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DNA sequence variations within the 22q11 DiGeorge chromosomal region are likely to confer susceptibility to psychotic disorders. In a previous report, we identified several heterozygous alterations, including a complete deletion, of the proline dehydrogenase (PRODH) gene, which were associated with moderate hyperprolinemia in a subset of DSM III schizophrenic patients. Our objective was (i) to determine whether hyperprolinemia is associated with increased susceptibility for any of three psychiatric conditions (schizophrenia, schizoaffective disorder and bipolar disorder) and (ii) to establish a correlation between hyperprolinemia and PRODH genotypes. We have conducted a case-control study including 114 control subjects, 188 patients with schizophrenia, 63 with schizoaffective disorder and 69 with bipolar disorder. We report that, taking into account a confounding effect due to valproate treatment, hyperprolinemia is a risk factor for DSM IIIR schizoaffective disorder (P=0.02, Odds ratio=4.6, 95% confidence interval 1.3-16.3). We did not detect 22q11 interstitial deletions associated with the DiGeorge syndrome among the 320 patients of our sample and we found no association between common PRODH polymorphisms and any of the psychotic disorders. In contrast, we found that five rare PRODH alterations (including a complete PRODH deletion and four missense substitutions) were associated with hyperprolinemia. In several cases, two variations were present simultaneously, either in cis or trans in the same subject. A total of 11 from 30 hyperprolinemic subjects bore at least one genetic variation associated with hyperprolinemia. This study demonstrates that moderate hyperprolinemia is an intermediate phenotype associated with certain forms of psychosis.

International audience; Microdeletions of the 22q11 region, responsible for the velo-cardio-facial syndrome (VCFS), are associated with an increased risk for psychosis and mental retardation. Recently, it has been shown in a hyperprolinemic mouse model that an interaction between two genes localized in the hemideleted region, proline dehydrogenase (PRODH) and catechol-o-methyl-transferase (COMT), could be involved in this phenotype. Here, we further characterize in eight children the molecular basis of type I hyperprolinemia (HPI), a recessive disorder resulting from reduced activity of proline dehydrogenase (POX). We show that these patients present with mental retardation, epilepsy and, in some cases, psychiatric features. We next report that, among 92 adult or adolescent VCFS subjects, a subset of patients with severe hyperprolinemia has a phenotype distinguishable from that of other VCFS patients and reminiscent of HPI. Forward stepwise multiple regression analysis selected hyperprolinemia, psychosis and COMT genotype as independent variables influencing IQ in the whole VCFS sample. An inverse correlation between plasma proline level and IQ was found. In addition, as predicted from the mouse model, hyperprolinemic VCFS subjects bearing the Met-COMT low activity allele are at risk for psychosis (OR = 2.8, 95% CI = 1.04-7.4). Finally, from the extensive analysis of the PRODH gene coding sequence variations, it is predicted that POX residual activity in the 0-30% range results into HPI, whereas residual activity in the 30-50% range is associated either with normal plasma proline levels or with mild-to-moderate hyperprolinemia.

The increased prevalence of schizophrenia among patients with the 22q11 interstitial deletion associated with DiGeorge syndrome has suggested the existence of a susceptibility gene for schizophrenia within the DiGeorge syndrome chromosomal region (DGCR) on 22q11. Screening for genomic rearrangements of 23 genes within or at the boundaries of the DGCR in 63 unrelated schizophrenic patients and 68 unaffected controls, using quantitative multiplex PCR of short fluorescent fragments (QMPSF), led us to identify, in a family including two schizophrenic subjects, a heterozygous deletion of the entire PRODH gene encoding proline dehydrogenase. This deletion was associated with hyperprolinemia in the schizophrenic patients. In addition, two heterozygous PRODH missense mutations (L441P and L289M), detected in 3 of 63 schizophrenic patients but in none among 68 controls, were also associated with increased plasma proline levels. Segregation analysis within the two families harboring respectively the PRODH deletion and the L441P mutation showed that the presence of a second PRODH nucleotide variation resulted in higher levels of prolinemia. In two unrelated patients suffering from severe type I hyperprolinemia with neurological manifestations, we identified a homozygous L441P PRODH mutation, associated with a heterozygous R453C substitution in one patient. These observations demonstrate that type I hyperprolinemia is present in a subset of schizophrenic patients, and suggest that the genetic determinism of type I hyperprolinemia is complex, the severity of hyperprolinemia depending on the nature and number of hits affecting the PRODH locus.

