Methodological problems in meta-analysis of association studies between bipolar affective disorders and the tyrosine hydroxylase gene.
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Bipolar Disorder↗
Biomedical subjects
M Leboyer
Publications and source records attributed to M Leboyer.
CAG repeat sequences in bipolar affective disorder: no evidence for association in a French population.
Anticipation has been described in bipolar affective disorder (BPAD). However, there are conflicting results from association studies screening for a link between BPAD and CAG/CTG repeat expansions, the molecular basis of anticipation in several hereditary neurodegenerative disorders. Here, the repeat expansion detection (RED) method was used to screen for CAG repeat expansion in 119 French BPAD patients. Western blotting was also used to search for polyglutamine stretches, encoded by CAG expansion, among proteins, extracted from lymphoblastoid cell lines, from six selected familial cases. Maximum CAG/CTG repeat length did not differ significantly (P = 0.38) between the 119 BPAD patients and the 88 controls included in the study. Several categories of subgroups were used, none of which showed significant association with a long repeat. Nor was a specific protein with an unusually long polyglutamine stretch (lower detection limit, approximately 33 polyglutamines) detected in cell lysates from the familial cases studied. In conclusion, an association between a long CAG/CTG repeat and BPAD in the French population sample studied was not found. Nonetheless, a short repeat (<40 repeats) might still be implicated, and this possibility warrants further study.
Adult↗
Association between the tryptophan hydroxylase gene and manic-depressive illness.
BACKGROUND: Genes encoding proteins involved in serotonergic metabolism are major candidates in association studies of mood disorders and suicidal behavior. This association study explores whether the tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme of serotonin biosynthesis, is a susceptibility factor for manic-depressive illness, with or without a history of suicide attempts. METHODS: The TPH intron 7 A218C polymorphism was determined using a polymerase chain reaction-based method in DNA samples from 152 patients with bipolar disorder and 94 healthy control subjects. RESULTS: There was a significant association between TPH genotypes and manic-depressive illness. Among patients with bipolar disorder, no association was found between TPH alleles and suicidal behavior. CONCLUSIONS: This result suggests the involvement of the TPH gene in susceptibility to manic-depressive illness. This preliminary result requires confirmation in further groups of patients and controls.
Adult↗
Psychiatric genetics: search for phenotypes.
Failure to obtain convincing results in psychiatric genetics can partly be attributed to the fact that progress in molecular biology and genetic epidemiology has not been followed by an equivalent development in phenotypic description. Instead of relying entirely on classical nosological approaches, we argue that identifying more homogeneous forms of diseases through a'candidate symptom approach' among affected subjects and an endophenotype approach that identifies sub-clinical traits among non-affected relatives might yield better results. Examples where these strategies have already been fruitful when applied to complex diseases are presented in this review. Focusing on vulnerability traits might stimulate the redefinition of traditional psychiatric syndromes and help to bridge the gap between clinical and experimental approaches.
Animals↗
A preliminary study on early onset schizophrenia and bipolar disorder: large polyglutamine expansions are not involved.
Genetic factors are of major aetiological importance in bipolar disorder and schizophrenia. The exact mode of inheritance is unknown, but recent arguments in favor of genetic anticipation in those two disorders suggest that dynamic mutations could be involved. Using a new antibody, we thus explored the implication of large expanded polyglutamine tracts in a sample of very early onset schizophrenic and bipolar patients. No evidence for a specific protein with polyglutamine expansion was found in either group.
Adolescent↗
Apolipoprotein E gene polymorphism in early and late onset bipolar patients.
