Alternative titles; symbols
HGNC Approved Gene Symbol: MAOA
SNOMEDCT: 718210003;
Cytogenetic location: Xp11.3 Genomic coordinates (GRCh38): X:43,655,006-43,746,817 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.3 | {Antisocial behavior} | 300615 | X-linked recessive | 3 |
| Brunner syndrome | 300615 | X-linked recessive | 3 |
Two monoamine oxidase (EC 1.4.3.4) isoenzymes, MAOA and MAOB (309860), are closely linked in opposite orientation on the X chromosome and are expressed in the outer mitochondrial membrane. MAOA and MAOB oxidize neurotransmitters and dietary amines, the regulation of which is important in maintaining normal mental states. MAOA prefers serotonin, norepinephrine, and dopamine as substrates, whereas MAOB prefers phenylethylamine. Low levels of MAO activity and mutations in the MAOA gene have been associated with violent, criminal, or impulsive behavior (Chen et al., 2004).
Hotamisligil and Breakefield (1991) determined the coding sequence of mRNA for MAOA.
Grimsby et al. (1991) showed that the MAOA and MAOB genes span at least 60 kb, consist of 15 exons, and exhibit identical exon-intron organization. Exon 12 codes for the covalent FAD-binding site and is the most conserved exon. These results, together with close linkage of the genes on chromosome X, suggested that MAOA and MAOB were derived through duplication of a common ancestral gene.
From family studies, Gershon and Goldin (1981) could not show segregation of MAO activity 'as a single major gene,' but a purely nongenetic hypothesis could be rejected. They found no evidence for X-linkage. From study of somatic cell hybrids, however, Breakefield et al. (1980) concluded that monoamine oxidase A is determined by an X-linked gene. In an atypical clone with a fragmented human X chromosome, MAOA segregated with phosphoglycerate kinase which is on the proximal half of Xq. Both forms of monoamine oxidase are X-linked in the rat. Kochersperger et al. (1986) concluded that both MAOA and MAOB are coded by genes on the X chromosome. Breakefield et al. (1987) used a bovine cDNA to screen a cDNA library from human placenta, which expresses only the A form of MAO. A clone of the MAO gene so derived was used to probe the DNA from a panel of human-rodent somatic cell hybrids, and the MAO gene was localized to Xp21-p11. Ozelius et al. (1988) used a nearly full-length cDNA clone for the human enzyme to map the gene to Xp21-p11. By means of a RFLP for this MAOA locus, they estimated its location relative to several other loci on Xp. MAOA lies between DXS14 and OTC, about 29 cM from the former, which is located on Xp11-cen. Levy et al. (1989) localized MAOA to Xp11.4-p11.23 by in situ hybridization using a cDNA probe. They presented evidence that this localization reflects the positions of the genes for both A and B forms of the enzyme. They quoted work indicating that restriction fragments detected by this probe are deleted in some patients with Norrie disease (310600), thus confirming the localization of that disorder.
Using full-length cDNA clones for human MAOA and MAOB, Lan et al. (1989) mapped the 2 genes. Using somatic cell hybrids, in situ hybridization, and field inversion gel electrophoresis as well as deletion mapping in a patient with Norrie disease, they concluded that the 2 genes are close to each other and close to the DXS7 locus in Xp11.3.
By characterizing a 265-kb YAC containing sequences for the MAOA and MAOB genes, Chen et al. (1992) localized these 2 genes within a region of about 240 kb and showed that they are arranged in a tail-to-tail configuration, with the 3-prime coding sequences separated by about 50 kb.
Ou et al. (2006) found that serum starvation-induced apoptosis in cultured human neuronal cell lines increased expression of MAOA, p38 kinase (MAPK14; 600289), and caspase-3 (CASP3; 600636) and reduced expression of BCL2 (151430) and the MAOA transcriptional repressor R1 (CDCA7L; 609685). They determined that MAOA and R1 were downstream of p38 kinase and BCL2, but upstream of CASP3, in the apoptotic signaling pathway. Inhibition of MAOA prevented apoptosis, and serum starvation of cortical brain cells from Maoa-deficient mice resulted in reduced apoptosis compared with wildtype mice. Ou et al. (2006) also found that MAOA and R1 were involved in the MYC (190080)-induced proliferative signaling pathway in the presence of serum. Using R1 overexpression, R1 small interfering RNA, and a MAOA inhibitor, they showed that R1 and MAOA acted upstream of cyclin D1 (168461) and E2F1 (189971) in the cell proliferation pathway.
