Evidence for a common Spinocerebellar ataxia type 7 (SCA7) founder mutation in Scandinavia

Spinocerebellar ataxia type 7 (SCA7) is a neuro-degenerative disorder characterised by progressive cerebellar ataxia and macular degeneration. SCA7 is one of the least common genetically verified autosomal dominant cerebellar ataxias (ADCAs) in the world (4.5 to 11.6%), but in Sweden and Finland SCA7 is the most commonly identified form of ADCA. In an inventory of hereditary ataxias in Scandinavia (Sweden, Norway, Denmark and Finland) we identified 15 SCA7 families, eight in Sweden and seven in Finland, while no cases of SCA7 could be found in Norway or Denmark. We examined whether the relatively high frequency of SCA7 families in Sweden and Finland was the result of a common founder effect. Only two out of 15 families could be connected genealogically. However, an extensive haplotype analysis over a 10.2 cM region surrounding the SCA7 gene locus showed that all 15 families studied shared a common haplotype over at least 1.9 cM. This strongly suggests that all Scandinavian SCA7 families originate from a common founder pre-mutation.     

Spinocerebellar ataxia type 1 (SCA1): phenotype-genotype correlation studies in intermediate alleles

CAG repeat expansions with loss of CAT interruptions in the coding region of the ataxin-1 gene are associated with spinocerebellar ataxia type 1 (SCA1). For molecular genetic diagnosis it is necessary to define the limits of normal and pathological size ranges. In most studies, normal alleles as measured by PCR range from 6-39 units with interruptions of 1-3 CAT trinucleotides that are thought to be involved in the stability of the trinucleotide stretch during DNA replication. Expanded alleles have been reported to carry 39-81 CAG trinucleotides without stabilising CAT interruptions. To evaluate the limits between normal and disease size ranges we analysed the repeat length and composition of the SCA1 gene in 15 individuals with alleles ranging from 36 and 41 triplets for genotype-phenotype correlation studies. We found the 39 trinucleotide-allele to be either interrupted by CAT repeats or formed by a pure CAG stretch. The clinical features of individuals carrying 39 uninterrupted CAG repeats did not differ from the SCA1 phenotype in general with dysphagia, pale discs, pyramidal signs and cerebellar tremor being more frequent as compared to other SCA genotypes. In contrast, the interrupted 39 trinucleotide-allele is not correlated with the SCA1 phenotype.     

Spinocerebellar ataxia 1 (SCA1) in the Japanese: Analysis of CAG trinucleitide repeat expansion and instability of the repeat for paternal transmission

Summary SCA1 is caused by expansion of an unstable CAG triplet repeat in a novel gene located on the short arm of chromosome 6. In 126 Japanese individuals from 12 pedigrees with SCA1, studies were done to determine if they carried this mutant gene. All the affected and presymptomatic individuals, determined by haplotype segregation analyses, carried an abnormally expanded allele with the range of 39–63 repeat units. This repeat size inversely correlated with the age at onset. However, contrary to reported results, size of the repeat did not correlate with gender of the transmitting parent. Therefore, the CAG triplet repeat instability on paternal transmission is not likely to be fundamental to SCA1.     

Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions

Autosomal dominant cerebellar ataxia with progressive macular degeneration is caused by a CAG/glutamine repeat expansion in the SCA7 gene/protein. Neuronal intranuclear inclusions were detected in the brain of an early onset SCA7 case with the 1C2 antibody directed against an expanded polyglutamine domain. Nuclear inclusions were most frequent in the inferior olivary complex, a site of severe neuronal loss in SCA7. They were also observed in other brain regions, including the cerebral cortex, not considered to be affected in the disease. Using confocal microscopy we showed that some inclusions were ubiquitinated, but to varying degrees, ranging from <1% in the cerebral cortex to 60% in the inferior olive. In addition, we also observed cytoplasmic staining using the 1C2 antibody, particularly in the supramarginal gyrus, the hippocampus, the thalamus, the lateral geniculate body and the pontine nuclei. These data confirm that the presence of intranuclear inclusions in neurons is a common characteristic of disorders caused by CAG/polyglutamine expansions, but unlike what has been reported for Huntington's disease, SCA1 and SCA3/MJD, in SCA7 the inclusions were not restricted to the sites of severe neuronal loss.      