To explore the involvement of apolipoprotein E gene (APO E) in major depression, we studied the APO E gene polymorphism in a sample of 156 unrelated bipolar patients and 91 healthy volunteers. This population was stratified for age at onset of the affective disorder (onset before 18 years, after 45 years and between 18 and 45 years). Early onset bipolar patients with psychotic symptoms exhibited a significant increase of epsilon4 allele frequency (28.9%) compared to either other bipolar patients (13.1%, chi2 = 6.52, df = 1, P < 0.02) or controls (12.1%, chi2 = 7.01, df = 1, P < 0.01). The association between epsilon4 and early onset bipolar disorder (BPD) with psychotic symptoms suggests that APO E gene is a risk factor for a subgroup of BPD, or influences the phenotypic expression (i.e. psychotic symptoms or age at onset) of manic depressive illness.
Adult↗
Serotonin transporter gene and manic depressive illness: an association study.
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Adult↗
Manic depressive illness and tyrosine hydroxylase gene: linkage heterogeneity and association.
Several studies have implicated the tyrosine hydroxylase (TH) locus within the 11p15 region in susceptibility to manic depressive illness (MDI). This possibility was further investigated by both parametric (lod score) and nonparametric (affected-pedigree-member and a case-control study) methods of analysis in 11 French MDI families and in a sample of 200 unrelated subjects. Both types of analyses corroborate the implication of this locus, and positive lod scores were obtained in two families, which most likely reflects genetic heterogeneity. Statistical analyses were also performed including available data from published reports. These analyses, which allowed for genetic heterogeneity, substantiated our findings. The combined maximum lod score for all the families studied was 3.68 at theta = 0.00 (number of families: 36) assuming heterogeneity (alpha = 15%, P = 0.01). Taken together these results converge to suggest that the risk factors for MDI lie in the 11p15 region with TH being the most likely candidate gene.
Alleles↗
Further epidemiological evidence for anticipation in schizophrenia.
Anticipation describes an inheritance pattern within a pedigree in which disease severity increases, and/or age at onset decreases, in successive generations. This phenomenon has been described in different samples of schizophrenic subjects, and could explain many inconsistencies in the inheritability of schizophrenia. Anticipation is, however, subject to numerous and significant biases, partially controlled by different methodologies used in different studies. We analyzed the anticipation effect on an original sample of schizophrenic patients (n = 57) who had at least one other schizophrenic in their family belonging to another generation (father/mother, uncle/aunt, son/daughter). We tested the anticipation effect according to previously published methodologies, such as percentages of parent-child pairs showing negative versus positive anticipation, comparison of anticipation limited to parent-child or uncle-nephew pairs, anticipation analysis on the basis of families with unilineal origins only, and comparison of the age at onset-survival distribution of the two generations. The 31 schizophrenic subjects who belonged to the younger generation had a significantly earlier age at onset (24.58 years) than the 26 schizophrenic subjects who belonged to the older generation (36.46 years). Whatever the method used to control biases, we significantly found earlier age at onset for schizophrenic patients from the younger generation. There is strong evidence for the existence of the anticipation effect in schizophrenia in our sample, as well as in various others, which may elucidate numerous inconsistencies in clinical and epidemiological data which characterize schizophrenia. Looking for expanded trinucleotide repeats is thus the next step to detect the gene(s) that are potentially involved.
Adult↗
Executive function in parents of children with autism.
BACKGROUND: Previous studies have shown that individuals with autism show impaired performance on tests of executive function (Ozonoff et al. 1991, 1993; Hughes & Russell, 1993; Hughes et al. 1994). There is also strong evidence for genetic involvement in autism (see Rutter, 1991 for review). If executive dysfunction is a core impairment in autism, then similar impairments are hypothesized to exist in a subtler form among the parents of autistic children. METHODS: Forty parents of autistic children were compared with 40 parents of learning disabled children and 36 adults from unaffected families on three computerized tests of executive function. These tasks tapped attentional-shifting skills, visuospatial planning and working memory. Participants also received a computerized control test of spatial memory-span. In addition, the interviewer's initial impressions of family members were coded using a new 33-item questionnaire. RESULTS: A significant proportion of parents of autistic children (especially fathers) showed impaired executive function. By contrast, parents did as well as both comparison groups on a control test of spatial span, and on other 'non-executive' measures from the tasks, indicating that the autism group were as able and motivated as comparison groups. Interestingly, impairment of executive function was significantly correlated with the interviewer's pre-test impression of social abnormality among parents of autistic children. CONCLUSIONS: The hypothesis that a significant proportion of parents of autistic children show impaired executive function was supported. Parents showed good memory ability, but relatively poor planning skills and attentional flexibility. The extent to which this is an inherent trait in family members, rather than a reflection of the difficulties involved in caring for an autistic child, remains to be examined.
