It is now well known that patients with 22q11.2 deletions have substantially elevated rates of psychotic illness. Multiple investigations have attempted to elucidate the specific mechanisms underlying the development of psychosis in some patients with this syndrome but not others. Given its role in prefrontal cortical dopamine metabolism, the COMT gene (located within the 22q11.2 deleted region) is of course a compelling candidate gene for this phenotype, although the evidence for this is equivocal (e.g. Murphy et al., 1999). In addition, mechanisms underlying variability in other CNS features of the VCFS phenotype have yet to be determined. For example, there is considerable variability in the cognitive phenotype, with IQ’s ranging from severe mental retardation to the average range, but the specific genes (and other epigenetic factors) that may be relevant to cognitive function in this syndrome are not clear.

Here, Raux and colleagues show that a subset of VCFS patients with severe hyperprolinemia have a phenotype distinct from that of other VCFS patients, and similar to that of Type I hyperprolinemia. This study provides compelling evidence that the high neuropsychiatric disease risk associated with 22q11.2 deletion syndrome may result from an interaction between the proline dehydrogenase (PRODH) and COMT genes, and that interactive effects of these genes may also play a role in determining IQ and possibly susceptibility to seizure disorder in this syndrome. Autistic features were also common in the VCFS patients with hyperprolinemia, suggesting an intriguing link between the 22q11 locus, child-onset schizophrenia, and pervasive developmental disorder (which frequently co-occur), and certainly warrants further investigation. These findings have important therapeutic implications, as plasma proline levels may be lowered by reduction of proline intake or by pharmacological treatment during early childhood. Importantly, the authors conduct a stepwise multiple regression analysis in order to examine the factors that, independently and jointly, are most predictive of IQ in VCFS. This highlights the importance of multivariate approaches when examining such complex genotype-phenotype relationships (even in the context of a disorder with extremely well-characterized genetic etiology).

Compelling as these findings are, the interaction between PRODH and COMT is unlikely to be the ‘whole story’ in determining susceptibility to psychosis and other CNS features of the VCFS phenotype. As several other genes in this region are expressed in the developing brain (e.g., GSCL, ZDHHC8; Abstract

Murphy KC, Jones LA, Owen MJ. high rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry. 1999 Oct;56(10):940-5. Abstract

View all comments by Carrie Bearden

In response to Carrie Bearden, I wonder whether these patients who suffer cognitive deficits and neuropsychiatric disease associated with 22q11.2 deletion syndrome may benefit specifically from alpha-Tocopherol and ascorbic acid? Delwing and colleagues find that these vitamins prevent memory deficits in rats with hyperprolinemia. Also of interest is the study by Kern and Bernards finding that ascorbic acid inhibits spinal meningeal COMT activity.

References:

Delwing D, Bavaresco CS, Monteiro SC, Matte C, Netto CA, Wyse AT. alpha-Tocopherol and ascorbic acid prevent memory deficits provoked by chronic hyperprolinemia in rats. Behav Brain Res. 2006 Apr 3;168(2):185-9. Epub 2005 Oct 6. Abstract

Kern C, Bernards CM. Ascorbic acid inhibits spinal meningeal catechol-o-methyl transferase in vitro, markedly increasing epinephrine bioavailability. Anesthesiology. 1997 Feb;86(2):405-9. Abstract

View all comments by Mary Reid