Only MAOB is present in platelets and only MAOA in trophoblasts; cultured skin fibroblasts show both. Castro Costa et al. (1980) measured monoamine oxidase activity of MAOA in homogenates of cultured human skin fibroblasts and found activities ranging over 50-fold with an apparent bimodal distribution. A genetic polymorphism was suggested. This enzyme is critical in the neuronal metabolism of catecholamine and indolamine transmitters. Fibroblasts are the only cells from living persons that may be used to assess MAOA activity in human populations. The level of MAOB activity in platelets and lymphocytes does not necessarily reflect A activity. MAOA of high and low activity lines did not differ in tryptamine affinity, thermal stability, or clorgyline sensitivity.
Two males with atypical Norrie disease, who were previously shown to have a submicroscopic deletion including the DXS7 locus (de la Chapelle et al., 1985), were shown by Breakefield et al. (1988) to be lacking detectable MAOA and MAOB activity in fibroblasts and platelets. Analysis of metabolites in urine and plasma confirmed a major disruption in the degradation of catecholamines. In the full report on these patients, Sims et al. (1989) demonstrated that the submicroscopic deletion was in the region of Xp21-p11; that the MAOA gene had been deleted; and that fibroblasts lacked mRNA for MAOA. The findings indicated that marked deficiency of MAO activity is compatible with life. Sims et al. (1989) raised a question as to whether some of the features in these patients with Norrie disease, including mental retardation, autistic behavior, abnormal sexual maturation, peripheral autonomic dysfunction, motor hyperactivity, seizures, and sleep disturbance, might be due to mutation in the MAOA or MAOB gene.
Hotamisligil and Breakefield (1991) observed 2 single-bp substitutions in MAOA from cells with a 30-fold difference in enzyme activities. These 2 substitutions were in the third base of a triplet codon; although they could not affect the amino acid sequence, they did result in the presence or absence of restriction enzyme sites. Using these 2 RFLPs plus a third one located in the noncoding region of the MAOA gene, Hotamisligil and Breakefield (1991) found statistically significant associations between particular alleles and the level of MAO activity in human male fibroblast lines. They interpreted this to indicate that the MAOA gene is itself a major determinant of activity levels, apparently, in part, through noncoding, regulatory elements.
Because some features of Brunner syndrome (300615) are similar to those exhibited by bipolar patients during the manic phase of their illness, Lim et al. (1994) carried out an association study using the same microsatellite repeat polymorphism that was used in the study by Brunner et al. (1993). In a sample of 57 unrelated bipolar patients compared with 59 matched normal controls of western European extraction, they found a weak but significant association which they interpreted as suggesting that alleles at the MAOA locus contribute to susceptibility to bipolar disorder but are not a major determinant. A finding of an overall association was replicated by Kawada et al. (1995) in Japanese patients although individual alleles that were found to be associated with disease differed from those in the study of Lim et al. (1994). Nothen et al. (1995) presented data, however, that did not support a widespread or consistent association between alleles at the MAOA locus and bipolar affective disorder. They considered it likely that the findings by Lim et al. (1994) and Kawada et al. (1995) occurred either as a result of population stratification or merely as a chance false-positive.
Association studies at the MAOA locus had been motivated by the finding that mutations in the gene result in the phenotype referred to as Brunner syndrome. It had been proposed that a broad range of interindividual human variability in behavioral phenotypes may be associated with nucleotide variation at the MAOA locus, in particular given the range of interindividual variability in the activity level of the gene product (Hotamisligil and Breakefield, 1991). By sequencing 5 regions totaling 18.8 kb and spanning 90 kb of the MAOA gene in 56 males from 7 different ethnogeographic groups, Gilad et al. (2002) uncovered 41 segregating sites that formed 46 distinct haplotypes. Consistent with differentiation between populations, linkage disequilibrium was higher than expected under panmixia, with no evidence of a decay with distance. The extent of linkage disequilibrium was not typical of nuclear loci and suggested that the underlying population structure may have been accentuated by a selective sweep that fixed different haplotypes in different populations, or by local adaptation. In support of this suggestion, Gilad et al. (2002) found both a reduction in levels of diversity and an excess of high frequency-derived variants, as expected after a recent episode of positive selection.