Adolescent↗
Diagnosing autism: analyses of data from the Autism Diagnostic Interview.
Results from ROC curves of items from two scales, the Autism Diagnostic Interview (ADI) and Autism Diagnostic Interview-Revised (ADI-R), operationalizing DSM-IV criteria for autism are presented for 319 autistic and 113 other subjects from 8 international autism centers. Analyses indicate that multiple items were necessary to attain adequate sensitivity and specificity if samples with varying levels of language were considered separately. Although considering only current behavior was generally sufficient when a combination cutoff and additive model was employed, predictive power was highest when history was taken into account. A single set of criteria, as operationalized by individually structured questions in the ADI/ADI-R, was effective in differentiating autism from mental handicap and language impairment in subjects with a range of chronological ages and developmental levels.
Adolescent↗
Anticipation in schizophrenia: new light on a controversial problem.
OBJECTIVE: Anticipation, recently found in several neuropsychiatric disorders, is an inheritance pattern within a pedigree in which disease severity increases or age at onset decreases in successive generations. Demonstration of genetic anticipation in schizophrenia could be of heuristic value, since unstable trinucleotide repeat DNA is known to be the biological basis of anticipation. However, to overcome one of the major ascertainment biases that might mimic anticipation--namely, the fact that patients in different generations are not interviewed at the same age, resulting in a greater chance of finding a later age at onset in the older generation--a new method of investigating anticipation was used. METHOD: The study subjects were 97 systematically ascertained schizophrenic patients belonging to 24 families with at least two generations affected who were identified during a 1-year prevalence study in a limited geographical area of Reunion Island (Indian Ocean). A method of calculating expected age at onset according to age at interview was used in the analyses. RESULTS: In the younger generation of patients, the observed age at onset (21.80 years) was earlier than the expected age at onset (24.95 years), demonstrating anticipation, even when five additional biases that can mimic this genetic effect--the proband effect, the presence of an affected father or mother, the bilineality of the illness, the fertility effect, and the cohort effect--were taken into account. CONCLUSIONS: Evidence for anticipation was demonstrated in this group of schizophrenic patients. This may help the search for pathological genes implicated in the genesis of schizophrenia.
Adult↗
Adenylosuccinate lyase (ADSL) and infantile autism: absence of previously reported point mutation.
Autism is a heterogeneous neuropsychiatric syndrome of unknown etiology. There is evidence that a deficiency in the enzyme adenylosuccinate lyase (ADSL), essential for de novo purine biosynthesis, could be involved in the pathogenesis of certain cases. A point mutation in the ADSL gene, resulting in a predicted serine-to-proline substitution and conferring structural instability to the mutant enzyme, has been reported previously in 3 affected siblings. In order to determine the prevalence of the mutation, we PCR-amplified the exon spanning the site of this mutation from the genomic DNA of patients fulfilling DSM-III-R criteria for autistic disorder. None of the 119 patients tested were found to have this mutation. Furthermore, on preliminary screening using singlestrand conformation polymorphism (SSCP), no novel mutations were detected in the coding sequence of four ADSL exons, spanning approximately 50% of the cDNA. In light of these findings, it appears that mutations in the ADSL gene represent a distinctly uncommon cause of autism.
Adenylosuccinate Lyase↗
Low-dose naltrexone effects on plasma chemistries and clinical symptoms in autism: a double-blind, placebo-controlled study.
