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Long repeat tracts at SCA8 in major psychosis
Abstract
Expansion at a recently identified unstable trinucleotide repeat on chromosome 13q21 has been reported as the molecular cause for spinocerebellar ataxia type 8 (SCA8). The trinucleotide repeat, which consists of a [CTA]n repeat and adjacent [CTG]n repeat, was reported to have a pathogenic range of 107–127 CTG repeats (or 110–130 combined CTA and CTG repeats) in a large ataxia kindred. This repeat region was also cloned by our group from a bipolar affective disorder (BPAD) patient, who has approximately 600 combined repeats, and large alleles (>100 repeats) were reported to be present in 0.7% of controls and 1.5% of major psychosis patients (n = 710 and n = 1,120, respectively). We have followed up these findings by screening three new samples of BPAD and schizophrenia (SCZ) patients and controls, including 272 individuals from 14 BPAD families from Sweden, 130 individuals from 32 SCZ and BPAD families/trios from the Azores Islands, and 206 SCZ individuals from the United Kingdom and Ireland, and 219 matched controls. We found large repeat alleles above the SCA8 pathogenic range in individuals from 3 of 32 Azorean pedigrees and in 1 of 206 SCZ individuals from the United Kingdom, and repeat alleles within the SCA8 pathogenic range in 1 of 14 Swedish families. Although the rarity of major psychosis patients carrying the SCA8 expansion mutation would require a much larger sample size to reach statistical significance, these results support the previously reported observation of increased occurrence of large repeats at SCA8 in major psychosis. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:873–876, 2000. © 2000 Wiley-Liss, Inc.
... Penetrance is reduced in some families, 1,2 with this expansion sometimes being observed in healthy people. 5 Additionally, the expansion has been identified in some psychiatric diseases 6 and other neurodegenerative diseases, such as amyotrophic lateral sclerosis, 7 Parkinson's disease, 4,8 Alzheimer's disease, 4,6 and progressive supranuclear palsy (PSP). 4 No significant difference was reported in the number of repeats between patients with SCA8 and those with Parkinson's disease or Alzheimer's disease. ...
... Penetrance is reduced in some families, 1,2 with this expansion sometimes being observed in healthy people. 5 Additionally, the expansion has been identified in some psychiatric diseases 6 and other neurodegenerative diseases, such as amyotrophic lateral sclerosis, 7 Parkinson's disease, 4,8 Alzheimer's disease, 4,6 and progressive supranuclear palsy (PSP). 4 No significant difference was reported in the number of repeats between patients with SCA8 and those with Parkinson's disease or Alzheimer's disease. ...
... These neuronal and glial inclusions were © 2023 Japanese Society of Neuropathology. 6 Y Yonenobu et al. ...
Spinocerebellar ataxia type 8 (SCA8) is a neurodegenerative condition that presents with several neurological symptoms, such as cerebellar ataxia, parkinsonism, and cognitive impairment. It is caused by a CTA/CTG repeat expansion on chromosome 13q21 (ataxin 8 opposite strand [ATXN8OS]). However, the pathological significance of this expansion remains unclear. Moreover, abnormal CTA/CTG repeat expansions in ATXN8OS have also been reported in other neurodegenerative diseases, including progressive supranuclear palsy. In this study, we analyzed all available autopsy cases in Japan to investigate common pathological features and profiles of tau pathology in each case. Severe neuronal loss in the substantia nigra and prominent loss of Purkinje cells, atrophy of the molecular layer, and proliferation of Bergmann glia in the cerebellum were common features. Regarding tauopathy, one case presented with progressive supranuclear palsy‐like 4‐repeat tauopathy in addition to mild Alzheimer‐type 3‐ and 4‐repeat tauopathy. Another case showed 3‐ and 4‐repeat tauopathy accentuated in the brainstem. The other two cases lacked tauopathy after extensive immunohistochemical studies. The present study confirmed common pathological features of SCA8 as degeneration of the substantia nigra in addition to the cerebellum. Our study also confirmed unique tauopathy in two of four cases, indicating the necessity to further collect autopsy cases.
... The repeat is located upstream of a gene called KLHL1 on 13q21.33 and appears to be in a noncoding antisense RNA, now termed ATXN8OS. However, our work and others showed clearly that expanded repeats at this locus are present in nonataxic individuals (Vincent et al., 2000a(Vincent et al., , 2000bStevanin et al., 2000;Worth et al., 2000;Sobrido et al., 2001;Schöls et al., 2003) and in individuals with major psychosis (Vincent et al., 2000a(Vincent et al., , 2000b. The trinucleotide repeat, which consists of a [CTA] n repeat and an adjacent [CTG] n repeat, was reported by Koob et al. (1999) to have a pathogenic range of 107-127 CTG repeats (or 110-130 combined CTA and CTG repeats) in a single large ataxia kindred. ...
... The repeat is located upstream of a gene called KLHL1 on 13q21.33 and appears to be in a noncoding antisense RNA, now termed ATXN8OS. However, our work and others showed clearly that expanded repeats at this locus are present in nonataxic individuals (Vincent et al., 2000a(Vincent et al., , 2000bStevanin et al., 2000;Worth et al., 2000;Sobrido et al., 2001;Schöls et al., 2003) and in individuals with major psychosis (Vincent et al., 2000a(Vincent et al., , 2000b. The trinucleotide repeat, which consists of a [CTA] n repeat and an adjacent [CTG] n repeat, was reported by Koob et al. (1999) to have a pathogenic range of 107-127 CTG repeats (or 110-130 combined CTA and CTG repeats) in a single large ataxia kindred. ...
... Large repeat alleles (>100 repeats) were also reported to be present in 0.7% of controls and 1.5% of major psychosis patients (n = 710 and n = 1120, respectively) (Vincent et al., 2000a). We also found repeat alleles within the reported pathogenic range for ataxia in three out of 32 Azorean major psychosis families, one out of 14 Swedish BD families (Vincent et al., and 2000b). ...
For a period in the mid-1990s, soon after the discovery of the involvement of trinucleotide repeat expansions in fragile-X syndrome (both A and E), Huntington's disease, myotonic dystrophy, and a number of hereditary ataxias, there was a clear sense that this new disease mechanism might provide answers for psychiatric disorders. Given the then failures to replicate initial genetic linkage findings for schizophrenia (SCZ) and bipolar disorder (BD), a greater emphasis was placed on the role of complex and non-Mendelian mechanisms, and repeat instability appeared to have the potential to provide adequate explanations for numerous apparently non-Mendelian features such as anticipation, incomplete penetrance, sporadic occurrence, and nonconcordance of monozygotic twins. Initial molecular studies using a ligation-based amplification method (repeat expansion detection) appeared to support the involvement of CAG CTG repeat expansion in SCZ and BD. However, subsequent studies that dissected the large repeats responsible for much of the positive signal showed that there were three main loci where CAG CTG repeat expansion was occurring (on 13q21.33, 17q21.33-q22, and 18q21.2). None of the expansions at these loci appeared to segregate with SCZ or BD, and research into repeat expansions in psychiatric illness petered out in the early 2000s. The 13q expansion occurs within a noncoding RNA and appears to be associated with spinocerebellar ataxia 8 (SCA8), but with a still unexplained dichotomy in penetrance - either very high or very low. The 17q expansion occurs within an intron of the carbonic anhydrase-like gene, CA10. The 18q expansion is located within an intron of the TCF4 gene. Mutations in TCF4 are a known cause of Pitt-Hopkins syndrome. Also, pertinently, genome-wide association studies have shown a well-replicated association between TCF4 and SCZ. Two decades on, in 2016, it appears to be an appropriate juncture to reflect on what we have learned, and, with the arrival of newer technologies, whether there is any mileage to be made in revisiting the unstable DNA hypothesis for psychiatric illness.
... The phenotype of SCA8 varies more widely than those of the other types of SCA, and its spectrum variance is not well established (7). Furthermore, the CTG expansion has been detected in patients with other neuropsychiatric diseases, such as other neurodegenerative diseases (8)(9)(10)(11) and psychiatric diseases (12), as well as in healthy controls (13). These findings have resulted in controversy surrounding testing for the ATXN8OS CTG expansion in ataxic individuals (14). ...
... Expanded ATXN8OS CTA/CTG repeats may rarely coexist with the expansion of SCA1, SCA3, SCA6, and SCA31 CAG repeats (3,14,17,18); however, our genetic analysis ruled out this possibility. Furthermore, expanded ATXN8OS CTA/CTG repeats have been detected in other neurodegenerative diseases, including Parkinson's disease (9,19), multiple system atrophy (8), progressive supranuclear palsy (11), amyotrophic lateral sclerosis (19,20), and Alzheimer's disease (10), as well as psychiatric diseases (12) and even in healthy controls (13). Therefore, abnormal expansions alone are not sufficient to make a diagnosis of SCA8. ...