Because the monoamine oxidase A inhibitors are effective in the treatment of panic disorder, the MAOA gene is a prime candidate for involvement. Deckert et al. (1999) investigated a novel repeat polymorphism in the promoter of the MAOA gene (309850.0002) for association with panic disorder in 2 independent samples, a German sample of 80 patients and an Italian sample of 129 patients. Two alleles containing 3 (3R) and 4 repeats (4R) were most common and constituted more than 97% of the observed alleles. Functional characterization in a luciferase assay demonstrated that the longer alleles (3.5R, 4R, and 5R) were more active than the 3R allele. The longer alleles were significantly more frequent among 209 females of both the German and the Italian samples of panic disorder patients than among 190 females of the corresponding control samples (P = 0.001).
Impairment in the central dopaminergic system has been suggested as a factor in the pathogenesis of restless legs syndrome (RLS; 102300). In 96 unrelated patients with RLS, Desautels et al. (2002) found that females with the high activity alleles (3.5R, 4R, and 5R) in the promoter region polymorphism of the MAOA gene had a greater risk (odds ratio = 2.0) of being affected with RLS than females carrying the low activity allele (3R). The association was not observed in males, and there were no differences for either group regarding the MAOB gene. Desautels et al. (2002) suggested that the MAOA gene may modulate the pathogenesis of RLS and that estrogen may interact with specific MAOA alleles.
Following up on the report of Fossella et al. (2002) in which polymorphisms in the dopamine receptor (DRD4; 126452) and MAOA genes showed significant associations with efficiency of handling conflict as measured by reaction time differences in the Attention Network Test (ANT), Fan et al. (2003) examined whether this genetic variation contributed to differences in brain activation within the anterior cingulate cortex. They genotyped the DRD4 and MAOA genes in 16 subjects who had been scanned during the ANT and identified in each of the 2 genes a polymorphism in which persons with the allele associated with better behavioral performance showed significantly more activation in the anterior cingulate while performing the ANT than those with the allele associated with worse performance. The polymorphisms were the 3R allele of the 30-bp repeat in the MAOA promoter (309850.0002) and the -1217G insertion/deletion polymorphism in the upstream region of the DRD4 gene.
Zalsman et al. (2005) studied the relationship of a MAOA promoter (u-VNTR) and COMT missense (V158M) polymorphisms to CSF monoamine metabolite levels in a psychiatric sample of 98 Caucasians who were assessed for axis I and II diagnoses. CSF was obtained by lumbar puncture and the relationships of the 2 polymorphisms to monoamine metabolites (HVA, 5-HIAA, and MHPG) were examined. The higher-expressing MAOA-uVNTR genotype was associated with higher CSF-HVA levels in males (N = 46) (195.80 pmol/ml, SD = 61.64 vs 161.13, SD = 50.23, respectively; p = 0.042). No association was found with the diagnosis. The COMT V158M polymorphism was not associated with CSF monoamine metabolite levels.
Brunner Syndrome
Brunner et al. (1993) reported a large Dutch kindred with a novel form of X-linked nondysmorphic mild mental retardation. All males in the family affected with the disorder, termed Brunner syndrome (BRNRS; 300615), showed characteristic abnormal behavior, in particular aggressive and sometimes violent behavior. Brunner et al. (1993) reported that each of 5 males affected with Brunner syndrome had a point mutation in the eighth exon of the MAOA structural gene, which changed a glutamine to a termination codon (Q296X; 309850.0001).
In a boy and his 2 maternal uncles with Brunner syndrome, Piton et al. (2014) identified a hemizygous mutation in the MAOA gene (C266F; 309850.0003). The mutation, which was found by high-throughput sequencing of coding exons of intellectual disability genes in the proband, was also present in the proband's unaffected mother. The mutation was present in cis with a low activity promoter polymorphism in the MAOA gene (309850.0002). In vitro studies of the proband's cells showed a significant reduction of MAOA activity as well as decreased levels of MAOA protein. Piton et al. (2014) suggested that the promoter polymorphism may have exacerbated the effect of the C266F mutation.