Spinocerebellar ataxia type 2 (SCA2) presenting with ophthalmoplegia and developmental delay in infancy

An 11-year-old boy was evaluated for progressive ataxia, cognitive deterioration, and ophthalmoplegia. The child initially presented with abnormal eye movements at the age of 2 months and was noted to have developmental delay at 6 months. At the age of 7 years, he developed ataxia and cognitive impairment, and subsequently manifested dysphagia and incontinence. The pertinent family history included gait difficulty in the paternal grandmother. At the age of 11, his general physical examination was normal. On neurological examination, he had bilateral external ophthalmoplegia, ataxic dysarthria, dysmetria and tremor in the upper extremities, and marked gait ataxia. An ophthalmological evaluation showed no evidence of pigmentary retinopathy. Brain MRI demonstrated cerebellar, brainstem, and cerebral atrophy. An ataxia panel showed 62 repeats in one allele of the SCA2 gene. Most cases of spinocerebellar ataxia type 2 (SCA2) present between 20 years and 40 years, and affected individuals typically have between 34 and 57 CAG repeats. Neonatal cases of SCA2 have been reported in individuals with over 200 CAG repeats. Childhood SCA2 has been reported previously in two patients but not described clinically. This case broadens the spectrum of the clinical features of infantile-onset SCA2 and highlights the importance of considering this diagnosis in infants and children.     

Spinocerebellar ataxia (SCA1) in two large Italian kindreds: evidence in favour of a locus position distal to GLO1 and the HLA cluster

Two large Italian pedigrees with HLA-linked spinocerebellar ataxia (SCA1) were typed for HLA-A, -B and -DR as well as for markers either distal ( F13A, D6S8 ) or proximal ( D6S29, GLOl ) to HLA. Pairwise linkage analyses of SCA1 vs. HLA-A, -B and -DR showed peak lodscores of 5-3, 5-6 and 3-3 respectively at 7 % recombination. Negative lodscores significantly excluded linkage with F13A at less than 5% and with GLOl at less than 10%. The lodscores with D6S8 and D6S29 had only low peaks.
Recombination events in the two pedigrees and the estimated genetic distances of SCAl from GLOl and HLA favour the hypothesis of a SCA1 location distal to both of them. An order cen-GLOl-HLA-SCAl-tel appears therefore most likely with present data. These results are discussed in relation to previous reports placing SCA1 distal to HLA in two families and proximal in another.     

Spinocerebellar ataxia type 23 is an uncommon SCA subtype in the Chinese Han population

The spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative diseases. In 2010, four missense mutations in the prodynorphin (PDYN) gene were found in two families and two sporadic cases of SCA type 23 (SCA23) from the Netherlands. In addition, one missense mutation in PDYN was also found in one sporadic SCA23 case in America in 2012. To date, there have been no reports of PDYN gene mutations in mainland China. To investigate the frequency of SCA23 among the Chinese Han population, we performed polymerase chain reaction (PCR) and DNA direct sequencing of the PDYN gene in 305 unrelated ataxia patients. Although no SCA23 mutation was identified, one novel single nucleotide polymorphism (c.255G>A, p.Lys85Lys) in exon 4 of the PDYN gene was found. This suggests that SCA23 is a rare form of dominant ataxia in the Chinese Han population.     

Spinocerebellar ataxia type 3 (SCA3): thalamic neurodegeneration occurs independently from thalamic ataxin-3 immunopositive neuronal intranuclear inclusions