Spinocerebellar ataxia type 8 (SCA8) is a rare hereditary cerebellar ataxia showing mainly pure cerebellar ataxia. We herein report cases of SCA8 in Japanese monozygotic twins that presented with nystagmus, dysarthria, and limb and truncal ataxia. Their ATXN8OS CTA/CTG repeats were 25/97. They showed similar manifestations, clinical courses, and cerebellar atrophy on magnetic resonance imaging. Some of their pedigrees had nystagmus but not ataxia. These are the first monozygotic twins with SCA8 to be reported anywhere in the world. Although not all subjects with the ATXN8OS CTG expansion develop cerebellar ataxia, these cases suggest the pathogenesis of ATXN8OS repeat expansions in hereditary cerebellar ataxia.
... The CTG expansion is unusual because it was the first untranslated repeat expansion thought to cause ataxia by a gain-of-function RNA mechanism and because it shows dramatic genetic instability and reduced disease penetrance (Koob et al. 1999; Day et al. 2000; Ikeda et al. 2000; Moseley et al. 2000a Moseley et al. , 2000b Cellini et al. 2002; Topisirovic et al. 2002). Surprisingly, SCA8 expansions have also been found on control chromosomes , leading to the suggestion that the SCA8 expansion in our MN-A family, reported elsewhere ( , ) (Koob et al. 1999; LOD p 6.8 v p .0 2000), may be in linkage disequilibrium with a neighboring disease-causing mutation and that the expansion is a coincidental background finding in the other families with ataxia and SCA8 expansions (Juvonen et al. 2000; Moseley et al. 2000a; Stevanin et al. 2000; Vincent et al. 2000a Vincent et al. , 2000b Worth et al. 2000; Sobrido et al. 2001; Izumi et al. 2003; Schols et al. 2003). To clarify the genetics of SCA8, we performed molecular genetic comparisons of a large number of SCA8 expansion carriers , including the large MN-A family and 36 smaller families with ataxia that are SCA8 positive. ...
... These samples had no clinical or family identifiers and may include both patients with ataxia as well as unaffected individuals sent for diagnostic testing. In addition , we studied 7 unrelated and apparently unaffected individuals (including members of CEPH families 1334 and 1416) and 14 patients, reported elsewhere, with major psychosis and SCA8 expansions (Day et al. 2000; Vincent et al. 2000b). In these two groups without ataxia, 74 combined CTA/CTG repeats (74 is the smallest expansion number found in a patient with ataxia) is the threshold for inclusion in the study. ...
We reported elsewhere that an untranslated CTG expansion causes the dominantly inherited neurodegenerative disorder spinocerebellar ataxia type 8 (SCA8). SCA8 shows a complex inheritance pattern with extremes of incomplete penetrance, in which often only one or two affected individuals are found in a given family. SCA8 expansions have also been found in control chromosomes, indicating that separate genetic or environmental factors increase disease penetrance among SCA8-expansion-carrying patients with ataxia. We describe the molecular genetic features and disease penetrance of 37 different families with SCA8 ataxia from the United States, Canada, Japan, and Mexico. Haplotype analysis using 17 STR markers spanning an approximately 1-Mb region was performed on the families with ataxia, on a group of expansion carriers in the general population, and on psychiatric patients, to clarify the genetic basis of the reduced penetrance and to investigate whether CTG expansions among different populations share a common ancestral background. Two major ancestrally related haplotypes (A and A') were found among white families with ataxia, normal controls, and patients with major psychosis, indicating a common ancestral origin of both pathogenic and nonpathogenic SCA8 expansions among whites. Two additional and distinct haplotypes were found among a group of Japanese families with ataxia (haplotype B) and a Mexican family with ataxia (haplotype C). Our finding that SCA8 expansions on three independently arising haplotypes are found among patients with ataxia and cosegregate with ataxia when multiple family members are affected further supports the direct role of the CTG expansion in disease pathogenesis.
... In a series of one-off case reports, in patients with features of psychosis or schizophrenia, an empiric strategy of targeted sequencing of select genes known to be associated with neurological disorders identified rare, repeat expansions (for example, in HTT, ATXN8OS and C9orf72, known to be associated with Huntington's disease (HD), hereditary ataxias, and amyotrophic lateral sclerosis, respectively) [35][36][37][38][39]. A broader, genomewide analysis of TREs in a modest-sized cohort of 257 individuals with schizophrenia compared to 2729 controls, identified TREs in individuals with schizophrenia involving 193 genes, including TREs in intronic and exonic regions, and several TREs proximal to schizophrenia GWAS loci (<10 kb), though the penetrance of the reported TREs could not be determined [40]. ...
Tandem repeats (TRs) are prevalent throughout the genome, constituting at least 3% of the genome, and often highly polymorphic. The high mutation rate of TRs, which can be orders of magnitude higher than single-nucleotide polymorphisms and indels, indicates that they are likely to make significant contributions to phenotypic variation, yet their contribution to schizophrenia has been largely ignored by recent genome-wide association studies (GWAS). Tandem repeat expansions are already known causative factors for over 50 disorders, while common tandem repeat variation is increasingly being identified as significantly associated with complex disease and gene regulation. The current review summarizes key background concepts of tandem repeat variation as pertains to disease risk, elucidating their potential for schizophrenia association. An overview of next-generation sequencing-based methods that may be applied for TR genome-wide identification is provided, and some key methodological challenges in TR analyses are delineated.
... Besides ataxia, some patients also exhibit cognitive, psychiatric dysfunction, multisystem atrophy (MSA), and other neurodegenerative disease phenotypes. Moreover, CTA/CTG expansion has also been detected in MSA [27], Parkinson's disease [23], Alzheimer's disease [28], amyotrophic lateral sclerosis [29], and psychosis [30]. In this study, two specific phenotypes, PKD and MSA, were found to be associated with CTA/CTG expansion. ...
Background
Spinocerebellar ataxia type 8 (SCA8) is a rare autosomal dominant neurodegenerative disease caused by CTA/CTG repeat expansion in the ATXN8/ATXN8OS gene.
Methods
To analyze the frequency and clinical characteristics of SCA8 patients in mainland China, we combined polymerase chain reaction (PCR) and triplet repeat-primed PCR (TRP-PCR) to detect the CTA/CTG expansion. We studied a cohort of 362 ataxia patients in which the other known causative genes had been previously excluded, from among 1294 index patients. Positive samples were validated by southern blotting.
Results
The CTA/CTG expansion was observed in six probands, accounting for approximately 0.46% (6/1294) in all patients, and 1.66% (6/362) in patients without definite molecular diagnosis. Clinically, aside from the typical SCA8 phenotype, some patients carrying the CTA/CTG expansion exhibited the cerebellar form of multisystem atrophy (MSA-C) and ataxia with paroxysmal kinesigenic dyskinesia (PKD).
Conclusion
For the first time, we described the PKD phenotype in association with CTA/CTG expansion, suggesting that CTA/CTG expansion might play a role in the pathogenesis of paroxysmal dyskinesia symptoms.
... Expansion of unstable trinucleotide repeat tracts in ATXN8OS has been associated with spinocerebellar ataxia type 8, a late-onset progressive neurodegenerative disorder also featuring severe gait, speech and sensory loss. Long repeat tracts of this transcript have been also reported in subjects with schizophrenia and bipolar disorder [37]. Down regulating KLHL1 expression through an antisense mechanism has been shown as a potential way that repeat expansions in this non protein-coding RNA may lead to neuropathogenesis [38]. ...
This file contains Figure S1, Hierarchical clustering and principal components analyses, Figure S2, Workflow describing the applied permutation analysis, Table S1, A summary of previously reported linkage results for autism, Table S2, The number of multiplex families, in each subgroup, without (n1) and with (n2) BroadSpectrum subjects, Table S3, Overlap between the subgroups at the G level, Table S5, Chromosomal locations of the positive linked loci (LOD≥2) and their associated genes per subgroups, Table S6, TDT result for two previously associated SNPs at chromosome 5p, Table S7, List of the genes associated with the SNPs with the highest LOD scores in 13q21 (G1 group), and Table S8, List of the genes associated with the SNPs with the highest LOD scores in 22q11 (G1s group).
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... While it is now clear that CTA/CTG repeat expansion can cause ataxia, several issues have yet to be clarified, including reduced penetrance, gender effects, normal and pathogenic expansion ranges, detection in other neurodegenerative psychiatric disorders and even in the normal population. [5][6][7][8][9][10][11] Furthermore, the phenomenology of SCA8 is relatively variable than those of the other types of SCA, and its spectrum variance is not well established. 12 A large number of clinical analyses have demonstrated that SCA8 presents as a very slowly progressive ataxia, 13,14 and affected individuals displayed gait, limb ataxia, speech, and oculomotor incoordination. ...
Spinocerebellar ataxia (SCA) type 8 (SCA8) is an inherited neurodegenerative disorder caused by the expansion of untranslated CTA/CTG triplet repeats on 13q21. The phenomenology of SCA8 is relatively varied when compared to the other types of SCAs and its spectrum is not well established.
