Cav3.1, ‐3.2, and ‐3.3 subunits. The three subunits were expressed in both the hypothalamus and the pituitary. E2 treatment increased the mRNA expression of Cav3.1 and ‐3.2, but not Cav3.3, in the medial preoptic area and the arcuate nucleus. In the pituitary, Cav3.1 was increased with E2 treatment, and Cav3.2 and ‐3.3 were decreased. To examine whether the classical estrogen receptors (ERs) were involved in the regulation, we used ERα‐ and ERβ‐deficient C57BL/6 mice and explored the effects of E2 on T‐type channel subtypes. Indeed, we found that the E2‐induced increase in Cav3.1 in the hypothalamus was dependent on ERα, whereas the E2 effect on Cav3.2 was dependent on both ERα and ERβ. However, the E2‐induced effects in the pituitary were dependent on only the expression of ERα. The robust E2 regulation of T‐type calcium channels could be an important mechanism by which E2 increases the excitability of hypothalamic neurons and modulates pituitary secretion. J. Comp. Neurol. 512:347–358, 2009. © 2008 Wiley‐Liss, Inc.     

Spinocerebellar ataxia type 5: clinical and molecular genetic features of a German kindred

The authors report a German family with autosomal dominant cerebellar ataxia tightly linked to the spinocerebellar ataxia type 5 (SCA5) locus (multipoint lod score 5.76). The phenotype is characterized by a purely cerebellar syndrome with a downbeat nystagmus occurring prior to the development of other features. Imaging studies demonstrated cortical cerebellar atrophy. Progression is slow even in patients with a disease onset during the second decade. The age at onset varies from 15 to 50 years.