Mechteld L.C. Hoogendoorn

Catatonia: Disappeared or Under-Diagnosed?

Background: Over the last century, especially during the latter half, the prevalence of the diagnosis of catatonic schizophrenia decreased considerably. Several explanations for this phenomenon have been put forward. Sampling and Methods: The present study investigated the frequency of the diagnosis of catatonic schizophrenia in a large sample of admitted psychiatric patients (n = 19,309). In addition, the presence of catatonic symptoms was studied in a sample of patients with schizophrenia (n = 701) and in a group of consecutively admitted psychotic patients (n = 139). In these two groups the effect of the diagnostic procedures on the recognition of catatonia was examined. Results: The diagnosis of catatonic schizophrenia dropped from 7.8% in 1980–1989 to 1.3% in 1990–2001 (p < 0.001). In addition, a possible under-diagnosis of catatonic schizophrenia was found in an independent sample of patients with schizophrenia. Application of a systematic catatonia rating scale in patients admitted with acute psychosis identified a bimodally distributed catatonic dimension. At least 18% of these patients fulfilled the criteria for catatonia. Interestingly, the catatonic subgroup used atypical antipsychotic compounds more frequently (p < 0.05). Conclusions: The results suggest that changes in diagnostic criteria and the diagnostic procedure itself are responsible for the under-recognition of catatonia.

An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia

Several lines of evidence, including expression analyses, brain imaging and genetic studies suggest that the integrity of myelin is disturbed in schizophrenia patients. In this study, we first reconstructed a pathway of 138 myelin-related genes, all involved in myelin structure, composition, development or maintenance. Then we performed a two-stage association analysis on these 138 genes using 771 single nucleotide polymorphisms (SNPs). Analysis of our data from 310 cases vs 880 controls demonstrated association of 10 SNPs from six genes. Specifically, we observed highly significant P-values for association in PIK4CA (observed P=6.1 × 10−6). These findings remained significant after Bonferroni correction for 771 tests. The PIK4CA gene is located in the chromosome 22q11 deletion syndrome region, which is of particular interest because it has been implicated in schizophrenia. We also report weak association of SNPs in PIK3C2G, FGF1, FGFR1, ARHGEF10 and PSAP (observed P⩽0.01). Our approach—of screening genes involved in a particular pathway for association—resulted in identification of several, mostly novel, genes associated with the risk of developing schizophrenia in the Dutch population.

Hyperhomocysteinemia, methylenetetrahydrofolate reductase 677TT genotype, and the risk for schizophrenia : A dutch population based case-control study

Evidence for an involvement of aberrant homocysteine metabolism in the aetiology of schizophrenia is limited and controversial. A case‐control study was performed to quantify the risk of schizophrenia in the presence of elevated homocysteine concentrations or homozygosity for the 677C → T polymorphism (677TT) in the methylenetetrahydrofolate reductase (MTHFR) gene in subjects of Dutch ancestry. We determined the 677C → T MTHFR genotype distribution in 254 well‐defined patients and 414 healthy controls. Plasma homocysteine concentrations were measured in 62 patients with schizophrenia and 432 control subjects. When homocysteine concentrations were stratified into quartiles of the control distribution, we calculated an increased risk for schizophrenia in the fourth and third quartile versus the lowest quartile [odds ratio (OR) = 3.3; 95% confidence interval (CI): 1.2–9.2, and OR = 3.1; 95% CI: 1.2–8.0, respectively]. A significant dose‐response relation of increasing homocysteine levels and increasing risk for schizophrenia was observed (P = 0.036). The 677TT genotype was associated with an OR of 1.6 [95% CI: 0.96–2.8] of having schizophrenia. Heterozygosity for the T allele compared to 677CC subjects accounted for an OR of 1.3 [95% CI: 0.91–1.8]. Elevated homocysteine levels and the MTHFR 677TT genotype are associated with an increased risk for schizophrenia. These observations support a causal relation between disturbed homocysteine metabolism and schizophrenia.

