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Brunner syndrome is a rare X-linked recessive disorder caused by loss-of-function variants in MAOA, characterized by impulsive aggression, mild intellectual disability, sleep disturbances, seizures, and serotonergic biochemical abnormalities. The association has been replicated in two unrelated Australian families and multiple independent case reports, with biochemical confirmation of MAO-A deficiency in patient-derived cells and concordant computational modeling of pathogenic variants. Genetic and functional data collectively support a robust gene–disease relationship.
Genetic evidence includes a maternally inherited missense variant c.410A>G (p.Glu137Gly) identified by whole-exome sequencing in a 5-year-old boy with developmental delay and myoclonic epilepsy and his mother with mild intellectual disability and serotonergic symptoms ([PMID:37750385]). Three additional unrelated males with MAOA variants—c.133C>T (p.Arg45Trp) in one family and c.749_750insT (p.Ser251fs) in another—presented with mild intellectual disability, episodic aggression, flushing, headaches, and diarrhea; segregation of these variants in affected males and carrier females confirms X-linked inheritance ([PMID:25807999]). Two more singletons with novel missense variants (p.Thr408Met and an intronic splice-site change) expand the allelic spectrum and neuropsychiatric phenotypes to include attention deficit hyperactivity disorder and REM sleep behavior disorder ([PMID:39450862], [PMID:38881510]).
Segregation analysis across five pedigrees revealed at least three additional affected male relatives harboring hemizygous MAOA variants and obligate carrier females with mild cognitive or serotonergic phenotypes, confirming co-segregation with disease in extended kindreds. The variant spectrum comprises predominantly missense changes (including recurrent Ser251fs and Arg45Trp), one frameshift insertion, and rare deep-intronic/splice variants.
Functional studies provide mechanistic support. A standardized MAO-A enzyme assay in patient fibroblasts demonstrated negligible catalytic activity in affected individuals versus normal or intermediate activity in carriers ([PMID:33728254]). Multiscale molecular simulations of pathogenic variants Cys266Phe and Val244Ile predict 18,000-fold and 300-fold reductions in serotonin catabolism, respectively, consistent with clinical hyperserotonemia and behavioral manifestations ([PMID:40135540]).
The data indicate that MAOA haploinsufficiency due to severe catalytic impairment underlies Brunner syndrome. Concordant patient biochemistry, enzyme assays, and in silico modeling establish a clear loss-of-function mechanism. No conflicting evidence has been reported to date.
In summary, MAOA fulfills ClinGen criteria for a strong gene–disease association with Brunner syndrome. Genetic testing for MAOA variants accompanied by enzyme activity assays enables definitive diagnosis and informs targeted interventions, including serotonin reuptake inhibitors and dietary modification. Key take-home: MAOA variant analysis combined with functional confirmation guides accurate diagnosis and personalized management of Brunner syndrome.
Gene–Disease AssociationStrongTwo unrelated families (4 affected males) and three additional unrelated probands with MAOA variants, multi-generational segregation, functional studies in patient cells and computational modeling support the association. Genetic EvidenceStrongVariants identified in >7 affected individuals across five pedigrees with segregation and enzyme assay confirmation. Functional EvidenceModerateMAO-A activity assays differentiate patients from carriers (100%), and simulations predict severe catalytic impairment for pathogenic variants. |