Two newly detected cases of SCA8 with the nonataxic phenotype and unusual clinical manifestations such as dopaminergic-treatment-responsive parkinsonism and amyotrophic lateral sclerosis (ALS) are described herein. Family A expressed good dopaminergic treatment-responsive parkinsonism as an initial manifestation and developed mild cerebellar ataxia with additional movements, including dystonic gait and unusual oscillatory movement of the trunk, during the disease course. The proband of family B presented as probable ALS with cerebellar atrophy on brain MRI, with a positive family history (a brother with typical cerebellar ataxia) and genetic confirmation for SCA8.
Our findings support that the non-ataxic phenotypes could be caused by a mutation of the SCA8 locus which might affect neurons other than the cerebellum.
... Because of these findings, we could not categorize this case as motor neuron disease or spinocerebellar ataxia involving motor neuron systems. However, based on clinical observations, the subjects with this abnormality of SCA8 mutation may either present no symptomatology 2,3 or be associated only with schizophrenia, 4 bipolar affective disorders, 4 Huntington phenocopy 5 or migraine. 6 This variable nature with inconsistent penetrance of the SCA8 mutation expansion suggests that corresponding phenotypes are influenced by factors other than this expansion itself. ...
It has been reported that abnormal processing of pre-mRNA is caused by abnormal triplet expansion. Non-coding triplet expansions produce toxic RNA to alter RNA splicing activities. However, there has been no report on the globular RNA aggregation in neuronal cytoplasmic inclusions (NCIs) up to now. We herein report on an autopsy case (genetically determined as spinocerebellar atrophy 8 (SCA8)) with hitherto undescribed NCIs throughout the brain. NCIs were chiefly composed of small granular particles, virtually identical to ribosomes. Neurological features are comparable to the widespread lesions of the brain, including the spinal cord. Although 1C2-positivity of NCIs might be induced by reverse transcription of the CTG expansion, it remains to be clarified how abnormal aggregations of ribosome and extensive brain degeneration are related to the reverse or forward transcripts of the expanded repeat.
... Multiple genes encoded by chromosome 13 have been suggested to contribute to schizophrenia susceptibility, including DAOA [42], 5-HTR2A [43], KPNA3 and KPNB3 [44], ESD [45], ATXN8OS [46], KFL5 [47], EFNB2 [48], and PCDH8 [49]. Since it was not possible to narrow down the candidate region of chromosome 13, two genes were chosen for sequence analysis based on their robust association with schizophrenia: DAOA [42] and 5-HTR2A [43]. ...
A small percentage of all cases of schizophrenia have a childhood onset. The impact on the individual and family can be devastating. We report the results of genetic analyses from a patient with onset of visual hallucinations at 5 years, and a subsequent diagnosis at 9 years of schizophrenia, attention deficit hyperactivity disorder (ADHD) with hyperactivity and impulsivity, and chronic motor tic disorder.
Karyotypic analysis found 45,XX,i(13)(q10) in all cells examined. Alpha satellite FISH of isochromosome 13 revealed a large unsplit centromeric region, interpreted as two centromeres separated by minimal or undetectable short-arm material or as a single monocentric centromere, indicating that the isochromosome likely formed post-zygotically by a short arm U-type or centromeric exchange. Characterization of chromosome 13 simple tandem repeats and Affymetrix whole-genome 6.0 SNP array hybridization found homozygosity for all markers, and the presence of only a single paternal allele in informative markers, consistent with an isodisomic isochromosome of paternal origin. Analysis of two chromosome 13 schizophrenia candidate genes, D-amino acid oxidase activator (DAOA) and 5-hydroxytryptamine (serotonin) receptor 2A (5-HTR2A), failed to identify non-synonymous coding mutations but did identify homozygous risk polymorphisms.
We report a female patient with childhood-onset schizophrenia, ADHD, and motor tic disorder associated with an isodisomic isochromosome 13 of paternal origin and a 45,XX,i(13)(q10q10) karyotype. We examined two potential mechanisms to explain chromosome 13 involvement in the patient's pathology, including reduction to homozygosity of a paternal mutation and reduction to homozygosity of a paternal copy number variation, but were unable to identify any overtly pathogenic abnormality. Future studies may consider whether epigenetic mechanisms resulting from uniparental disomy (UPD) and the lack of chromosome 13 maternal alleles lead to the patient's features.
... It is not clear whether repeat sizes ranging from 50 to 70 repeats can be pathogenic, and it is known that not all expanded alleles are pathogenic. Moreover, ex pa nsions have been fou nd i n individuals with positive gene test results for other SCDs 5,9,10) and other diseases 5,9,11,12) . Therefore, we believe it is possible to obtain new insights by increasing the number of screening tests and confirming expansions by the use of our method. ...
Spinocerebellar ataxia type 8 (SCA8) is a neurodegenerative disorder characterized by slowly progressive cerebellar ataxia. It is caused by bidirectional expression of (CUG)n expansion in the ATXN80S/ATXN8 gene and (CAG)n expansion transcripts in ATXN8. The diagnosis of SCA8 must be confirmed by the presence of a (CTG)n trinucleotide repeat expansion in the ATXN8OS gene. On the other hand, there are many human genetic diseases that are caused by expansion of short tandem repeats. Since Werner et al proposed a repeat-primed fluorescent PCR to detect large CTG-repeats in myotonic dystrophy, Friedreich ataxia, SCA2, SCA7, SCA10 and SCA12 have been reported. In this study, we applied a fluorescent PCR method for detection of expanded repeats in the ATXN8OS/ATXN8 gene. Although this test cannot give a precise estimate of the size of the expansion, it proved useful for confirming the presence of expansions in SCA8.
... High SK3 levels in dopaminergic midbrain neurons [reviewed in [26,47,78]], and its role in producing a medium-duration after-hyperpolarization (mAHP) that regulates rhythmic firing in the normal caudate putamen/striatum [79] have made it an attractive target for Parkinson's and schizophrenia. Although controversial, several studies have correlated trinucleotide polymorphisms in SK3 with schizophrenia and migraine [80,81], and changes in SK3 expression with sleep apnoea, sudden infant death syndrome, mood disorders, epilepsy and schizophrenia [24,26,46,82]. SK3 channels also regulate neuron firing in the dorsal motor nucleus and superior cervical ganglion neurons [26] and, in the hippocampus, the SK3 current increases with age and correlates with age-dependent deficits in synaptic plasticity and learning [24]. ...
Small-conductance Ca2+ activated K+ channels are expressed in the CNS, where KCNN2/SK2/KCa2.2 and KCNN3/SK3/KCa2.3 help shape the electrical activity of some neurons. The SK3 channel is considered a potential therapeutic target for diseases and disorders involving neuron hyper-excitability but little is known about its expression and roles in non-neuronal cells in either the healthy or damaged CNS. The purpose of this study was to examine expression of KCNN3/SK3 in CNS microglia in vivo and in vitro, and to use an established in vitro model to determine if this channel contributes to the neurotoxic capacity of activated microglia.
KCNN3 mRNA (real-time RT-PCR) and SK3 immunoreactivity were examined in rat microglia. Lipopolysaccharide was then used to activate microglia (monitored by iNOS, nitric oxide, activation of NF-kappaB and p38 MAPK) and transform them to a neurotoxic state. Microglia-mediated neuron damage (TUNEL, activated caspase 3) and nitrotyrosine levels were quantified using a two-chamber system that allowed microglia to be treated with channel blockers, washed and then added to neuron/astrocyte cultures. Contributions of SK3 to these processes were discriminated using a subtractive pharmacological approach with apamin and tamapin. ANOVA and post-hoc tests were used to assess the statistical significance of differences between treatment groups. SK3 immunoreactivity was then compared in the normal and damaged adult rat striatum, by injecting collagenase (a hemorrhagic stroke) or endothelin-1 (a transient ischemic stroke).
KCNN3 mRNA was prevalent in cultured microglia and increased after lipopolysaccharide-induced activation; SK3 channel blockade inhibited microglial activation and reduced their ability to kill neurons. SK3 immunoreactivity was prevalent in cultured microglia and throughout the adult rat striatum (except white matter tracts). After strokes, SK3 was highly expressed in activated microglia/macrophages within the lesions, but reduced in other cells.
SK3 is expressed in microglia in both the healthy and damaged adult striatum, and mechanistic in vitro studies show it contributes to transformation of microglia to an activated neurotoxic phenotype. Thus, SK3 might be a therapeutic target for reducing inflammation-mediated acute CNS damage. Moreover, its roles in microglia must be considered when targeting this channel for CNS diseases, disorders and reducing neuron hyper-excitability.
... 9 The gene for spinocerebellar ataxia type 8 ( SCA8 ) maps to 13q21, and a case-control study reported increased occurrence of large triplet repeats in SCA8 associated with major psychosis. 10 The gene encoding Wolframin ( WFS1 ) maps to 4p16. 11 Mutation of WFS1 causes Wolfram syndrome, which frequently (approx. ...