Do mood symptoms subdivide the schizophrenia phenotype?: Association of the GMP6A gene with a depression subgroup

Genetic studies of clinically defined subgroups of schizophrenia patients may reduce the phenotypic heterogeneity of schizophrenia and thus facilitate the identification of genes that confer risk to this disorder. Several latent class analyses have provided subgroups of psychotic disorders that show considerable consistency over these studies. The presence or absence of mood symptoms was found to contribute most to the delineations of these subgroups. In this study we used six previously published subtypes of psychosis derived from latent class analysis of a large sample of psychosis patients. In 280 schizophrenia patients and 525 healthy controls we investigated the associations of these subgroups with myelin related genes. After bonferroni correction we found an association of the glycoprotein M6A gene (GPM6A) with the subgroup of schizophrenia patients with high levels of depression (P‐corrected = 0.006). Borderline association of the microtubulin associated protein tau (MAPT) with a primarily non‐affective group of schizophrenia patients (P‐corrected = 0.052) was also observed. GPM6A modulates the influence of stress on the hippocampus in animals. Thus our findings could suggest that GMP6A plays a role in the stress‐induced hippocampal alterations that are found in psychiatric disorders in general and schizophrenia in particular. Overall, these finding suggests that investigating subgroups of schizophrenia based symptoms profile and particularly mood symptoms can facilitate genetic studies of schizophrenia.

Prevalence of 22q11.2 deletions in 311 Dutch patients with schizophrenia

UNLABELLED The objectives of this study were 1) to examine whether the prevalence of 22q11.2 deletion syndrome (22q11DS) in schizophrenia patients with the Deficit syndrome is higher than the reported approximately 2% for the population of schizophrenia patients as a whole, and 2) to estimate the overall prevalence of 22q11DS among schizophrenia patients by combining all available studies. Our sample, enriched for patients with the Deficit syndrome, had 88% power to detect an estimated prevalence of 5% of 22q11.2 deletions. No 22q11.2 deletions were detected in 311 schizophrenia patients, 146 of whom met criteria for the Deficit syndrome. Our literature research revealed that in eight studies sixteen deletions were identified in 2133 patients with schizophrenia. This corresponds to a prevalence of 0.75% (95%CI: 0.5%-1.2%). IN CONCLUSION The prevalence of 22q11.2DS in schizophrenia patients with the Deficit syndrome is not higher than in the population of schizophrenia patients as a whole. The prevalence of 22q11.2DS in schizophrenia patients is lower than the frequently reported prevalence of 2% or more.

Polymorphisms in the brain-derived neurotrophic factor gene are not associated with either anorexia nervosa or schizophrenia in Dutch patients.

Two polymorphisms in the brain-derived neurotrophic factor (BDNF) gene, the – 270C/T SNP and the Val66Met SNP have been reported to show association with anorexia nervosa and schizophrenia, although the results are not unambiguous (Nanko et al., 2003; Szekeres et al., 2003; Ribases et al., 2004). We performed a case– control study with these single-nucleotide polymorphisms (SNPs) and two new markers (BDNF up: 20 kb upstream of the ATG and BDNF down: 33 kb downstream of exon 2) to test whether BDNF is a susceptibility gene for the development of psychiatric disorders across diagnostic boundaries. The study included anorexia nervosa (n=195) and schizophrenia patients (n=273), all diagnosed according to the DSM-IV and all of Dutch origin. The controls were healthy Dutch individuals (n=580). The DNA was genotyped for the markers as described (Bakker et al., 2003) and an allelespecific polymerase chain reaction was used for the two SNPs. The – 270C/T SNP was not polymorphic. The remaining markers were in Hardy Weinberg Equilibrium (HWE) in patients and controls. The BDNF_up had nine alleles, four with frequencies > 5% (heterozygosity= 0.69). The BDNF_down had 12 alleles, four with frequencies > 5% (heterozygosity= 0.67). There was strong Linkage Disequilibrium (LD) between the remaining markers (Val66Met-BDNF_up: D0 0.7502; Val66Met-BDNF_down: D0 0.8919 and BDNF_down: D0 0.6432); however, no significant association could be shown between any of the markers and both disorders. Likelihood ratio tests using the UNPHASED program showed P-values of P=0.98 and P=0.5, respectively, for the anorexia nervosa and schizophrenia patients for marker BDNF_up; P=0.59 and P=0.71 for BDNF_down; and P=0.6 and P=0.73 for the Val66Met alleles, with allele frequencies for the Val allele of 79% in anorexia nervosa patients, 80% in schizophrenia patients and 80% in controls, and for the Met allele of 21% in anorexia nervosa patients, 20% in schizophrenia patients and 20% in controls. In conclusion, in Dutch anorexia nervosa and schizophrenia patients, BDNF does not seem to play a role.