In the last years progress has been made regarding the involvement of the thalamus during the course of the currently known polyglutamine diseases. Although recent studies have shown that the thalamus consistently undergoes neurodegeneration in Huntington's disease (HD) and spinocerebellar ataxia type 2 (SCA2) it is still unclear whether it is also a consistent target of the pathological process of spinocerebellar ataxia type 3 (SCA3). Accordingly we studied the thalamic pathoanatomy and distribution pattern of ataxin-3 immunopositive neuronal intranuclear inclusions (NI) in nine clinically diagnosed and genetically confirmed SCA3 patients and carried out a detailed statistical analysis of our findings. During our pathoanatomical study we disclosed (i) a consistent degeneration of the ventral anterior, ventral lateral and reticular thalamic nuclei; (ii) a degeneration of the ventral posterior lateral nucleus and inferior and lateral subnuclei of the pulvinar in the majority of these SCA3 patients; and (iii) a degeneration of the ventral posterior medial and lateral posterior thalamic nuclei, the lateral geniculate body and some of the limbic thalamic nuclei in some of them. Upon immunocytochemical analysis we detected NI in all of the thalamic nuclei of all of our SCA3 patients. According to our statistical analysis (i) thalamic neurodegeneration and the occurrence of ataxin-3 immunopositive thalamic NI was not associated with the individual length of the CAG-repeats in the mutated SCA3 allele, the patients age at disease onset and the duration of SCA3 and (ii) thalamic neurodegeneration was not correlated with the occurrence of ataxin-3 immunopositive thalamic NI. This lack of correlation may suggest that ataxin-3 immunopositive NI are not immediately decisive for the fate of affected nerve cells but rather represent unspecific and pathognomonic morphological markers of SCA3.     

Linkage studies in spinocerebellar ataxia (SCA)

Data are now available on 9 pedigrees in detail and 4 pedigrees as lod scores only. Linkage to HLA is significant (? = 5.53 at recombination rates of 0.223 in males and 0.327 in females). Tight linkage is excluded. Nine pedigrees which appear to be typical olivopontocerebellar atrophy (OPCA I) have recombination rates of 0.150 in males and 0.300 in females. The remaining 4 pedigrees are clinically atypical or include discrepant data and give no evidence for linkage. The symbol SCA1 is proposed for a locus on chromosome 6 (loosely linked to HLA), at which at least one allele produces OPCA I (Menzel type). It is not yet clear whether other clinical types are determined by alleles at different loci, although this is suggested by several pedigrees, including a Danish pedigree of OPCA with dementia. Linkage evidence will be decisive in delineating the ataxias.     

Influence of interleukin-1beta gene polymorphism on age-at-onset of spinocerebellar ataxia 6 (SCA6) in Japanese patients.

An inverse correlation is observed between the expanded CAG repeat number and age-at-onset of spinocerebellar ataxia 6 (SCA6). To detect another modifying genetic factor for SCA6, we studied polymorphisms in the genes for interleukin (IL)-1beta and tumor necrosis factor in 122 Japanese patients with SCA6. No contribution of these polymorphisms to the variance in disease onset was observed by regression analysis or by ANOVA. The IL-1beta promoter polymorphism, however, significantly affected the age-at-onset, when adjusted for the CAG repeat number as a covariate (P=0.0004, by ANCOVA), suggesting that IL-1beta may be a genetic factor other than the SCA6 gene that modifies the age-at-onset of the disease.     

Comparative studies of the CAG repeats in the spinocerebellar ataxia type 1 (SCA1) gene

The CAG repeat tract at the autosomal dominant spinocerebellar ataxia type 1 (SCA1) locus was analyzed in SCA1 families and French-Acadian, African-American, Caucasian, Greenland Inuit, and Thai populations. The normal alleles had 9–37 repeats, whereas disease alleles contained 44–64 repeats. The CAG repeat tract contained one or two CAT interruptions in 44 of 47 normal human chromosomes and in all five chimpanzees examined. In contrast, no CAT interruptions were found in Old World monkeys or expanded human alleles. The number and positions of CAT interruptions may be important in stabilizing CAG repeat tracts in normal chromosomes. At least five codons occupy the region corresponding to the polyglutamine tract at the SCA1 locus in mice, rats, and other rodents. They comprise three or four CCN (coding for proline) in addition to one or two CAG repeats. Am. J. Med. Genet. 74:488–493, 1997. © 1997 Wiley-Liss, Inc.     

Spinocerebellar ataxia type 6 and episodic ataxia type 2 in a Korean family.

Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine (FHM) have been known as allelic disorders, which are caused by the alteration of the alpha1A voltage-dependent calcium channel subunit. Expansions of the CAG repeat in the CACNA1A gene on the short arm of the chromosome 19 induce SCA6, and point mutations in the same gene are responsible for EA2 and FHM. In recent studies, both SCA6 and EA2 have been concurrently found in families with 26 CAG repeats without previously reported point mutations either in coding sequences or in intron-exon junctions. We describe a Korean family with CAG26 repeats in the CACNA1A gene. Some of the affected family members had progressive ataxia typical of SCA6 whereas others had episodic vertigo responsive to acetazolamide typical of EA2. Our family support that SCA6 and EA2 are allelic disorders with a high phenotypic variability.     