Herein is reported the case of a male patient with schizophrenia who displayed a de novo balanced translocation between the short arm of chromosome 4 and the long arm of chromosome 13, t(4; 13)(p16.1; q21.31). The 4p16.1 region is where the causative gene (WFS1) for Wolfram syndrome has been mapped. In Wolfram syndrome, approximately 60% of patients suffer from major mental illness. The other breakpoint, chromosome 13q21.31, is another region where previous linkage studies have repeatedly detected linkage to schizophrenia. The documentation of the present case could therefore provide a valuable resource for identifying disease susceptibility genes by localizing the breakpoints.
Spinocerebellar ataxia type 8 (SCA8) is a progressive neurological disorder caused by the expanded repeat CTA/CTG of two overlapping genes, ATXN8OS and ATXN8, expressed bidirectionally. Normal alleles have 15-50 repeats, and pathogenic alleles range from 71 to 1300 repeats. The disorder is relatively rare, accounting for about 2%-5% of the autosomal dominant forms of hereditary ataxia worldwide. However, the prevalence of disease-causing ATXN8OS/ATXN8 expansions is higher than the disease because of the reduced penetrance of the expanded allele. The aim of this study was to describe the first fully penetrant SCA8 family showing mixed Brazilian African and Amerindian origin. Eight members of this family were evaluated-the mother and seven offspring-through a complete neurological examination conducted at the Neurogenetics Clinic, HCFMRP-USP in Brazil. The number of CTA/CTG repeats was obtained after polymerase chain reaction (PCR) and fragment analysis. The haplotype analysis was conducted using a microsatellite marker, D13S1296, and four single nucleotide polymorphisms (SNPs), rs1831189, rs8002227, rs11841483, and rs72284461, all spanning a 70.1 Mb region on chromosome 13q21.3. The molecular analysis showed that the expansions ranged from 104 to 109 CTA/CTG repeats in the six affected individuals and were absent in two asymptomatic daughters (aged 53 and 40 years). Three SNPs cosegregate with the expanded alleles, confirming the connection between expansion and disease in this family. As the SCA8 diagnosis demands careful interpretation, we suggest the use of linkage analysis to observe segregation of the mutation, making more accurate its genotyping.
This chapter provides an overview on phenotype, gene function, and diagnosis of spinocerebellar ataxia 8 (SCA8). Spinocerebellar ataxia type 8 (SCA8) patients have a slowly progressive, predominantly cerebellar disease involving dysarthria, limb and gait ataxia, impaired smooth pursuit, and nystagmus. A broad range of other clinical symptoms are also reported, including tremor, spasticity, and various kinds of cognitive impairment. Although this clinical picture is not clearly distinguishable from that of other forms of inherited ataxia, SCA8 is unique among this group of diseases in many ways. The inheritance pattern for SCA8 in particular is the most complicated of all of the inherited spinocerebellar ataxias. SCA8 is caused by a CTG expansion mutation that has been shown to vary widely in size between generations. The SCAB CTG repeat is transcribed as part of a natural, untranslated antisense RNA, but the precise molecular pathogenic mechanism through which this repeat expansion causes disease is currently unknown.
Autosomal-dominante Ataxien sind eine heterogene Gruppe von Erkrankungen, denen ein zerebelläres Syndrom gemeinsam ist. Neben motorischen Einschränkungen zeigen sich auch häufig kognitive Beeinträchtigungen und affektive Störungen. Exekutive Dysfunktion und Gedächtnisdefizite stehen dabei im Vordergrund. In dieser Arbeit wird ein Überblick über die bisher veröffentlichten Befunde zur Neuropsychologie bei verschiedenen spinozerebellären Ataxien und weiteren seltenen hereditären Ataxien gegeben. Die Notwendigkeit von neuropsychologischen Untersuchungen bei diesen Patientengruppen wird deutlich. Weitere Forschungen über den Verlauf der kognitiven Entwicklung und über den Zusammenhang mit klinischen Parametern (u. a. Krankheitsbeginn, Repeatlänge, Schweregrad der Erkrankung) sind notwendig, um in Zukunft Patienten entsprechend beraten zu können. Eine Empfehlung für neuropsychologische Tests zur Diagnostik wird genannt.
This chapter discusses the clinical and genetical aspects of spinocerebellar ataxias with emphasis on polyglutamine expansions. Autosomal dominant cerebellar ataxias (ADCAs), alternatively called spinocerebellar ataxias (SCAs), are a highly heterogeneous group of neurodegenerative disorders characterized by cerebellar ataxia variably associated with other neurological signs. Seven of these disorders are often referred to as polyglutamine diseases caused by translated CAG repeat expansions. Clinically, these disorders are characterized by a wide range of phenotypes depending on the responsible locus, the size of the expansion, and disease duration. These disorders manifest above a threshold of CAG repeats that varies according to the gene. When large and not interrupted, the CAG repeats are unstable upon transmission, mostly resulting in expansions particularly during paternal transmissions. This observation and the strong negative correlation between the size of the expansion and the age at onset account for the phenomenon of anticipation often observed in families. The relative frequency of the responsible genes varies according to geographical origin, and polyglutamine diseases account for 40–80% of ADCAs. Genetic diagnosis, now possible in several of these disorders, does not yet permit specific treatment but allows accurate genetic counseling and offers the possibility of presymptomatic and prenatal testing.
A 31-year-old man was referred to our hospital because of progressive tremor and clumsiness in his limbs and trunk. His symptoms were started in the right leg then gradually spread to all extremities as well as his trunk for 2 years. Neurological examinations revealed muscle rigidity with resting tremor predominantly right limbs. Akinesia and retropulsion were positive. Neither pyramidal tract sign nor cerebellar ataxia was detected. Genetic testing showed the expansion of SCA8 CTA/CTG repeats as 28/141 repeats. Though moderate expansion (less than 92) of SCA8 repeats has been reported in healthy subjects and patients with various diseases, the extraordinary long expansion of CTA/CTG repeats in SCA8 gene in our patient could be significantly pathological. 600 mg/day of L-DOPA clearly improved his symptoms. Dedicate follow up of the clinical course of our patient and the accumulation of the further cases is essential.
Psychosis has many causes. Psychiatrists typically receive a thorough training in its diagnosis, but the diagnosis of psychosis secondary to non-psychiatric conditions is often not emphasized. An understanding of the underlying cause is important so that effective management programs can be implemented. The Diagnosis of Psychosis bridges the gap between psychiatry and medicine, providing a comprehensive review of primary and secondary causes of psychosis. It covers both common and rare causes in a clinically focused guide. Useful for both teaching and reference, the text covers physical and mental state examination, describes key investigations, and summarises the non-psychiatric features of medical conditions causing psychosis. Particularly relevant for psychiatrists and trainees in psychiatry, this volume will also assist neurologists and general physicians who encounter psychosis in their practice.
Neuropsychiatry, like many other biomedical sciences, has been revolutionized by the advances in genomic technologies over the years. The advent of PCR (polymerase chain reaction) and the sequencing of the human genome have provided invaluable insights into the molecular genetics of the various psychiatric disorders through the study of candidate genes and linkage analyses. However, biological phenotype is dictated by protein expression, which has been shown to stray from the genetic blueprint designated by the genome. Consequently, the field of proteomics has recently emerged as a powerful means of exploring protein structure, function, and expression patterns. The ability to study disease at the gene and protein levels presents a tremendous opportunity for neuropsychiatric research, particularly in terms of the potential for developing therapeutic agents for novel protein targets.
Many diseases, most with a strong neurodegenerative component, are now known to result from an expansion of a trinucleotide repeat sequence within the genome. In many cases, the longer the repeat the earlier the onset, and the more rapid and severe is the disease progression. Almost all of these diseases may be divided into three groups. In the first group, the expansion is either in an untranslated region/intron of the gene (e.g., fragile X syndrome, myotonic dystrophy type 1 (MD1), Friedreich ataxia, or spinocerebellar ataxia type 12 (SCA12)), or is in a DNA stretch that does not code for a protein (spinocerebellar ataxia type 8 (SCA8)). In group 1, with the exception of SCA12, the repeat triplet is not CAG. Generally, the mutations in group 1 result in low or absent levels of the protein corresponding to the affected gene and/or altered message RNA metabolism. In the second group, caused by (CAG)n
expansions, the mutation is in an exon of the gene and each protein is expressed with an expanded polyglutamine (Qn
) domain. At least nine neurodegenerative diseases belong in this second group. The most common of these diseases is Huntington disease (HD). Others are dentatorubralpallidoluysian atrophy (DPLA; Haw River syndrome), spinobulbar muscular atrophy (SBMA; Kennedy disease) and seven forms of spinocerebellar ataxia [SCA1, SCA2, SCA3 (Machado–Joseph disease), SCA6, SCA7, and SCA17]. The mutated genes appear to be unrelated except for the fact that each possesses a (CAG)n
/Qn
expansion. These diseases are characterized by insoluble protein aggregates in the affected areas. The aggregates contain the mutated protein. The CAG-expansions are widely thought to confer a pathological gain of function to the mutated protein, although in some cases a pathological decrease of function may also contribute. In eight of the Qn
-expansion disorders, the disease phenotype occurs when n is greater than about 36. Disease expansions may result in n values up to about 80, but larger values may sometimes occur. In the third group, the nucleotide expansion is in a coding exon and gives rise to an elongation of a polyalanine (An
) stretch in the mutated expressed protein. At least nine diseases have been shown to be due to an An
expansion. Eight of the mutations are in transcription factors, and in one case the mutation is in the polyadenylate-binding protein. The disease phenotypes variably include mental retardation and malformations of the brain, genitourinary tract, skull, and digits. Both the normal size of the amino acid repeat and the pathological length of the repeat tend to be smaller in the An
-expansion diseases than in the Qn
-expansion diseases. Although many of the trinucleotide-expansion diseases are rare (some exceedingly rare), they offer insights into pathophysiological processes that may pertain to the more common neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson disease (PD).