No association between 12 dopaminergic genes and schizophrenia in a large Dutch sample

It has been suggested that genes involved in dopamine neurotransmission contribute to the pathogenesis of schizophrenia. However, reported associations of the disorder with genetic markers in dopaminergic genes have yielded inconsistent results. Possible explanations are differences in phenotyping, genetic heterogeneity, low marker informativity, and the use of small sample sizes. Here, we present a two‐stage analysis of 12 dopaminergic genes in a large sample of Dutch schizophrenic patients. To reduce genetic heterogeneity, only patients with at least three Caucasian grandparents of Dutch ancestry were ascertained. An efficient genotyping strategy was used, in which polymorphic microsatellite markers were first screened for association in DNA pools. Promising results were followed up by individual genotyping in an extended sample. The pooled samples consisted of 208 schizophrenic patients and 288 unmatched control individuals. For each of the genes, more than one microsatellite marker was selected where possible, either intragenic or close to the gene. After correcting for multiple testing, significantly different allele frequencies were detected for DRD5 marker D4S615. Subsequently, we individually genotyped this particular marker and another DRD5 marker, as well as a DRD3 marker that could not be analyzed using the pooling strategy. This was done in an extended sample of 282 schizophrenic patients and a control sample of 585 individuals. In this second stage of the study, we found no association between these three markers and schizophrenia. The results of our comprehensive analysis provide no evidence for association between schizophrenia and 12 dopaminergic genes in a large Dutch sample.

Polymorphisms in catechol-O-methyltransferase and methylenetetrahydrofolate reductase in relation to the risk of schizophrenia.

BACKGROUND Evidence is emerging for the association of aberrant homocysteine-methylation cycle and increased risk of schizophrenia. METHODS We examined the prevalence of the catechol-O-methyltransferase (COMT) 324G>A (Val108/158Met) and methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphisms in 252 patients with schizophrenia and 405 control subjects. All subjects were of Dutch ancestry. RESULTS The COMT 324AA genotype was not associated with an increased risk of schizophrenia (odds ratio (OR)=1.38 [95% CI: 0.88-2.16], P=0.162), and the MTHFR 677TT genotype showed a nearly significant increased risk for schizophrenia (OR=1.65 [95% CI: 0.97-2.82], P=0.067). The odds ratio for schizophrenia associated with joint occurrence of the COMT 324AA and MTHFR 677TT genotype was 3.08 (95% CI: 1.08-8.76) (P=0.035). Increasing number of low enzyme activity alleles in the COMT and MTHFR genotype combinations were associated with an increased risk of schizophrenia (test for trend, P=0.017). CONCLUSIONS Our findings do not support a major role for the COMT 324AA and MTHFR 677TT genotype alone, but the combination of both genotypes might increase schizophrenia susceptibility.

No evidence for a preferential transmission of the methylenetetrahydrofolate reductase 677T allele in families with schizophrenia offspring

The methylenetetrahydrofolate reductase (MTHFR) 677C > T polymorphism has been associated with an increased risk of schizophrenia in various case‐control studies. However, case‐control studies are sensitive to population stratification, which is not an issue in family‐based studies. We conducted a family‐based study comprising 120 families with a schizophrenic family member to explore the association between the parental MTHFR 677C > T polymorphism and schizophrenia risk in offspring. In addition, a meta‐analysis was performed using the available studies with data on this subject. Transmission Disequilibrium Test (TDT) analysis showed no preferential transmission of the 677T allele from parents heterozygous for the MTHFR 677C > T polymorphism to schizophrenia offspring (P = 0.27). The genotype relative risks were 1.43 (95% CI: 0.83–2.47) for the 677TT and 1.42 (95% CI: 0.54–3.78) for the 677CT genotype, relative to the 677CC genotype. A meta‐analysis using data from family‐based studies comprising a total of 416 parent‐child triads yielded no evidence implicating the 677T allele in schizophrenia risk (P = 0.58). By applying a log‐linear model, we found no asymmetry within parental mating type. Our data provided no evidence that transmission of the MTHFR 677T allele is associated with schizophrenia risk. In addition, we found no evidence that the maternal genotype influences the risk of having schizophrenia offspring substantially.

MRI, volumetry, 1H spectroscopy, and cerebropetal blood flowmetry in childhood idiopathic anatomic megalencephaly

To evaluate cerebral abnormalities in childhood idiopathic anatomic megalencephaly (MC) by means of different magnetic resonance (MR) modalities.