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PubMed1996

Frequency analysis of large CAG/CTG trinucleotide repeats in schizophrenia and bipolar affective disorder.

Much interest has recently been focussed on the possibility of the involvement of unstable DNA in the etiology of schizophrenia and bipolar affective disorder (BPAD), following several publications that report increases in frequency of large CAG/CTG repeats in affected individuals. Using the Repeat Expansion Detection (RED) technique, we have performed a matched control pair analysis for both disorders. No significant differences in CAG/CTG repeat sizes were observed for 52 bipolar affecteds and matched controls (P = 0.15), and borderline significance was observed for 54 schizophrenia affecteds and matched controls (P = 0.05), using a (CTG)10 oligonucleotide (one-tailed t-tests for paired samples). Furthermore, using a (CTG)17 oligonucleotide, no significant differences were observed for 58 bipolar affecteds and 55 schizophrenia affecteds compared to 81 unmatched controls. No significant sex effect was observed for either group, and no significant differences in repeat size were found for responders and non-responders to drug treatments. More importantly, there was no significant correlation (either positive or negative) between age of onset of disease and size of repeat. We thus cannot conclude that CAG/CTG trinucleotides are involved in psychotic disorders and that either the differences observed in similar studies may be the result of population stratification, or that the increased frequency of larger repeats amongst affected individuals is a much smaller effect than previously thought.

Adult↗
PubMed2005

Real-time PCR analysis of trinucleotide repeat allele expansions in the androgen receptor gene.

INTRODUCTION: The expansion of specific trinucleotide repeats results in certain genetic disorders. METHOD: Real-time PCR analysis was used to rapidly discriminate between normal and expanded (CAG)(n) alleles in the androgen receptor gene. RESULT: The difference in melting temperature (T(m)) between the most common normal and expanded alleles was approximately 1 degrees C. CONCLUSION: Real-time PCR analysis seems to be a highly reliable and rapid method, which may facilitate the first molecular approach to human trinucleotide repeat disorders.

Alleles↗
PubMed1998

Two commonly expanded CAG/CTG repeat loci: involvement in affective disorders?

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.

Bipolar Disorder↗
PubMed1998

Genes involved in hereditary ataxias.

The hereditary ataxias are a group of inherited neurodegenerative disorders characterized by progressive ataxia that results from degeneration of the cerebellum and its afferent and efferent connections. Recent molecular research has led not only to the discovery of a number of causative mutations, but also shed light on the likely mechanisms by which these mutations cause the respective phenotypes. In Friedreich's ataxia (FRDA), the most common type of autosomal recessive ataxia, the loss of a mitochondrial protein, frataxin, results in overload of mitochondrial iron and oxidative stress. The autosomal dominant ataxias, spinocerebellar ataxia type I (SCAI), SCA2, SCA3 and SCA7, are caused by inheritance of an unstable, expanded CAG trinucleotide repeat. These disorders are assumed to be due to a novel deleterious function of the extended polyglutamine sequences within the proteins encoded by the respective genes. Recent observations in transgenic mice and in human post-mortem tissue suggest that the extended proteins are transported into the nucleus of neurons where they form intranuclear inclusions that disrupt normal nuclear function. In another group of dominant disorders, episodic ataxia type I and type 2 (EA-I, EA-2) and SCA6, the mutations affect genes that code for ion channels.

Animals↗
PubMed2004

Cognitive impairments in Machado-Joseph disease.

BACKGROUND: Cognitive function of Machado-Joseph disease (MJD) patients has not been clarified. OBJECTIVES: To determine the characteristics of cognitive dysfunction in MJD patients and to assess the relationship of dysfunction to age at onset, age at examination, disease duration, education, ataxia, depression, anxiety, and CAG repeat length. DESIGN: Case-control study. SETTING: Research-oriented hospitals. PARTICIPANTS: Sixteen genetically confirmed MJD patients able to complete neuropsychological tests and 20 control subjects matched to patients by age and education. MAIN OUTCOME MEASURES: Neuropsychological tests, including general cognition, verbal and visual memory, working memory, visuospatial and constructional ability, language, executive function, depression, and anxiety. RESULTS: Machado-Joseph disease patients scored significantly lower than controls in verbal and visual memory, in visuospatial and constructional tasks, and in phonemic and semantic fluency tasks. None of these impairments correlated with CAG repeat length, age at onset, age at examination, disease duration, or education. Verbal fluency (words named in a category) correlated with the International Cooperative Ataxia Rating Scale score. CONCLUSION: Machado-Joseph disease patients have verbal and visual memory deficits, visuospatial and constructional dysfunction, and verbal fluency deficits, all unrelated to CAG repeat length.