The effect of month-long naltrexone (NTX) treatment at a daily oral dose of 0.5 mg/kg/day was contrasted with placebo (PLC) in a double-blind study with conjoint clinical and biochemical evaluations of therapeutic effects. Modest clinical benefits were achieved with both PLC and NTX, with marginally better overall results following NTX, and degree of improvement appeared to be related to plasma chemical profiles. Massively elevated levels of beta-endorphin were observed in all children with assays using C-terminal antibody but not with an N-terminal antibody assay. In addition, 70% of the children exhibited abnormally low levels of adrenocorticotropic hormone, and smaller subsets exhibited elevated norepinephrine (60%), arginine-vasopressin (50%), and serotonin (20%). The best clinical responders exhibited the clearest normalization of the elevated plasma chemistries, especially in C-terminal-beta-endorphin and serotonin. There was some evidence of therapeutic carry-over effects in both clinical and biochemical measures in those children who received NTX before PLC. The results suggest that NTX only benefits a subgroup of autistic children, who may be identified by the presence of certain plasma abnormalities. These results suggest a possible linkage between abnormal plasma chemistries, especially those related to the pro-opiomelanocortin system, and autistic symptoms.
Adolescent↗
Association of manic-depressive illness with tyrosine hydroxylase microsatellite marker.
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Adult↗
Verbal skills in relatives of autistic females.
First-degree relatives of 26 autistic females and 26 Down's syndrome females were tested on a battery of verbal tasks designed to detect subtle anomalies. No differences were found when comparing parents of the two groups, but there was a significant difference between siblings. This result was accounted for by a lower performance of the brothers of autistic subjects. The verbal scores of the relatives, either parents or siblings, were not related to the IQ of the proband. Findings are discussed in relation to the hypothesis of genetic and/or environmental factors in autism.
Adolescent↗
SPECT of the brain in childhood autism: evidence for a lack of normal hemispheric asymmetry.
Autism is thought to be associated with abnormal hemispheric specialization and left-hemispheric dysfunction. Brain functional imaging using 133Xe-SPECT (single photon emission computed tomography) was used to measure left/right asymmetry and absolute values of regional cerebral blood flow (rCBF) in 18 children with autism aged from four to 17 years and 10 age-matched controls. All controls but only 10 children with autism were right-handed. The left-to-right indices, both hemispheric and regional, were positive in controls, indicating higher left than right rCBF values, but were negative in patients with autism. This inversion was statically significant for total hemispheres, sensorimotor and language-related cortex and was explained by a significant decrease of the left absolute rCBF values in these regions in the patients with autism. The inversion was independent of handedness, sex and age. These results confirm the existence of left-hemispheric dysfunction in childhood autism, especially in the cortical areas devoted to language and handedness, leading to anomalous hemispheric specialization.
Adolescent↗
Gender and age at onset in schizophrenia: impact of family history.
OBJECTIVE: The 1-year prevalence of schizophrenia was studied in a limited geographical area of Reunion Island (Indian Ocean) to assess the impact of family history of schizophrenia on the well-known association between gender and age at onset. METHOD: The population of schizophrenic patients meeting the DSM-III-R criteria for schizophrenia (N = 663) was identified and divided according to the presence of another schizophrenic patient among the first- and second-degree relatives. RESULTS: As previously reported, the median age at onset differed between the sexes: the males had an earlier onset (mean age = 27.8 years) than the females (31.5 years). Comparison of the ages at onset according to family history revealed that onset was later for female subjects with a negative family history than for the three other groups (i.e., males with or without a family history and females with a family history). No difference emerged in the comparison of the ages at onset of the males and females with a positive family history. CONCLUSIONS: Comparison of schizophrenic patients with familial versus sporadic disorder confirms the absence of a gender effect for age at onset in the subgroup with familial disorder. This approach also demonstrates the existence of a subgroup composed of affected females having late onset and no family history of schizophrenia.
Adolescent↗