Presymptomatic analysis of spinocerebellar ataxia type 1 (SCA1) via the expansion of the SCA1 CAG-repeat in a large pedigree displaying anticipation and parental male bias

Autosomal dominant cerebellar ataxia type 1 (ADCA1) is a clinicaland genetic heterogeneous neurodegenerative disorder which leadsto progressive cerebellar ataxia. One defective gene responsiblefor the disease was first localised to 6p (SCA1, splnocerebellarataxia type 1) and the mutation has been more recently characterised.We have analysed the CAG-repeat mutation responsible for theSCA1 phenotype in a large Spanish kindred with 41 affected members,in which positive linkage with D6S89 was previously shown. All(10) clinically affected members analysed were heterozygouswith one disease allele being between 41 to 57 CAG repeats,and the other in the normal range, from 6 to 39 repeats. Nineclinically unaffected individuals who were between the agesof 18 and 40, were found to have expansions of the CAG repeat(41 to 59), and 22 other ‘at risk’ individuals werefound to have inherited the SCA1 gene with copies of the CAGrepeat in the normal range. We have also observed that affectedfathers passed on the mutated SCA1 gene with larger increasesin the number of CAG repeats than affected mothers did. In onecase a decrease in the number of CAG repeats (51 to 50) wasdetected in the transmission from the affected mother, and intwo cases no change was observed in the transmission of a 41allele repeat by a mother. As in the other disorders in whichknowledge of the mutation has been obtained, analysis of therepeat expansion dramatically changes diagnosis of SCA1.     

Spinocerebellar ataxia type 7 (SCA7): first report of a systematic neuropathological study of the brain of a patient with a very short expanded CAG-repeat

Spinocerebellar ataxia type 7 (SCA7) represents a very rare and severe autosomal dominantly inherited cerebellar ataxia (ADCA). It belongs to the group of CAG-repeat or polyglutamine diseases with its underlying molecular genetical defect on chromosome 3p12-p21.1. Here, we performed a systematic study of the neuropathology on unconventional thick serial sections of the first available brain tissue of a genetically confirmed late-onset SCA7 patient with a very short CAG-repeat expansion. Along with myelin pallor of a variety of central nervous fiber tracts, we observed i) neurodegeneration in select areas of the cerebral cortex, and ii) widespread nerve cell loss in the cerebellum, thalamus, nuclei of the basal ganglia, and brainstem. In addition, upon immunocytochemical analysis using the anti-polyglutamine antibody 1C2, immunopositive neuronal intranuclear inclusions bodies (NI) were observed in all cerebellar regions, in all parts of the cerebral cortex, and in telencephalic and brainstem nuclei, irrespective of whether they underwent neurodegeneration. These novel findings provide explanations for a variety of clinical symptoms and paraclinical findings of both our and other SCA7 patients. Finally, our immunocytochemical analysis confirms previous studies which described the presence of NI in obviously degenerated brain and retinal regions as well as in apparently well-preserved brain regions and retina of SCA7 patients.     

A common disease haplotype segregating in spinocerebellar ataxia 2 (SCA2) pedigrees of diverse ethnic origin

The identification of a CAG trinucleotide repeat expansion, located within the coding sequence of the ataxin-2 gene, as the mutation underlying spinocerebellar ataxia 2 (SCA2) has facilitated direct investigation of pedigrees previously excluded from linkage analysis due to insufficient size or pedigree structure. We have previously described the identification of the ancestral disease haplotype segregating in the Cuban founder population used to assign the disease locus to chromosome 12q23-24.1. We now report evidence for the segregation of the identical core haplotype in pedigrees of diverse ethnic origin from India, Japan and England, established by the analysis of the loci D12S1672 and D12S1333 located 20kb proximal and 200 kb distal to the triplet repeat motif respectively. Interpretation of this data is suggestive that for these pedigrees at least, the mutation has arisen on a single ancestral or predisposing chromosome.     

