Disrupted Dopaminergic Neurotransmission in 22q11 Deletion Syndrome

Abstract

22q11 Deletion syndrome (22q11DS) is associated with chromosome 22q11 microdeletions and high rates of psychiatric disorders. Susceptibility for these disorders could be explained by haploinsufficiency of the catechol-O-methyltransferase gene, which encodes an enzyme involved in dopamine (DA) breakdown. It is unknown how dopaminergic neurotransmission is affected in people with 22q11DS. To date, there have been no controlled studies investigating dopaminergic neurotransmission in people with 22q11DS. We report the results of a challenge study in high-functioning adults with 22q11DS and age-and gender-matched controls using neuro-endocrine and peripheral dopaminergic markers. At baseline, 22q11DS subjects compared to controls had higher urine DA levels and lower plasma levels of the predominant DA metabolite homovanillic acid (HVA). Following DA depletion, 22q11DS subjects showed lower urine and plasma HVA levels and a lower prolactin response than controls. The ratio of DA/HVA, a rough index of DA turnover, was significantly higher in the 22q11DS subjects at baseline and after DA depletion. Our results suggest that adults with 22q11DS have disrupted dopaminergic neurotransmission, which might explain their susceptibility for psychiatric disorders.

Genes, brain development and psychiatric phenotypes in velo‐cardio‐facial syndrome

“…Since subjects with VCFS carry only one copy of the COMT gene, those with the COMT Met probably suffer from deficient COMT enzyme activity and are thus putatively exposed to unusually high brain dopamine levels from an early age. This may place them at higher risk of psychiatric disorders [Gothelf et al, 2005[Gothelf et al, , 2007dPapolos et al, 1996] and cognitive [Gothelf et al, 2005] and neurophysiological deficits Boot et al, 2007;Gothelf et al, 2007b] than VCFS carriers of the COMT Val allele. In a longitudinal study of children with VCFS followed into late adolescence, those carrying the low-activity Met allele showed a more significant decline in verbal IQ and language scores and more severe psychotic symptoms than those carrying the high-activity Val allele [Gothelf et al, 2005].…”

PRODH rs450046 and proline x COMT Val158Met interaction effects on intelligence and startle in adults with 22q11 deletion syndrome

“…Characteristics of subgroups of these subjects were published previously (Boot et al 2008(Boot et al , 2011ada Silva Alves et al 2011;de Koning et al 2012) and proline levels of 19 of these subjects were reported in previous studies (Raux et al 2007;da Silva Alves et al 2011). The subjects were recruited as described previously (Boot et al 2011a).…”

Co‐occurrence of early‐onset Parkinson disease and 22q11.2 deletion syndrome: Potential role for dopamine transporter imaging

“…Patients with 22q11.2 deletion syndrome (22q11DS) are hemizygous for the COMT gene, and consequently show increased dopamine levels [Boot et al, 2008]. Contrarily, Parkinson disease (PD) is characterized by severe loss of dopaminergic neurons [Booij et al, 1999a].…”