Marked Amine and Amine Metabolite Changes in Norrie Disease Patients with an X‐Chromosomal Deletion Affecting Monoamine Oxidase

Abstract

Urinary and plasma amines and amine metabolites were quantified in two individuals with Norrie disease resulting from a deletion in chromosomal region Xp11.3, recently reported to be associated with absence of the gene encoding monoamine oxidase (MAO)-A and nondetectable MAO-A activity in fibroblasts and MAO-B activity in platelets. Marked (four-to 100-fold) elevations in levels of urinary phenylethylamine, o-tyramine, and m-tyramine (which are preferential substrates for MAO-B) and marked reductions (90%) in levels of 3-methoxy-4-hydroxyphenylglycol (a deaminated metabolite of norepinephrine, a preferential substrate for MAO-A) in urine and plasma confirmed the presence of a systemic, functionally significant reduction in the activities of both MAO isozymes. The magnitude of these changes, which are equivalent to those found in subjects taking MAO-inhibiting antidepressants, suggests that early initiation of dietary and drug restrictions may be clinically important in these and other patients with X-chromosomal mutations involving MAO. These findings further support the proposition that the MAOA and MAOB genes are located in close proximity on the X chromosome. Negligible changes in the metabolites of dopamine and serotonin raise the possibility that other metabolic pathways are of importance for their production, that dietary or intestinal bacterial sources contribute substantially to the presence of these amine metabolites in urine, or both.

Biochemical, behavioral, physiologic, and neurodevelopmental changes in mice deficient in monoamine oxidase A or B

“…Hence, it is surprising that in the resting, restrained state MAO A KO mice compared to wild-type mice demonstrate a low to normal basal blood pressure and heart rate. These findings are consistent with anecdotal reports of altered peripheral autonomic function and resting hypotension in patients with Norrie disease, an X-linked recessive disorder which may encompass deletions in the gene for MAO-A [57,77]. It is possible in the face of the markedly enhanced levels of pressor amines that adaptational responses may be elicited in MAO A KO mice, which act to maintain a lowered blood pressure and heart rate.…”

Molecular aspects of monoamine oxidase B

“…The affected males have no MAO B activity in platelets and marked changes in the amine metabolites (Murphy et al, 1990). Subsequently, males with micro-deletions were identified, revealing that MAO A deletion has a strong influence on both amine metabolism and behavior, whereas those with the MAO B micro-deletion showed neither mental retardation nor abnormal behavior.…”

“…MAOA/B knockout mice displaying anxiety-like symptoms have greatly elevated monoamine levels . Humans lacking MAO B have greatly elevated levels of phenylethylamine (Murphy et al, 1990). In rats, numerous microdialysis experiments have been conducted to measure amine changes in different disease models (including addiction) or to assess the effects of MAO inhibitors (for example, (Butcher et al, 1990, Lamensdorf et al, 1996, Bazzu et al, 2013, Sader-Mazbar et al, 2013, Bolea et al, 2014).…”

Cluster B Personality Disorders are Associated with Allelic Variation of Monoamine Oxidase A Activity

“…Norrie disease, which is caused by X-chromosomal microdeletions including the MAOA gene, is associated with mental retardation, autistic behavior, motor hyperactivity, and sleep disturbances, which may, at least in part, be attributed to deficient MAO activity (Sims et al, 1989;Murphy et al, 1990). A hemizygous chain termination mutation in exon 8 of MAOA, resulting in an absence of MAOA enzymatic activity in cultured fibroblasts, causes mild mental retardation and episodes of impulsive aggression, arson, and hypersexual behavior, such as attempted rape and exhibitionism, in affected males from a single extended pedigree (Brunner et al, 1993).…”