The present experiment was undertaken to verify if the demand of tissues for pteroylglutamic (folic) acid, evaluated by serum clearance and urinary excretion of folates, is different between multiparous dairy cows in late gestation (five gestating dry cows, 52.6 (SD 8.4) d before parturition), and in early lactation (four lactating non-gestating cows, 18.0 (SD 5.9) d after parturition). On day 1 the cows received one intravenous (i.v.) injection of 50 micrograms pteroylmonoglutamic acid/kg body weight (BW). Blood samples were taken at 0, 5, 15, 30 min, 1, 2, 4, 8 and 24 h after the i.v. injection. On day 3 the cows received one intramuscular (i.m.) injection of 0.3 mg pteroylmonoglutamic acid/kg BW. Blood and urine samples, as well as urine volume, were taken at 0, 1, 2, 4, 8, 12, 24, 36 and 48 h after the i.m. injection. On days 5, 6 and 7 a daily i.m. injection of 0.5 mg pteroylmonoglutamic acid/kg BW was given in an attempt to saturate tissues with folates. Then the cows received one i.v. (day 8) and one i.m. (day 10) injection of pteroylmonoglutamic acid according to the same procedures described previously for days 1 and 3. On day 12 plasma volume was determined. Before tissue saturation, serum clearance of folates during the 24 h following an i.v. injection was similar for gestating and lactating cows but after tissue saturation serum clearance was slower for lactating than gestating cows (stage x saturation, P = 0.04). The percentage of folates excreted in urine was not affected by the physiological stage (P > or = 0.6) or the level of tissue saturation (P > or = 0.5). In conclusion, serum clearance and urinary excretion of pteroylmonoglutamic acid seem to support the hypothesis that, in multiparous cows, although there are no deficiency symptoms, tissue demand for folic acid is high, especially during gestation.

In a previous report [Jacquet et al., 2005] we have shown that mild to moderate hyperprolinemia resulting from several alterations (either a complete deletion or missense mutations) of the proline dehydrogenase (PRODH) gene located on chromosome 22q11 is a risk factor for schizoaffective disorder but not for DSM3 R schizophrenia or bipolar disorder. We now report that hyperprolinemia is not associated with childhood onset schizophrenia (COS).

Although cyclic nocturnal total parenteral nutrition is a widely used technique, its metabolic consequences have not been fully investigated. During two successive 7-day periods, 12 patients received randomly either standard continuous (infusion 24 hr/day) or cyclic (infusion between 5 pm and 9 am) total parenteral nutrition (TPN). Calorie and nitrogen intakes were identical during both periods. Energy expenditure was investigated by indirect calorimetry and showed practically no difference between continuous standard (1383 +/- 41 kcal/day-1) and cyclic total parenteral nutrition (1428 +/- 46 kcal/day-1). However, in the cyclic regimen, when compared with continuous infusion, energy expenditure was higher between 5 pm and 9 am and lower between 9 am and 5 pm. At the end of the noninfusion period, the 24-hr profile of the nonprotein respiratory quotient showed a slight decrease in patients receiving the cyclic infusion, in contrast with the stability of the quotient in the standard regimen. However, the nitrogen balance and variations in nutritional status did not differ significantly. In conclusion cyclic TPN is efficient for achieving a positive energy and nitrogen balance and in addition it induces a metabolic profile closer to physiological conditions.