Knowledge of genetics and attitudes toward genetic testing in two hereditary ataxia (SCA 1) Kindreds

Molecular genetic predictive or prenatal genetic testing is now possible in families with one form of adult-onset, autosomal dominant ataxia (SCA 1). Before the SCA 1 gene was isolated, we began a study of the knowledge of genetics, the perception of the disease, and the intended use of genetic testing among members of two large SCA 1 kindreds. Questionnaires were sent to 210 consenting affected, at-risk, and spouse members of two SCA 1 kindreds; data from the 117 respondents were analyzed on a personal computer. Sixty-nine percent of respondents thought predictive testing (by genetic linkage) should be made available immediately, and 42% thought prenatal testing should be made available. The kindreds differed in several important aspects: knowledge of genetic concepts, family size, and anticipated emotional responses to genetic testing. No respondent had obtained individualized genetic counseling. There is moderate interest in genetic testing for this fatal neurodegenerative disease of adulthood. Members of our kindreds have not received genetic counseling outside of the research setting. Finally, factors specific to a particular kindred may influence or predict individual responses to genetic testing. © 1994 Wiley-Liss, Inc.     

Molecular features of the CAG repeats of spinocerebellar ataxia 6 (SCA6)

Spinocerebellar ataxia 6 (SCA6) is an autosomal dominant spinocerebellar degeneration caused by the expansion of the polymorphic CAG repeat in the human alpha1A voltage-dependent calcium channel subunit gene (CACNL1A4 gene). We have analyzed 60 SCA6 individuals from 39 independent SCA6 Japanese families and found that the CAG repeat length is inversely correlated with the age of onset (n = 58, r = - 0.51, P < 0.0001). SCA6 chromosomes contained 21-30 repeat units, whereas normal chromosomes displayed 6-17 repeats. There was no overlap between the normal and affected CAG repeat number. The anticipation of the disease was observed clinically in all eight parent-child pairs that we examined; the mean age of onset was significantly lower (P = 0.0042) in children than in parents. However, a parent-child analysis showed the increase in the expansion of CAG repeats only in one pair and no diminution in any affected cases. This result suggests that factors other than CAG repeats may produce the clinical anticipation. A homozygotic case could not demonstrate an unequivocal gene dosage effect on the age of onset.      

Understanding the dynamics of Spinocerebellar Ataxia 8 (SCA8) locus through a comparative genetic approach in humans and apes

Spinocerebellar Ataxia 8 (SCA8) is a neurodegenerative disorder caused by expansion of a trinucleotide repeat. We undertake a comparative genetic analysis among human populations and primate species in the normal variation range, where forces that shaped present diversity can be recognised. We determinate number of repeats of the short tandem repeat through allele length sizing and sequencing methods. Human allele distributions are very similar among populations, ruling out ethnicity as a genetic risk for allele expansion. Primate comparison shows human-specific features, with longer human alleles due to a novel variable trinucleotide repeat, not present in non-human primates, which increased the disease-causing expansion likelihood. SCA8 seems to be a human specific disease.     

The effect of CAT trinucleotide interruptions on the age at onset of spinocerebellar ataxia type 1 (SCA1)

The effect of CAT trinucleotide interruptions in the CAG trinucleotide repeats of the SCA1 gene on the age at onset of spinocerebellar ataxia type 1 (SCA1) was investigated. The number of CAG repeats in SCA1 was determined by polymerase chain reaction (PCR) analysis, and the presence of CAT interruptions was assessed on the basis of the sensitivity of the PCR products to the restriction endonuclease SfaNI, which recognises CAT trinucleotides. Only one in 17 expanded SCA1 alleles from 17 SCA1 patients was interrupted by CAT. The SfaNI sensitive SCA1 allele from this single patient contained 58 CAG repeats, which would predict an age at onset of SCA1 of 22.0 years, in contrast to the actual 50 years. In addition, the brain stem atrophy of this patient was mild compared with that of a patient with 52 uninterrupted CAG repeats. A sequence analysis showed that the repeat portion of the patient contained (CAG)45CATCAG CAT(CAG)10. From these results, we suggest that the age at onset of SCA1 is not determined by the total number of CAG repeats (58) but by the number of uninterrupted CAG repeats.