Brunner Syndrome

A number sign (#) is used with this entry because of evidence that Brunner syndrome (BRNRS) is caused by mutation in the gene encoding monoamine oxidase A (MAOA; 309850) on chromosome Xp11.

Description

Brunner syndrome is a recessive X-linked disorder characterized by impulsive aggressiveness and mild mental retardation associated with MAOA deficiency (Brunner et al., 1993).

Clinical Features

In a large Dutch kindred, Brunner et al. (1993) identified a novel form of X-linked nondysmorphic mild mental retardation. All affected males in the family showed characteristic abnormal behavior, in particular aggressive and sometimes violent behavior. Other types of impulsive behavior included arson, attempted rape, and exhibitionism. Attempted suicide was reported in a single case. Results of urinalysis in 3 affected males indicated a marked disturbance of monoamine metabolism. These data were considered consistent with a primary defect in the structural gene for MAOA and/or MAOB (309860). Normal platelet MAOB activity suggested that the unusual behavior pattern in this family may be caused by isolated MAOA deficiency.

Piton et al. (2014) reported a French family in which several affected males manifested a cognitive disorder similar to Brunner syndrome. The 7-year-old proband had autism as well as impulsive and autoaggressive behavior, and showed anger when frustrated. Other features included feeding and sleep difficulties in early life, delayed motor development, and amimic facial expressions. Laboratory studies showed increased urinary levels of the MAOA substrates normetanephrine and metanephrine, as well as decreased serum levels of MAOA products. The proband's 2 maternal uncles had severely delayed psychomotor development requiring placement in a school for special needs in childhood. They had autistic features and auto- and heteroaggressive outbursts, could not read or write, and had poor autonomy. Both suffered from familial neglect and had been maltreated and sexually abused in early childhood. Two deceased maternal great-uncles of the proband reportedly had encephalopathy and had been institutionalized their whole lives. The maternal grandmother of the proband had depression and psychotic disturbances; the proband's mother was unaffected.

Palmer et al. (2016) reported 2 unrelated families from Australia with Brunner syndrome. All patients were adults at the time of the report. In family H, 2 brothers had mild intellectual disability with limited literacy and a history of impulsivity, school expulsions, violent episodes, explosive tempers, limited interests with obsessive behavior, disturbed wake/sleep cycle, occasional body twitches, and essential tremor. The patients did not receive psychopharmacologic treatment, and no specific serotonergic symptoms or worsening of behavior with high tyramine foods or medication were noted. In family R, previously reported by Cheung and Earl (2001), 2 brothers had mild intellectual disability with poor or absent literacy and attention deficit-hyperactivity disorder (ADHD). The patients were generally 'placid,' but 1 had a history of impulsive and aggressive behavior when ingesting high tyramine foods, severe night terrors, and episodic flushing, diarrhea, and headache. The other patient had difficulty sustaining friendships and some obsessive traits, but only occasional episodes of flushing, diarrhea, and headache. Both also had essential tremor. Their mother had normal intelligence with paroxysmal episodes of flushing, diarrhea, headache, and palpitations. All affected members of family R had exacerbation of serotonergic symptoms when consuming food and drink high in tyramine, and responded favorably to treatment with a selective serotonin reuptake inhibitor (SSRI). Biochemical studies of patient tissue samples showed high serum serotonin and urinary metanephrines and low urinary 5-hydroxyindoleacetic acid (5-HIAA) and vanillylmandelic acid (VMA).

Clinical Management

Palmer et al. (2016) found that treatment of a mother and her 2 sons (family R) with Brunner syndrome using a selective serotonin reuptake inhibitor (SSRI) resulted in a reduction of symptoms. The patients did have initial exacerbation of symptoms, but after some time showed a reduction of symptoms, including normalization of biochemical parameters. Palmer et al. (2016) noted the paradoxical response to SSRI treatment, which theoretically would increase serotonin levels and thus exacerbate symptoms. The authors recommended that patients with Brunner syndrome avoid food and medications contraindicated in patients on MAO inhibitors and that they be issued medical alert bracelets.

Inheritance

The transmission pattern of Brunner syndrome in the families reported by Brunner et al. (1993) and Piton et al. (2014) was consistent with X-linked recessive inheritance.

Mapping

By genetic linkage analysis using markers spanning the X chromosome, Brunner et al. (1993) assigned the locus for Brunner syndrome to chromosome Xp21-p11 between DXS7 and DXS77. A maximal multipoint lod score of 3.69 was obtained for linkage to MAOA at chromosome Xp11.4-p11.23.

Molecular Genetics

Brunner et al. (1993) reported that each of 5 affected males with Brunner syndrome had a point mutation in exon 8 of the MAOA gene, which changed a glutamine to a termination codon (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) that has been associated with decreased MAOA activity and with behavioral disturbances after childhood neglect. 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, and that the protective familial environment of the proband may have mitigated his phenotype compared to that of his uncles.

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 increased serotonin and metanephrines and decreased HVA, VMA, and 5-HIAA, 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 whereas others do not. A 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.

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.

Genotype/Phenotype Correlations

The difficulties in relating a cognitive or behavioral phenotype to a specific genotype were indicated by the criticism of Brunner et al. (1993) leveled by Hebebrand and Klug (1995) that the 'clinical delineation of the phenotype appears so vague that it can be questioned whether it indeed results from the mutation.' (A similar question existed about the phenotype/karyotype relationships in the XYY 'syndrome.') Their criticism pertained to (1) inadequate delineation of the cognitive and behavioral phenotype, (2) the assumed X-linked inheritance of the phenotype, and (3) the lod score calculation, which was performed without assuming a phenocopy rate. Brunner and Ropers (1995) responded that 'Hebebrand and Klug's desire for phenotypes that are specific enough to allow recognition in the general population is somewhat unrealistic given the complex basis of any behaviour in humans, both normal and abnormal. Although the genes may be simple, the behaviour they affect is necessarily much more complex.' They stated further that 'there has always been a clear dichotomy between affected and unaffected males, both from the perspective of the family, as well as from our interviews with affected and unaffected family members.' In a response to the response, Hebebrand and Klug (1995) stated that the psychiatric and forensic evaluations seemed inadequate. 'Thus, did the affected males (n = ?) with exhibitionism fulfill the DSM-III-R or DSM-IV criteria for exhibitionism? What exactly did the individuals do who had a history of voyeurism or arson? Can it be excluded that some of the 'unaffected' males, who perhaps have a high intelligence level, refused to disclose their socially unacceptable behavior to the interviewer (or other family members)?'