Huntington's disease (HD) is an autosomal dominant disorder characterized by a triad of chorea, psychiatric disturbance and cognitive decline. Around 1% of patients with HD-like symptoms lack the causative HD expansion and are considered HD phenocopies. Genetic diseases that can present as HD phenocopies include HD-like syndromes such as HDL1, HDL2 and HDL4 (SCA17), some spinocerebellar ataxias (SCAs) and dentatorubral-pallidoluysian atrophy (DRPLA). In this study we screened a cohort of 21 Greek patients with HD phenocopy syndromes for mutations causing HDL2, SCA17, SCA1, SCA2, SCA3, SCA8, SCA12 and DRPLA. Fifteen patients (71%) had a positive family history. We identified one patient (4.8% of the total cohort) with an expansion of 81 combined CTA/CTG repeats at the SCA8 locus. This falls within what is believed to be the high-penetrance allele range. In addition to the classic HD triad, the patient had features of dystonia and oculomotor apraxia. There were no cases of HDL2, SCA17, SCA1, SCA2, SCA3, SCA12 or DRPLA. Given the controversy surrounding the SCA8 expansion, the present finding may be incidental. However, if pathogenic, it broadens the phenotype that may be associated with SCA8 expansions. The absence of any other mutations in our cohort is not surprising, given the low probability of reaching a genetic diagnosis in HD phenocopy patients.
Increasing evidence links genomic and epigenomic instability, including multiple fragile sites regions to neuropsychiatric diseases including schizophrenia and autism. Cancer is the only other disease associated with multiple fragile site regions, and genome and epigenomic instability is a characteristic of cancer. Research on cancer is far more advanced than research on neuropsychiatric disease; hence, insight into neuropsychiatric disease may be derived from cancer research results. Towards this end, this article will review the evidence linking schizophrenia and other neuropsychiatric diseases (especially autism) to genomic and epigenomic instability, and fragile sites. The results of studies on genetic, epigenetic and environmental components of schizophrenia and autism point to the importance of the folate-methionine-transulfuration metabolic hub that is diseases also perturbed in cancer. The idea that the folate-methionine-transulfuration hub is important in neuropsychiatric is exciting because this hub present novel targets for drug development, suggests some drugs used in cancer may be useful in neuropsychiatric disease, and raises the possibility that nutrition interventions may influence the severity, presentation, or dynamics of disease.
Spinocerebellar ataxia 8 (SCA8), a triplet repeat expansion disorder, is genetically distinct from the other inherited ataxias, but its unusually variable phenotype can make its diagnosis difficult. In this review we describe 3 new cases of genetically verified SCA8 to highlight the broad clinical spectrum of symptoms observed with this disorder and to draw attention to the features of myoclonus and migraine headaches, which in the context of cerebellar ataxia warrants the clinician to consider SCA8 as a potential diagnosis. We also address the controversy surrounding the genetic testing approach for diagnosing SCA8. Finally, we evaluate the evidence that SCA8 may affect calcium channel function and that the presentation of episodic ataxia and migraines suggests a clinical and pathogenic overlap of SCA8 with the channelopathies.
"Clinicians should be quick to evaluate unexpected cognitive or neurological symptoms that may be interpreted mistakenly as psychiatric in origin or as side effects ofneuroleptics and anticholinergic medications."
Until today, nineteen trinucleotide repeat expansions larger than forty repeat copies have been found in the human genome. Of these, the CAG/CTG repeat is predominant motif with twelve loci identified, ten of which have been associated with the development of neurodegenerative diseases. We have developed a cloning approach which isolates disease genes containing trinucleotide repeat expansions. The method is based on size separation of genomic fragments, followed by subcloning and library hybridization with an oligonucleotide probe. Fractions and clones containing expanded repeats are identified by the repeat expansion detection (RED) method throughout the cloning procedure. Large family materials are not required and as little as 10 microg genomic DNA from a single individual is sufficient for this method. Using this strategy we have cloned two DNA fragments containing expanded repeats from two unrelated patients with a clinical diagnosis of cerebellar ataxia. Sequencing of the two fragments showed sequence identities with two disease genes, the Huntington gene and the ataxin 3 gene, respectively. The method should be adaptable to the cloning of any long repeat motif in any species. Furthermore the experimental steps can be performed in less than a month, making it very effective and time efficient to disease gene identification.
Despite substantial evidence for heritability in affective disorders the contributing genes have proven elusive. Here we discuss the genetic epidemiology of depression, as well as methodological issues and results from molecular genetic studies. There has been rapid advances in genetics, genomics and statistical modelling, facilitating the search for molecular mechanisms underlying affective disorders and several strategies reviewed in this paper hold promise to provide progress in the field. Considering the poorly understood biological basis of vulnerability to affective disorders, the identification of genes involved in the pathophysiology will unravel mechanisms and pathways that could permit more personalized therapeutic strategies and result in new targets for pharmacological intervention.
It is now well established that non-Mendelian examples of DNA instability are associated with human disease. Most malignancies are associated with various chromosomal instabilities, such as aneuploidy, gene amplification, and chromosomal deletion. Furthermore, widespread microsatellite instability (MSI) is associated with a variety of tumors, and instability at specific dynamic repeat expansions underlies a family of neurologic disorders. Inactivation of DNA mismatch repair genes results in genomic instabilities affecting microsatellite regions. Mutations in genes involved in DNA polymerization or Okazaki fragment processing are also associated with MSI. Such instabilities convey a 'mutator' phenotype which is pathogenic. The mechanisms controlling trinucleotide repeat expansions are less well understood. Why this type of genomic instability is particularly pathogenic to neurons is also not clear. An understanding of what normally maintains stability is the first step towards preventing such loss of control and maintaining health.
Non-coding ribonucleic acids (RNAs) do not contain a peptide-encoding open reading frame and are therefore not translated into proteins. They are expressed in all phyla, and in eukaryotic cells they are found in the nucleus, cytoplasm, and mitochondria. Non-coding RNAs either can exert structural functions, as do transfer and ribosomal RNAs, or they can regulate gene expression. Non-coding RNAs with regulatory functions differ in size ranging from a few nucleotides to over 100 kb and have diverse cell- or development-specific functions. Some of the non-coding RNAs associate with human diseases. This chapter summarizes the current knowledge about regulatory non-coding RNAs.
Dominant autosomic ataxias include a group of neurodegenerative diseases characterized by the abnormal expansion of triplets.
Male aged 33, with expansion of the SCA 8 gene (100 repetitions), who presented a clinical picture compatible with a pancerebellar syndrome. The patient had been diagnosed 11 years earlier as suffering from previously of histiocytosis X. A clinico genetic study was conducted on the patient and several members of his family (parents and two sisters). Both sisters and the father were found to be carriers of the expansion (110 and 150 repetitions, respectively), and are currently asymptomatic. RESULTS and
There is no relation between the number of repetitions and the age of onset of the disease. The normal interval in our population oscillates between 16 37 repetitions, and the pathological interval has not been well determined. There may be a relation between the SCA 8 form and histiocytosis X.
Quantitative and molecular genetics have made important developments in the last three decades. There is increasing evidence of the role of heredity in the field of neuropsychiatric disorders in children. So far, only a few pathways between genes and behaviour have been unravelled.
Quantitative genetics puts polygenic inheritance models forward. Molecular genetic research based on these models seems promising, but until now has provided only a limited explanation for the variance in the studied neuropsychiatric disorders. In these models the complexity of the expression of a single gene grows exponentially with the number of genes involved. Consequently, research on the gene-phenotype relationships and phenotypical variability in such models is extremely complex.
The candidate gene approach, in which the gene-phenotype pathway of a single gene is studied, is more manageable, and in our opinion essential in understanding multiple gene models. We discuss recent findings in the field and their relevance for neuropsychiatric phenotypes. Single gene defects will only explain a part of the range of neuropsychiatric disorders in children, but the evidence that this approach can generate may help to clarify neuropsychiatric phenotypes. The discovery of single gene disorders in subgroups of subjects with a neuropsychiatric phenotype may result in new perspectives for their treatment.
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.