In affected members of 2 unrelated Australian families with Brunner syndrome, Palmer et al. (2016) identified hemizygous or heterozygous mutations in the MAOA gene (309850.0004 and 309850.0005). Functional studies of the variants were not performed, but patient samples showed high serum serotonin and urinary metanephrines and low urinary 5-hydroxyindoleacetic acid (5-HIAA) and vanillylmandelic acid (VMA), consistent with the diagnosis.
Antisocial Behavior, Susceptibility to
Caspi et al. (2002) studied a large sample of male children from birth to adulthood to determine why some children who are maltreated grow up to develop antisocial behavior (see 300615), whereas others do not. Functional promoter polymorphism (309850.0002) in the MAOA gene was found to moderate the effect of maltreatment. Maltreated children with a genotype conferring high levels of MAOA expression were less likely to develop antisocial problems. Caspi et al. (2002) concluded that their findings may partly explain why not all victims of maltreatment grow up to victimize others, and they provided epidemiologic evidence that genotypes can moderate children's sensitivity to environmental insults.
Among 2,524 participants in a longitudinal study of delinquent behavior in adolescence and young adulthood, Guo et al. (2008) found a significant association between the rare MAOA*2R polymorphism and serious delinquency and violent delinquency. Men with the MAOA*2R variant had about twice the levels of delinquency compared to those with the other MAOA promoter variants. The results for women were similar, but weaker. In vitro functional expression studies in human brain-derived cell lines showed that the 2R promoter exhibited much lower levels of promoter activity than the 3R or 4R promoters, with about 25 to 30% of activity exhibited by the 4R promoter.
Whibley et al. (2010) reported 2 Caucasian brothers with a 240-kb deletion of chromosome Xp11.4-p11.3 that encompassed exon 2 through 15 of the MAOA gene and all exons of the MAOB gene. The NDP gene (300658) was not involved. The brothers had severe developmental delay, mental retardation, seizures, and hang-wringing/lip-smacking behavior. Both had hypotonia in infancy, with worsening episodic hypotonia resembling seizures. The older boy had recurrent screaming episodes with head banging, self scratching of the face, and chewing of the hands. He died unexpectedly at age 5 years. The other boy had episodes of restlessness followed by hypotonia and loss of consciousness. At age 15 years, he could walk, run clumsily, and was social, using single words and sign language. Both had mild facial dysmorphism, with epicanthal folds and long eyelashes, The unaffected mother was a heterozygous carrier of the deletion. Detailed analysis of the deletion indicated that the proximal breakpoint occurred in an L1PA7 LINE element and the distal breakpoint within an AluY element; the authors suggested the occurrence of a nonhomologous end-joining (NHEJ) event. Whibley et al. (2010) concluded that both MAO genes are critical for early brain development and function, since both of their patients had severe to profound mental retardation appearing shortly after birth. This was in contrast to the report of Lenders et al. (1996), which found that MAOB-deficient individuals exhibited neither abnormal behavior nor mental retardation.
Cases et al. (1995) isolated a line of transgenic mice in which transgene integration caused deletion in the gene encoding MAOA, thus providing an animal model of MAOA deficiency. In pup brains, serotonin concentrations were increased up to 9-fold, and serotonin-like immunoreactivity was present in catecholaminergic neurons. In pup and adult brains, norepinephrine concentrations were increased up to 2-fold, and cytoarchitectural changes were observed in the somatosensory cortex. Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness, were reversed by the serotonin synthesis inhibitor parachlorophenylalanine. Adults manifested a distinct behavioral syndrome, including enhanced aggression in males. Shih et al. (1999) contrasted the distinct differences in neurotransmitter metabolism and behavior in MAOA and MAOB knockout mice.
Newman et al. (2005) examined the influence of a monoamine oxidase A gene promoter variation and rearing experience on aggressive behavior in 45 male rhesus monkeys and found that behavioral expression of the MAOA gene is sensitive to social experiences early in development. Specifically, mother-raised male monkeys with the low-activity-associated allele had higher aggression scores.