Adult↗
PubMed2002

Early development and unstable genes in schizophrenia: preliminary results.

BACKGROUND: Trinucleotide repeats have been associated with schizophrenia, but the evidence, based on cross-sectional clinical information, is equivocal. AIMS: To examine the relationship between genomic CAG/CTG repeat size and premorbid development in schizophrenia. METHOD: Early development and premorbid functioning of 22 patients with DSM-IV diagnosis of schizophrenia were assessed by parental interviews. Repeat expansion detection (RED) technique was used to measure genomic CAG/CTG repeat size, and PCR for CAG repeat size at the ERDA-1 and CTG 18.1 loci. RESULTS: There was an inverse association between CAG/CTG size and perinatal complications. Patients with speech and motor developmental delay had larger repeats. The results were not due to expansion in the ERDA-1 and CTG 18.1 genes. CONCLUSIONS: CAG/CTG repeat expansion is associated with speech and motor developmental delay in schizophrenia. We propose that the developmental model may be useful for research into the genetics of schizophrenia.

Adult↗
PubMedDate not supplied

Evaluation of psychological symptoms among presymptomatic HD gene carriers as measured by selected MMPI scales.

Individuals at-risk for Huntington disease (HD), both HD gene carriers and nongene carriers, were recruited to determine whether psychological changes are detectable among clinically presymptomatic individuals who carry the HD allele. Each participant underwent genotyping to determine HD gene carrier status and a clinical assessment that included a quantified neurological examination and an abbreviated Minnesota Multiphasic Personality Inventory (MMPI): the Hypochondriasis, Depression, Psychasthenia, Neuroticism, Cynical Hostility, and Irritability Scales and the Harris Subscales of Depression. The results of the MMPI were evaluated for differences between nongene carriers (NGC) (n = 363), presymptomatic gene carriers (PSGC) (n = 149), and those with manifest HD (MHD) (n = 26). The overall multiple analysis of variance was not significant, indicating that there was no overall difference among the three groups. However, when subscales of the MMPI were examined individually, participants with manifest HD scored higher on the Psychasthenia scale (MHD vs. PSGC, P = 0.005; MHD vs. NGC, P = 0.03) and the Harris Depression subscale, Brooding (MHD vs. PSGC, P=0.0005; MHD vs. NGC, P = 0.003). No significant correlation was found between the number of trinucleotide repeats on the disease-producing allele and any of the MMPI scales for the gene carriers, MHD or PSGC. These results verify the presence of psychological symptoms in the early phases of MHD but not in PSGC. Thus, further study of the behavioral and mood symptoms thought to accompany HD using measures designed specifically to detect depressive symptoms and changes in behavior specific to HD is warranted to delineate the timing of onset of the psychological symptoms.

Adult↗
PubMed1996

Analysis of thirteen trinucleotide repeat loci as candidate genes for schizophrenia and bipolar affective disorder.

A group of diseases are due to abnormal expansions of trinucleotide repeats. These diseases all affect the nervous system. In addition, they manifest the phenomenon of anticipation, in which the disease tends to present at an earlier age or with greater severity in successive generations. Many additional genes with trinucleotide repeats are believed to be expressed in the human brain. As anticipation has been reported in schizophrenia and bipolar affective disorder, we have examined allele distributions of 13 trinucleotide repeat-containing genes, many novel and all expressed in the brain, in genomic DNA from schizophrenic (n = 20-97) and bipolar affective disorder patients (23-30) and controls (n = 43-146). No evidence was obtained to implicate expanded alleles in these 13 genes as causal factors in these diseases.

Base Sequence↗
PubMed2004

[Case of dentatorubral-pallidoluysian atrophy with onset of psychomotor retardation in infancy].

We report a patient with dentatorubral-pallidoluysian atrophy (DRPLA). She developed normally until the age of 6 month, when she could sit by herself. However, her psychomotor development was subsequently slow with gradual appearance of equilibrium disturbances and involuntary movements such as polymyoclonia and chorea. Her development deteriorated after myoclonic seizures developed at 4.5 years of age. Electroencephalograms showed semi-continuous bursts of diffuse irregular spike-wave complexes and MRI of the brain showed atrophy of the cerebellum and brainstem, and high signal intensities in the posterior periventricular triangle portion on T2-weighted images. Gene analysis performed at the age of 6 years revealed an expanded CAG repeat (17/74) at the DRPLA locus. The CAG repeat size was larger in this case than in cases of the adult and juvenile types with later onset, suggesting a correlation between repeat length and age at onset. Genetic examination of the family members was not performed because of her mother's fear and emotional confusion.