Autosomal dominant cerebellar ataxias (ADCA) constitute a group of disorders, clinically and molecularly heterogeneous. They are characterized by variable degrees of cerebellar and brainstem degeneration or dysfunction. Neuronal loss variably affects the pons, the inferior olive, the basal ganglia, the cerebellum and its afferent and efferent fibers. Onset is generally during the third or fourth decade but can also occur in childhood or in the old age. Patients usually present with progressive cerebellar ataxia and associated neurological signs, such as ophthalmoplegia, pyramidal or extrapyramidal signs, deep sensory loss and dementia. Attempts to classify subtypes of ADCA were largely unsatisfactory until AE Harding distinguished three phenotypes based on clinical associated signs.1 ADCA type I is the most common subtype and variably combines cerebellar ataxia, dysarthria, ophthalmoplegia, pyramidal and extrapyramidal signs, deep sensory loss, amyotrophy and dementia. However, several other signs and symptoms may also be associated, i.e., slow eye movements, sphincter disturbances, axonal neuropathy, fasciculation and/ or swallowing difficulties. ADCA type II was first described by Froment et al2 and is characterized by the association of progressive macular degeneration with cerebellar ataxia. Finally, ADCA type III denotes a “pure”, generally late onset, cerebellar syndrome.
Drug induced aseptic meningitis has been reported in response to various agents, in particular non-steroidal anti-inflammatory drugs, intravenous immunoglobulins, anti-CD3 monoclonal antibody (OKT3), and antibiotics.1 Hypersensitivity reactions (especially type 1 and type 3) have been invoked as the cause by many investigators.1 This hypothesis is supported by the detection of immune complexes in the serum or cerebrospinal fluid (CSF) of some patients.1
To our knowledge, only two cases of aseptic meningitis induced by amoxicillin with or without clavulanic acid have been reported.2,3 We report a third case of probable amoxicillin induced aseptic meningitis where we performed laboratory studies …
The frequent co-occurrence of degenerative cerebellar pathology and schizophrenia, as well as the recently reported increased association rate between autosomal dominant ataxias and major psychosis, strongly suggests the involvement of the cerebellum in the pathophysiology of schizophrenia.1–3 The analysis of associations between psychosis and neurodegenerative diseases may improve our understanding of the pathophysiology of schizophrenia and facilitate the search for susceptibility genes for this disorder.4
To our best knowledge, there have been no previous reports about an association between schizophrenia and the periodic autosomal dominant ataxias, such as episodic ataxia type 1 and type 2 (EA1 and EA2). We present a case of a young man who has been diagnosed with paranoid schizophrenia (ICD-10: F20.0) and episodic ataxia type 2.
The patient, a man aged 27 years, was first admitted to our hospital with psychotic symptoms in June 1995. He presented with paranoid delusions and delusions of reference, acoustic hallucinations (commenting voices), formal thought disorder, and behaviour disorganisation, as well as negative symptoms such as blunted affect, poor rapport, and lack of spontaneity. At this time, he was diagnosed as having paranoid schizophrenia (ICD-10: F20.0) and showed a PANSS (positive and negative symptom scale) total score of 137 (fig …
All the different seven serotypes of BTXs have in common the mechanism of action (block of the neuroexocytosis machinery inside the end plate, responsible for the release of acetylcholine into the neuromuscular junction), acting on different targets. The two commercially available serotypes, botulinum toxin type A and botulinum toxin type B (abbreviated BTX-A and BTX-B, respectively) are reported to act as zinc dependent endopeptidases on different intraneuronal target proteins. The clinical value of BTX-A has been recognised for a long time and is widely demonstrated by hundreds of clinical reports. More recently a clinical usefulness of BTX-B has been investigated. Two controlled clinical trials have demonstrated that local intramuscular injections of BTX-B are effective in the treatment of cervical dystonia in patients with BTX-A responsive disease, 2 as well as in patients with BTX-A resistant disease (secondary non-responders). 3 BTX-B was found to be effective in both studies, with a significant improvement observed in all the parameters investigated (severity, disability, and pain); action was found to last as long as 16 weeks. 23
Amyotrophic lateral sclerosis (ALS) is characterised by progressive degeneration of upper and lower motor neurones. Clinical symptoms involve weakness, dysphagia, dysarthria, muscle atrophy and fasciculations, hyperreflexia, spasticity, Babinski signs, and clonus. Here we report on two patients with sporadic ALS in whom the disease initially presented with a persistent bitter “metallic” taste.
Patient 1 was a previously healthy 60 year old women. Six months before admission, she noticed a persistent bitter taste, dysarthria, and emotional liability. Several weeks later she noticed a progressive weakness in both legs which spread to both arms within four months. At the time of admission, she had bilateral bulbar weakness, episodes of pathological crying, generalised spasticity, muscle atrophy, weakness, and fasciculations. The plantar reflex was extensor on the left side. The remaining neurological examination was unremarkable.
Patient 2 was a previously healthy 64 year old women. At the time of admission, she reported a four month history of a persistent bitter “metallic” taste confined to the posterior tongue, …
The goal of these experiments was to understand DNA changes relevant to schizophrenia. This work compared DNA of monozygotic (MZ) twins surrounding (CAG)(n) repeating sequences, and characterized the relationship between fragile sites and schizophrenia. Twelve twin-pairs, previously classified as MZ and 18 unrelated sib-pairs, from seven families were studied. Eight twin-pairs were affected by schizophrenia, four concordantly and four discordantly. DNA comparisons were made using profiles of electrophoretic size fractionations of PCR amplified (CAG)(n) containing genomic fragments. These profiles were generated by a new method, developed by us, called targeted genomic differential display (TGDD). Surprisingly, the number of peak profile differences in MZ twin-pairs discordant for schizophrenia was greater than the concordantly ill twins and the well twins and, in some cases, overlapped the range of sib-pairs. These results might mean that some twins were not MZ but it was not possible to definitively test these samples for zygosity. Alternatively, the results might be explained as an increased mutation rate (or genomic instability) around (CAG)(n) sites in individuals afflicted with schizophrenia. Also, we uncovered an association of schizophrenia (i.e., a linkage of chromosomal abnormalities and gene localizations) with fragile sites spread throughout the genome (chi(2), P = 0.001). Furthermore, it appears that an increasing number of genes linked to schizophrenia are associated with (CAG)(n) sequences. Fragile sites and (CAG)(n) repeat sequences are known to be unstable. We speculate the association of genomic instability with schizophrenia accounts for seemingly disparate biological and environmental factors that influence disease occurrence.
We recently noted a profound decline in brain sulfatides (ST) in subjects who died with incipient dementia due to Alzheimer's disease. Herein, we measured ST levels in cerebrospinal fluid in cognitively normal elderly and in subjects with mild cognitive impairment due to incipient demenia of the Alzheimer type. There was a significant decrease in cerebrospinal fluid ST and in the ST to phosphatidylinositol ratio in MCI subjects. The ST to phosphatidylinositol ratio accurately differentiated very mildly impaired subjects from controls on an individual basis. The cerebrospinal fluid ST to phosphatidylinositol ratio may be a very useful biomarker for the earliest clinical stage of Alzheimer's disease.
To evaluate the significance of expanded CTG repeats at the SCA8 locus, we analyzed the allele distribution in 1,262 German ataxia patients. We found intermediate and expanded CTG repeats with similar frequencies in ataxia patients with and without established genetic diseases. One family linked to the SCA8 locus showed incomplete penetrance and an association of smaller CTG repeats with more severe disease. Our data question the disease-causing character of CTG expansions for SCA8 and advise great caution in genetic testing.
We previously reported that a transcribed but untranslated CTG expansion causes a novel form of ataxia, spinocerebellar ataxia type 8 (SCA8) (Koob et al., 1999). SCA8 was the first example of a dominant spinocerebellar ataxia that is not caused by the expansion of a CAG repeat translated into a polyglutamine tract. This slowly progressive form of ataxia is characterized by dramatic repeat instability and a high degree of reduced penetrance. The clinical and genetic features of the disease are discussed below.
Anticipation is the phenomenon whereby a disease becomes more severe and/or presents with earlier onset as it is transmitted down through generations of a family. The only known mechanism for true anticipation is a class of mutations containing repetitive sequences exemplified by the pathogenic trinucleotide repeat. Studies of bipolar disorder (BPD) are consistent with the presence of anticipation and, by inference, the possibility that trinucleotide repeats contribute to this disorder, although it is possible that these data are the result of methodological problems. On the assumption that anticipation in BPD may be real, several surveys of the genome of BPD probands for large trinucleotide repeats have been conducted, as have studies of many repeat-containing candidate genes. No pathogenic triplet repeat has yet been unambiguously implicated.
The possible presence of anticipation in bipolar affective disorder and schizophrenia has led to the hypothesis that repeat expansion mutations could contribute to the genetic etiology of these diseases. Using the repeat expansion detection (RED) assay, we have systematically examined genomic DNA from 100 unrelated probands with schizophrenia and 68 unrelated probands with bipolar affective disorder for the presence of CAG/CTG repeat expansions. Our results show that 28% of the probands with schizophrenia and 30% of probands with bipolar disorder have a CAG/CTG repeat in the expanded range, but that each expansion could be explained by one of three nonpathogenic repeat expansions known to exist in the general population. We conclude that novel CAG/CTG repeat expansions are not a common genetic risk factor for bipolar disorder or schizophrenia.