Chen et al. (2004) identified, bred, and characterized a line of Maoa/Maob double-knockout mice that arose by spontaneous point mutation in Maoa exon 8 in a litter of Maob knockout mice. Double-knockout mice showed reduced body weight compared with wildtype mice. Brain levels of serotonin, norepinephrine, dopamine, and phenylethylamine increased and levels of the serotonin metabolite 5-hydroxyindoleacetic acid decreased to a much greater degree than in either Maoa or Maob single-knockout mice. Chase/escape and anxiety-like behavior in the double-knockout mice differed from that in Maoa or Maob single-knockout mice, suggesting that varying monoamine levels result in both a unique biochemical and behavioral phenotype.
In 5 affected members of a Dutch family with Brunner syndrome (BRNRS; 300615), Brunner et al. (1993) identified hemizygosity for a 936C-T transition in the MAOA gene, resulting in a gln296-to-ter (Q296X) substitution.
Sabol et al. (1998) identified a polymorphism 1.2 kb upstream of the MAOA coding sequences that consists of a 30-bp repeated sequence present in 3, 3.5, 4, or 5 copies (3R, 3.5R, 4R, and 5R, respectively). The polymorphism was in linkage disequilibrium with other MAOA and MAOB (309860) gene markers and displayed significant variation in allele frequency across ethnic groups. The polymorphism was shown to affect transcriptional activity of the MAOA gene promoter by gene fusion and transfection experiments involving 3 different cell types. Alleles with 3.5 or 4 copies of the repeat sequence are transcribed 2 to 10 times more efficiently than those with 3 or 5 copies of the repeat, suggesting an optimal length for the regulatory region. Cohen et al. (2003) referred to this polymorphism as MAOA-uVNTR (for the upstream variable-number tandem repeat region).
Autism
Cohen et al. (2003) examined the relation between this promoter polymorphism and the phenotypic expression of autism (see 209850) in 41 males younger than 12.6 years of age. Children with the low-activity MAOA allele had both lower IQs and more severe autistic behavior than children with the high-activity allele. In follow-up testing of 34 of the males at the 1 year time-point, those with the low-activity allele showed a worsening in IQ but no change in the severity of their autistic behavior. Cohen et al. (2003) concluded that functional MAOA-uVNTR alleles may act as a genetic modifier of the severity of autism in males.
Cohen et al. (2011) presented evidence suggesting that autism severity is associated with child and maternal MAOA genotypes. Among 119 boys with autism, those with the low activity 3-repeat MAOA allele had more severe sensory behaviors, arousal regulation problems, aggression, and worse social communication skills than males with the high activity 4-repeat allele. These findings replicated those of Cohen et al. (2003). Boys with the 3R allele were less affected by maternal genotype than those with the 4R allele. Boys with the 4R allele born of heterozygous 3R/4R mothers were the least affected overall, with greater social communication skills, fewer problem behaviors, and the lowest mean scores for autism. Boys with the 4R allele born of homozygous 4R/4R mothers presented as a high-functioning group, although with excessive anxiety-mediated problems and high levels of irritability. These findings indicated the importance of considering maternal genotype in examining associations of MAOA and other genes with behavior in male offspring.
Antisocial Behavior, Susceptibility to
Caspi et al. (2002) studied a population of 1,037 children, 52% of whom were male, who had been assessed from birth through age 26 years. Between the ages of 3 and 11 years, 8% of the study children experienced severe maltreatment, 28% experienced probable maltreatment, and 64% experienced no maltreatment. Caspi et al. (2002) found that those with low MAOA activity were much more likely to develop antisocial behavior, conduct disorder, a disposition toward violent behavior, or conviction for violent offense than were those with high MAOA activity.
Passamonti et al. (2006) studied the relationship between the MAOA VNTR polymorphism and brain activity elicited by a response inhibition task (go/no go task) using blood oxygenation level-dependent (BOLD) functional MRI in 24 healthy men. Direct comparison between groups revealed a greater BOLD response in the right ventrolateral prefrontal cortex (Brodmann's area (BA) 45 and 47) in high-activity allele carriers, whereas a greater response in the right superior parietal cortex (BA 7) and bilateral extrastriate cortex (BA 18) was found in low-activity allele carriers, suggesting that a specific genetic variation involving serotonergic catabolism can modulate BOLD response associated with human impulsivity.
