Partial deletion of the Monoamine Oxidase A (MAOA) gene in a 3-generation family with two severely affected intellectually disabled males and a healthy female carrier. N. de Leeuw1,4, M. I. Schouten1, R. van Beek1, R. Pfundt1, M. M. Verbeek2,3,4, H. G. Brunner1, 1) Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands; 2) Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands; 3) Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; 4) Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.
Genome wide high resolution array analysis in a 12-year-old boy with severe intellectual disability (ID), absent speech, autism, stereotyped behaviour, cheerful, pulmonary stenosis and dysmorphic features revealed a 30 kb interstitial deletion in Xp11.3 which resulted in the loss of the last six exons of the MAOA gene (MIM 309850). The deletion was also detected in the healthy mother with normal intelligence and in a 79-year-old maternal grand-uncle with severe intellectual disability. Monoamine oxidase A (MAOA) is the major enzyme catalyzing the oxidative deamination of monoamine neurotransmitters, such as serotonin (5-hydroxytryptamine (5-HT)) and (nor)adrenalin, and plays a critically important role in brain development and functions. Abnormal MAOA activity has been reported to be associated with borderline ID (Brunner syndrome [MIM 300615]), depression, abnormal behaviour and autism spectrum disorder, but the molecular basis for these disease processes is unclear. Therefore, subsequent metabolic testing using UPLC was performed in this family and showed that serotonin levels in serum were dramatically increased in the index patient (3,892 nmol/l) and to a lesser extent in his mother (1,635 nmol/l), whereas 5-hydroxyindole-3-acetic acid (5-HIAA) was not detectable in serum of either two. The urinary concentration of 5-HIAA as well as homovanillic acid (HVA) and vanillylmandelic acid (MVA) were very low in the index patient, which is in agreement with the serum levels and indicates MAOA deficiency. Unexpected low levels of (nor)adrenalin and dopamine were measured in the patients urine. Urinary values for 5-HIAA, HVA, VMA, (nor)adrenalin and dopamine were all normal in the mother. Although few single nucleotide variants in the MAOA gene and multiple gene deletions involving MAOA have been reported, this is the first report of a deletion restricted to the MAOA gene, without the concomitant loss of any other gene in Xp11.3. While the genetic findings show that only exons 10 through 15 of MAOA are deleted, we note that the severity of ID and of the biochemical changes suggest that MAOB activity might be compromised through a position effect on the neighbouring MAOB gene (MIM 309860). The clinical, genetic and metabolic findings in these three family members with the same deletion (two affected males and one healthy female) provide new insights into the molecular basis of neuropsychiatric disorders associated with MAOA dysfunction.
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