DNA tests in normal subjects and patients with ataxia and Parkinson's disease (PD) were carried out to assess the frequency of spinocerebellar ataxia (SCA) and to document the distribution of SCA mutations underlying ethnic Chinese in Taiwan. MJD/SCA3 (46%) was the most common autosomal dominant SCA in the Taiwanese cohort, followed by SCA6 (18%) and SCA1 (3%). No expansions of SCA types 2, 10, 12, or dentatorubropallidoluysian atrophy (DRPLA) were detected. The clinical phenotypes of these affected SCA patients were very heterogeneous. All of them showed clinical symptoms of cerebellar ataxia, with or without other associated features. The frequencies of large normal alleles are closely associated with the prevalence of SCA1, SCA2, MJD/SCA3, SCA6, and DRPLA among Taiwanese, Japanese, and Caucasians. Interestingly, abnormal expansions of SCA8 and SCA17 genes were detected in patients with PD. The clinical presentation for these patients is typical of idiopathic PD with the following characteristics: late onset of disease, resting tremor in the limbs, rigidity, bradykinesia, and a good response to levodopa. This study appears to be the first report describing the PD phenotype in association with an expanded allele in the TATA-binding protein gene and suggests that SCA8 may also be a cause of typical PD.
To establish whether the DNA expansion linked to spinocerebellar ataxia type 8 (SCA 8) is associated with ataxia in Scotland; to clarify the range of associated clinical phenotypes; and to compare the findings with previous reports.
DNA was screened from 1190 anonymised controls, 137 subjects who had tested negative for Huntington's disease, 176 with schizophrenia, and 173 with undiagnosed ataxia. Five unrelated ataxic patients with the SCA 8 expansion and a sixth identified subsequently had clinical and psychometric assessment; the clinical features were available in a seventh. A systematic search for other reports of SCA 8 was undertaken.
Over 98% of SCA 8 CTA/CTG repeat lengths fell between 14 and 40. Repeat lengths over 91 were observed in three healthy controls (0.12%), two patients with suspected Huntington's disease (0.73%), and six ataxic subjects (1.74%; p<0.0005 v healthy controls). Repeat lengths over 100 occurred in five ataxic subjects but in only one control. All seven symptomatic subjects with the SCA 8 expansion had a cerebellar syndrome; four had upper motor neurone signs; and 5/6 assessed had cognitive complaints. There was personality change in two and mood disturbance in three. In published reports, SCA 8 repeat lengths over 91 occurred in approximately 0.5% of the healthy population but were over-represented among ataxic patients (3.4%; p<0.0001). The predominant clinical phenotype was cerebellar, with pyramidal signs in 50%, and neuropsychiatric features in some cases.
SCA 8 expansion is a risk factor for a cerebellar syndrome, often associated with upper motor neurone and neuropsychiatric features. The expansion occurs unexpectedly often in the general population.
The gene expression profiles of human postmortem parietal and prefrontal cortex samples of normal controls and patients with bipolar disease, or human neuroblastoma flat (NBFL) cells treated with the mood-stabilizing drug, valproate, were used to compare the performance of Affymetrix oligonucleotide U133A GeneChips and Agilent Human 1 cDNA microarrays. Among those genes represented on both platforms, the oligo array identified 26-53% more differentially expressed genes compared to the cDNA array in the three experiments, when identical fold change and t-test criteria were applied. The increased sensitivity was primarily the result of more robust fold changes measured by the oligonucleotide system. Essentially all gene changes overlapping between the two platforms were co-directional, and ranged from 4 to 19% depending upon the amount of biological variability within and between the comparison groups. Q-PCR validation rates were virtually identical for the two platforms, with 23-24% validation in the prefrontal cortex experiment, and 56% for both platforms in the cell culture experiment. Validated genes included dopa decarboxylase, dopamine beta-hydroxylase, and dihydropyrimidinase-related protein 3, which were decreased in NBFL cells exposed to valproate, and spinocerebellar ataxia 7, which was increased in bipolar disease. The modest overlap but similar validation rates show that each microarray system identifies a unique set of differentially expressed genes, and thus the greatest information is obtained from the use of both platforms.
Spinocerebellar ataxia type 8 (SCA8) is caused by the expansion of CTA/CTG triplet repeats on 13q21. Cases can be familial or sporadic. The clinical findings include cerebellar ataxia with upper motor neuron dysfunction, dysphagia, peripheral sensory disturbances, or cognitive and psychiatric impairments, indicating phenotypic variability in SCA8. We report on a patient with rapidly progressive parkinsonism-plus syndrome resembling corticobasal degeneration and triplet expansions in the SCA8 locus. The relationship between clinical phenotype and triplet expansions in the SCA8 locus requires further study.
A recent study has suggested that a polymorphism in the hKCa3 potassium channel may be associated with raised susceptibility to schizophrenia. Despite its modest statistical significance, the study is intriguing for two reasons. First, hKCa3 contains a polymorphic CAG repeat in its coding sequence, with large repeats more common in schizophrenics compared with controls. This is interesting in view of several repeat expansion detection (RED) studies that have reported an excess of large CAG repeats in psychotic probands. Second, the hKCa3 gene is a functional candidate gene because studies of antipsychotic and psychotogenic compounds suggest that glutamatergic systems modulated by SKCa channels may be important in schizophrenia pathogenesis. In the light of the above, we have tested the hypothesis of an association between schizophrenia and the hKCa3 CAG repeat polymorphism using a case control study design. Under the same model of analysis as the earlier study, schizophrenic probands had a higher frequency of alleles with greater than 19 repeats than controls (chi 2 = 2.820, P = 0.047, 1-tail). Our data therefore provide modest support for the hypothesis that polymorphism in the hKCa3 gene may contribute to susceptibility to schizophrenia.
An association between bipolar affective disorder and CAG/CTG trinucleotide repeat expansions (TRE) has previously been detected using the repeat expansion detection (RED) method. Here we report that 89% of RED products (CAG/CTG repeats) > 120 nt (n = 202) detected in affective disorder patients as well as unaffected family members and controls correlate with expansions at two repeat loci, ERDA1 on chromosome 17q21.3 and CTG18.1 on 18q21.1. In a set of patients and controls in which we had previously found a significant difference in RED size distribution, the frequency of expansions at the CTG18.1 locus was 13% in bipolar patients (n = 60) and 5% in controls (n = 114) (P < 0.07) with a significantly different size distribution (P < 0.03). A second set of patients were ascertained from 14 affective disorder families showing anticipation. Twelve of the families had members with RED products > 120 nt. The RED product distribution was significantly different (P < 0.0007) between affected (n = 53) and unaffected (n = 123) offspring. Using PCR, a higher frequency (P < 0.04) of CTG18.1 expansions as well as a different (P < 0.02) repeat size distribution was seen between affected and unaffected offspring. In addition, a negative correlation between RED product size and the age-of-onset could be seen in affected offspring (rs = -0.3, P = 0.05, n = 43). This effect was due to an earlier onset in individuals with long CTG18.1 expansions. No difference in ERDA1 expansion frequency was seen either between bipolar patients (35%, n = 60) and matched controls (29%, n = 114), or between affected and unaffected offspring in the families. We conclude that expanded alleles at the CTG18.1 locus confers an odds ratio of 2.6-2.8 and may thus act as a vulnerability factor for affective disorder, while the ERDA1 locus seems unrelated to disease.
A balanced (1;11)(q42.1;q14.3) translocation segregates with schizophrenia and related psychiatric disorders in a large Scottish family (maximum LOD = 6.0). We hypothesize that the translocation is the causative event and that it directly disrupts gene function. We previously reported a dearth of genes in the breakpoint region of chromosome 11 and it is therefore unlikely that the expression of any genes on this chromosome has been affected by the translocation. By contrast, the corresponding region on chromosome 1 is gene dense and, not one, but two novel genes are directly disrupted by the translocation. These genes have been provisionally named Disrupted-In-Schizophrenia 1 and 2 ( DISC1 and DISC2 ). DISC1 encodes a large protein with no significant sequence homology to other known proteins. It is predicted to consist of a globular N-terminal domain(s) and helical C-terminal domain which has the potential to form a coiled-coil by interaction with another, as yet, unidentified protein(s). Similar structures are thought to be present in a variety of unrelated proteins that are known to function in the nervous system. The putative structure of the protein encoded by DISC1 is therefore compatible with a role in the nervous system. DISC2 apparently specifies a non-coding RNA molecule that is antisense to DISC1, an arrangement that has been observed at other loci where it is thought that the antisense RNA is involved in regulating expression of the sense gene. Altogether, these observations indicate that DISC1 and DISC2 should be considered formal candidate genes for susceptibility to psychiatric illness.