In a large sample of healthy volunteers, Meyer-Lindenberg et al. (2006) found that those with the low-expression MAOA polymorphism (MAOA-L; 2R, 3R, or 5R) showed an approximately 8% decrease of gray matter volumes in the cingulate gyrus and amygdala, as well as the insula and hypothalamus, compared to those with the high-expression polymorphism (MAOA-H; 3.5R or 4R). MAOA-L males had an approximately 14% increase in volumes in the lateral orbitofrontal cortex compared to MAOA-H males; no such difference in this area was seen in women, suggesting a sex-by-genotype interaction. Functional MRI studies during emotional arousal showed that MAOA-L carriers demonstrated increased amygdala arousal as well as diminished reactivity of regulatory prefrontal regions compared to MAOA-H carriers. Studies of aversive emotional memory retrieval showed that male, but not female, MAOA-L carriers had increased activity in the amygdala and hippocampus and impaired cingulate activation during cognitive inhibition compared to MAOA-H carriers. The findings suggested that sex- and genotype-specific differences in limbic circuitry for emotion regulation and cognitive control may be involved in the association of MAOA with impulsive aggression and/or violence.
Among 2,524 participants in a longitudinal study of delinquent behavior in adolescence and young adulthood, Guo et al. (2008) found a significant association between the rare MAOA*2R polymorphism and serious delinquency and violent delinquency. Men with the MAOA*2R variant had about twice the levels of delinquency compared to those with the other MAOA promoter variants. The results for women were similar, but weaker. In vitro functional expression studies in human brain-derived cell lines showed that the 2R promoter exhibited much lower levels of promoter activity than the 3R or 4R promoters, with about 25 to 30% of activity exhibited by the 4R promoter.
In a behavioral experiment in which male subjects paid to punish those they believed had taken money from them by administering varying amounts of unpleasantly hot (spicy) sauce to their opponent, McDermott et al. (2009) found that those with the MAOA-L genotype were more likely to act aggressively than those with the MAOA-H genotype. The association was significant when the amount of money taken was higher (high provocative situation), suggesting an environmental interaction. The findings suggested that individual variance in genetic factors may contribute to everyday behaviors and decisions.
For discussions of genetic contributions to similar phenotypes, see also COMT (116790.0001) and HTR2B (601122).
In a boy and his 2 maternal uncles with Brunner syndrome (BRNRS; 300615), Piton et al. (2014) identified a hemizygous c.797_798delinsTT mutation in exon 8 of the MAOA gene, resulting in a cys266-to-phe (C266F) substitution in a beta-sheet close to the FAD-binding pocket. The mutation, which was found by high-throughput sequencing of coding exons of intellectual disability genes in the proband, was confirmed by Sanger sequencing. It was not present in the dbSNP or Exome Sequencing Project databases but was present in the boy's unaffected mother. In vitro studies of the proband's cells showed a significant reduction of MAOA activity in patient cells as well as decreased levels of MAOA protein. The mutation was present in cis with a low activity promoter polymorphism in the MAOA gene (309850.0002) that has been associated with decreased MAOA activity and with behavioral disturbances after childhood neglect. Piton et al. (2014) suggested that the promoter polymorphism may have exacerbated the effect of the C266F mutation. The maternal uncles, who had suffered from familial neglect and had been maltreated and sexually abused in early childhood, were more severely affected than the proband.
In 2 adult brothers (family H) from Australia with Brunner syndrome (BRNRS; 300615), Palmer et al. (2016) identified a hemizygous 1-bp insertion (c.749insT, NM_000240) in exon 7 of the MAOA gene, predicted to result in a frameshift and premature termination (Ser251LysfsTer2) in the second FAD domain. The location of the mutation was noted as exon 5 in the text. The mutation was found by X-chromosome exome capture and confirmed by Sanger sequencing. Functional studies of the variant were not performed, but patient samples showed increased serotonin and metanephrines and decreased HVA, VMA, and 5-HIAA, consistent with the diagnosis.
In 2 adult brothers (family R) from Australia with Brunner syndrome (BRNRS; 300615), Palmer et al. (2016) identified a hemizygous c.133C-T transition (c.133C-T, NM_000240) in exon 2 of the MAOA gene, resulting in an arg45-to-trp (R45W) substitution in the first FAD domain. The mutation, which was found by Sanger sequencing of the MAOA gene, was also present in their symptomatic mother in the heterozygous state. It was not present in the ExAC database. Functional studies of the variant were not performed, but patient samples showed increased serotonin and normetanephrine. The family had previously been reported by Cheung and Earl (2001).
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