Child↗
PubMed2000

Familial aggregation of psychotic symptoms in Huntington's disease.

OBJECTIVE: The mutation responsible for Huntington's disease is an elongated and unstable trinucleotide (CAG) repeat on the short arm of chromosome 4. Psychotic symptoms are more common in patients with Huntington's disease than in the general population. This study explored the relationship of psychosis in Huntington's disease patients with the number of CAG repeats and family history of psychosis. METHOD: Forty-four patients with Huntington's disease, 22 with and 22 without psychotic symptoms, were recruited from two university-affiliated medical genetics clinics in Seattle and Vancouver, B.C. Psychiatric assessments of the subjects were made through chart review, and diagnoses were validated by structured interviews in a subset of patients. The demographic and clinical characteristics of the psychotic and nonpsychotic patients were compared. RESULTS: The two groups did not differ in demographic and clinical characteristics, except that subjects with psychosis were significantly more likely than nonpsychotic subjects to have a first-degree relative with psychosis. In eight of nine families in which Huntington's disease probands with psychosis had a first-degree relative with psychosis, the relative's psychosis co-occurred with Huntington's disease. In the Huntington's disease probands with psychosis, the onset of psychosis correlated with the onset of the neurological symptoms of Huntington's disease, and the age at onset of psychosis was lower in probands with a higher number of CAG repeats. CONCLUSIONS: Patients with Huntington's disease and psychotic symptoms may have a familial predisposition to develop psychosis. This finding suggests that other genetic factors may influence susceptibility to a particular phenotype precipitated by CAG expansion in the Huntington's disease gene.

Adolescent↗
PubMed1997

Association between the cannabinoid receptor gene (CNR1) and the P300 event-related potential.

In our prior study we observed a significant association between homozygosity for the > or = alleles of a microsatellite polymorphism of cannabinoid receptor genes (CNR1) and drug dependence. Decreased amplitude of the P300 wave of evoked related potentials (ERP) has long been shown to be associated with alcohol and drug dependence. The P300 wave reflects attentional resource allocation and active working memory. Since marijuana intoxication has a potent blocking effect on short-term memory we examined the association between the CNR1 alleles and the P300 wave amplitude at three electrodes in 35 alcohol and drug addicts, by MANOVA. There was a significant decrease in amplitude of the P300 wave for all three electrodes (P = 0.028) that was most marked for the frontal lobes (P = 0.008) in subjects homozygous for the CNR1 > or = 5 repeat alleles. Multivariate regression analysis indicated the CNR1 gene contributed to 20% of the variance of the frontal lobe P300 wave amplitude.

Alcoholism↗
PubMed2000

Atypical movement disorders in the early stages of Huntington's disease: clinical and genetic analysis.

Huntington's disease (HD) is notably difficult to diagnose in the early stages. One reason is that the early clinical manifestations of HD vary widely and sometimes have an atypical onset. In this paper we primarily sought information on affected patients who initially presented with movement disorders other than chorea. We also investigated atypical motor presentations in relation to triplet CAG expansions. After reviewing the clinical records of two neurological centres, we identified patients with a final, documented diagnosis of HD and selected for study 205 patients according to their onset of motor manifestations. CAG repeats were analysed. Of the 205 patients studied, 15 had atypical motor symptoms at onset. In this group we identified three types of initial clinical manifestations other than chorea: parkinsonism, ataxia and dystonia. We conclude that HD patients may have different motor manifestations at the initiation of the illness. Patients with atypical movement disorders in the early stages have larger CAG expansions and an earlier age at onset than HD patients with typical onset chorea.

Adolescent↗
PubMed1997

Cannabinoid receptor gene (CNR1): association with i.v. drug use.