Larger CAG/CTG trinucleotide-repeat tracts in individuals affected with schizophrenia (SCZ) and bipolar affective disorder (BPAD) in comparison with control individuals have previously been reported, implying a possible etiological role for trinucleotide repeats in these diseases. Two unstable CAG/CTG repeats, SEF2-1B and ERDA1, have recently been cloned, and studies indicate that the majority of individuals with large repeats as detected by repeat-expansion detection (RED) have large repeat alleles at these loci. These repeats do not show association of large alleles with either BPAD or SCZ. Using RED, we have identified a BPAD individual with a very large CAG/CTG repeat that is not due to expansion at SEF2-1B or ERDA1. From this individual’s DNA, we have cloned a highly polymorphic trinucleotide repeat consisting of (CTA)n (CTG)n, which is very long (∼1,800 bp) in this patient. The repeat region localizes to chromosome 13q21, within 1.2 cM of fragile site FRA13C. Repeat alleles in our sample were unstable in 13 (5.6%) of 231 meioses. Large alleles (>100 repeats) were observed in 14 (1.25%) of 1,120 patients with psychosis, borderline personality disorder, or juvenile-onset depression and in 5 (.7%) of 710 healthy controls. Very large alleles were also detected for Centre d’Etude Polymorphisme Humaine (CEPH) reference family 1334. This triplet expansion has recently been reported to be the cause of spinocerebellar ataxia type 8 (SCA8); however, none of our large alleles above the disease threshold occurred in individuals either affected by SCA or with known family history of SCA. The high frequency of large alleles at this locus is inconsistent with the much rarer occurrence of SCA8. Thus, it seems unlikely that expansion alone causes SCA8; other genetic mechanisms may be necessary to explain SCA8 etiology.
Expansion of trinucleotide repeats can give rise to genetic disease. We have developed a technique, repeat expansion detection (RED), that can identify potentially pathological repeat expansion without prior knowledge of chromosomal location. Human genomic DNA is used as a template for a two-step cycling process that generates oligonucleotide multimers when expanded trinucleotide sequences are present at the level found in myotonic dystrophy and fragile-X patients. We have identified at least one new locus exhibiting trinucleotide expansion. Analysis of three families transmitting a long CTG repeat shows that the allele in these families corresponds to a locus on chromosome 18. RED constitutes a powerful tool to identify other diseases caused by this mechanism, particularly diseases associated with anticipation.
Myotonic dystrophy (DM) is the only disease reported to be caused by a CTG expansion. We now report that a non-coding CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). This expansion, located on chromosome 13q21, was isolated directly from the genomic DNA of an ataxia patient by RAPID cloning. SCA8 patients have expansions similar in size (107-127 CTG repeats) to those found among adult-onset DM patients. SCA8 is the first example of a dominant SCA not caused by a CAG expansion translated as a polyglutamine tract.
New hopes for cloning susceptibility genes for schizophrenia and bipolar affective disorder followed the discovery of a novel type of DNA mutation, namely unstable DNA. One class of unstable DNA, trinucleotide repeat expansion, is the causal mutation in myotonic dystrophy, fragile X mental retardation, Huntington disease and a number of other rare Mendelian neurological disorders. This finding has led researchers in psychiatric genetics to search for unstable DNA sites as susceptibility factors for schizophrenia and bipolar affective disorder. Increased severity and decreased age at onset of disease in successive generations, known as genetic anticipation, was reported for undifferentiated psychiatric diseases and for myotonic dystrophy early in the twentieth century, but was initially dismissed as the consequence of ascertainment bias. Because unstable DNA was demonstrated to be a molecular substrate for genetic anticipation in the majority of trinucleotide repeat diseases including myotonic dystrophy, many recent studies looking for genetic anticipation have been performed for schizophrenia and bipolar affective disorder with surprisingly consistent positive results. These studies are reviewed, with particular emphasis placed on relevant sampling and statistical considerations, and concerns are raised regarding the interpretation of such studies. In parallel, molecular genetic investigations looking for evidence of trinucleotide repeat expansion in both schizophrenia and bipolar disorder are reviewed. Initial studies of genome-wide trinucleotide repeats using the repeat expansion detection technique suggested possible association of large CAG/CTG repeat tracts with schizophrenia and bipolar affective disorder. More recently, three loci have been identified that contain large, unstable CAG/CTG repeats that occur frequently in the population and seem to account for the majority of large products identified using the repeat expansion detection method. These repeats localize to an intron in transcription factor gene SEF2-1B at 18q21, a site named ERDA1 on 17q21 with no associated coding region, and the 3' end of a gene on 13q21, SCA8, that is believed to be responsible for a form of spinocerebellar ataxia. At present no strong evidence exists that large repeat alleles at either SEF2-1B or ERDA1 are involved in the etiology of schizophrenia or bipolar disorder. Preliminary evidence suggests that large repeat alleles at SCA8 that are non-penetrant for ataxia may be a susceptibility factor for major psychosis. A fourth, but much more infrequently unstable CAG/CTG repeat has been identified within the 5' untranslated region of the gene, MAB21L1, on 13q13. A fifth CAG/CTG repeat locus has been identified within the coding region of an ion transporter, KCNN3 (hSKCa3), on 1q21. Although neither large alleles nor instability have been observed at KCNN3, this repeat locus has been extensively analyzed in association and family studies of major psychosis, with conflicting findings. Studies of polyglutamine containing genes in major psychosis have also shown some intriguing results. These findings, reviewed here, suggest that, although a major role for unstable trinucleotides in psychosis is unlikely, involvement at a more modest level in a minority of cases cannot be excluded, and warrants further investigation.
Spinocerebellar ataxia type 8 (SCA8) is a neurodegenerative disorder caused by the expansion of a CTG trinucleotide repeat that is transcribed as part of an untranslated RNA. As a step towards understanding the molecular pathology of SCA8, we have defined the genomic organization of the SCA8 RNA transcripts and assembled a 166 kb segment of genomic sequence containing the repeat. The most striking feature of the SCA8 transcripts is that the most 5' exon is transcribed through the first exon of another gene that is transcribed in the opposite orientation. This gene arrangement suggests that the SCA8 transcript is an endogenous antisense RNA that overlaps the transcription and translation start sites as well as the first splice donor sequence of the sense gene. The sense transcript encodes a 748 amino acid protein with a predicted domain structure typical of a family of actin-organizing proteins related to the Drosophila Kelch gene, and so has been given the name Kelch-like 1 (KLHL1). We have identified the full-length cDNA sequence for both the human and mouse KLHLI genes, and have elucidated the general genomic organization of the human gene. The predicted open reading frame and promoter region are highly conserved, and both genes are primarily expressed in specific brain tissues, including the cerebellum, the tissue most affected by SCA8. Transfection studies with epitope-tagged KLHL1 demonstrate that the protein localizes to the cytoplasm, suggesting that it may play a role in organizing the actin cytoskeleton of the brain cells in which it is expressed.
We have studied 24 families with multiple affected members with bipolar disorder to test the hypothesis that in those families clinically showing genetic anticipation [Macedo et al., 1999] we would find large repeat expansions. The families meeting inclusion criteria had a minimum of two affected members over two generations and showed marked anticipation both in terms of age of onset and disease severity. We used the repeat expansion detection (RED) method to test patients (n = 24) and controls from these families and unrelated controls (n = 53). We also genotyped patients and family members from two families with large expansions at the known expansion loci on chromosomes 13, 17, and 18. The RED method revealed a higher number of large expansions in patients compared with controls (t-test; P < 0.0055: Mann-Whitney U; P = 0.02). The patients with the largest expansions were typed at the specific loci on chromosomes 13, 17, and 18 and the chromosome 18 expansion locus segregated with disease in one family, and a second family showed segregation with the expansion located at the SCA8 locus on chromosome 13. Genetic anticipation had been analyzed in this cohort of families, with correction for potential ascertainment bias, possible proband effects, cohort effects, regression to the mean, gender effects, and maternal vs. paternal transmission. None of these potential confounds appeared to account for the observed anticipation. We also identified that the presence of large expansions in affected family members derives primarily from two families from the genetically isolated Azores population. One family shows segregation with the chromosome 18 locus, whereas the other family segregates with expansions at the SCA8 locus. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:854-857, 2000.
Are (CTG)n expansions at the SCA8 locus rare polymorphisms Un-stable DNA in major psychosis: cloning of a new unstable trinucleotide repeat region on chromosome 13 An unstable trinucleotide repeat region on chromosome 13 im-plicated in spinocerebellar ataxia: a common expansion locus
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Unstable DNA in major psychosis: cloning of a new unstable trinucleotide repeat region on chromosome 13
- Vincent JB
- Parikh SV
- Petronis A
- Meltzer HY
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Unstable DNA in major psychosis: cloning of a new unstable trinucleotide repeat region on chromosome 13
- J B Vincent
- S V Parikh
- A Petronis
- H Y Meltzer
- J L Kennedy
Vincent JB, Parikh SV, Petronis A Meltzer HY, Kennedy JL. 1998. Unstable DNA in major psychosis: cloning of a new unstable trinucleotide
repeat region on chromosome 13. Am J Hum Genet 63:A344.