The receptors for tetrahydrocannabinol, the active ingredient of marijuana, have been identified. A microsatellite polymorphism (AAT)n at the cannabinoid CB1 (brain) receptor gene (CNR1) consists of 9 alleles. Since the cannabinoid system is part of the reward pathway we examined the hypothesis that genetic variants of the CNR1 gene might be associated with susceptibility to alcohol or drug dependence. The study consisted of 92 subjects on an Addiction Treatment Unit (ATU) and 114 controls. All were non-Hispanic Caucasians. The ATU subjects were screened for all types of substance dependence using the Diagnostic Interview Schedule (DIS), and for a variety of substance abuse symptoms using the Addiction Severity Index (ASI). Since inspection of the distribution of alleles in controls vs i.v. drug use showed a decrease in the frequency of the 4 allele, and the < 4 alleles were rare, the alleles were divided into two groups, < 5 and < or = 5, and three genotypes < 5/< 5, heterozygotes, and > or =/> or = 5. When all variables were subjected to factor analysis, factor 1 showed a clustering of drug dependence variables and factor 2 of alcohol dependence variables. By ANOVA only factor 1 showed significant differences by genotype consistent with a model where homozygosity for the > or = 5 repeat alleles showed the greatest effect. The number of i.v. drugs used was significantly greater for those carrying the > or =/> or = 5 genotype than for other genotypes (P = 0.005). The association with specific types of drug dependence was greatest for cocaine, amphetamine, and cannabis dependence. The results are consistent with a role of cannabinoid receptors in the modulation of dopamine and cannabinoid reward pathways. Independent studies should be designed to further confirm the hypothesis that cannabinoid receptors may contribute to the susceptibility to drug abuse.

Administration, Inhalation↗
PubMedDate not supplied

Parent-daughter transmission of the androgen receptor gene as an explanation of the effect of father absence on age of menarche.

Based on an evolutionary theory of socialization, Belsky and colleagues proposed that girls exposed to a stressful environment, especially when due to father absence in the first 7 years of life, showed an early onset of puberty, precocious sexuality, and unstable relationships as adults. The authors of this article examined an alternative explanation that a variant X-linked androgen receptor (AR) gene, predisposing the father to behaviors that include family abandonment, may be passed to their daughters causing early puberty, precocious sexuality, and behavior problems. The results of a study of 121 White males and 164 White females showed a significant association of the short alleles of the GGC repeat polymorphism of the AR gene with a range of measures of aggression and impulsivity, increased number of sexual partners, sexual compulsivity, and lifetime number of sex partners in males; and paternal divorce, father absence, and early age of menarche in females. These findings support a genetic explanation of the Belsky psychosocial evolutionary hypothesis regarding the association of fathers' absence and parental stress with early age of onset of menarche and early sexual activity in their daughters. A genetic explanation of the father absence effect is proposed in which fathers carrying the AR alleles are more likely to abandon a marriage (father absence) and pass those alleles to their daughters in whom they produce an earlier age of menarche and behavioral problems.

Adult↗
PubMed2000

Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome.

Fragile-X syndrome is a trinucleotide-repeat-expansion disorder in which the clinical phenotype is believed to result from transcriptional silencing of the fragile-X mental retardation 1 (FMR1) gene as the number of CGG repeats exceeds approximately 200. For premutation alleles ( approximately 55-200 repeats), no abnormalities in FMR1-gene expression have been described, despite growing evidence of clinical involvement in premutation carriers. To address this (apparent) paradox, we have determined, for 16 carrier males (55-192 repeats), the relative levels of leukocyte FMR1 mRNA, by use of automated fluorescence-detection reverse transcriptase-PCR, and the percent of lymphocytes that are immunoreactive for FMR1 protein (FMRP). For some alleles with>100 repeats, there was a reduction in the number of FMRP-positive cells. Unexpectedly, FMR1 mRNA levels were elevated at least fivefold within this same range. No significant increase in FMR1 mRNA stability was observed in a lymphoblastoid cell line (160 repeats) derived from one of the carrier males, suggesting that the increased message levels are due to an increased rate of transcription. Current results support a mechanism of involvement in premutation carriers, in which reduced translational efficiency is at least partially compensated through increased transcriptional activity. Thus, diminished translational efficiency may be important throughout much of the premutation range, with a mechanistic switch occurring in the full-mutation range as the FMR1 gene is silenced.

Fragile X Messenger Ribonucleoprotein 1↗
PubMed2004

Hereditary haemochromatosis is unlikely to cause movement disorders--a critical review.

Hereditary haemochromatosis (HH) is a common autosomal recessive systemic iron overload disorder in which CNS manifestations, particularly movement disorders, have been reported. We report a 63-year-old woman with familial HH with a four-year history of progressive gait disturbance, chorea, and mild cervical and laryngeal dystonia. Her movement disorder was thought to be related to the haemochromatosis. On further investigation, analysis for the Huntington's disease expansion was positive. A review of the seven published cases of movement disorders associated with HH as well as data concerning brain iron deposition in this condition leads us to debate the causal link between movement disorders and HH. We suggest that movement disorders are rare in association with HH, and that such patients should be thoroughly investigated for another cause for their movement disorder.

Basal Ganglia↗