New insights into Brunner syndrome and potential for targeted therapy

• Published in: Clinical genetics Vol. 89; no. 1; pp. 120 - 127
• Main Authors: Palmer, E.E., Leffler, M., Rogers, C., Shaw, M., Carroll, R., Earl, J., Cheung, N.W., Champion, B., Hu, H., Haas, S.A., Kalscheuer, V.M., Gecz, J., Field, M.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2016
• Subjects: Aggression; Amine oxidase (flavin-containing); Amino Acid Sequence; Antidepressants; Attention Deficit Hyperactivity Disorder; autism spectrum disorder; Brunner syndrome; Children; diagnosis; Diarrhea; Disruptive, Impulse Control, and Conduct Disorders - drug therapy; Disruptive, Impulse Control, and Conduct Disorders - genetics; Exome; Genes, X-Linked; Genetic Association Studies; Genetic Diseases, X-Linked - drug therapy; Genetic Diseases, X-Linked - genetics; Genetic disorders; Genetic Loci; Headache; High-Throughput Nucleotide Sequencing; Humans; intellectual disability; Intellectual Disability - drug therapy; Intellectual Disability - genetics; Intelligence; Male; MAO-A deficiency; Mental disorders; Middle Aged; Models, Molecular; Molecular Sequence Data; Molecular Targeted Therapy; Monoamine Oxidase - chemistry; Monoamine Oxidase - deficiency; Monoamine Oxidase - genetics; Pedigree; Phenotype; Protein Conformation; Sequence Alignment; Serotonin; Serotonin uptake inhibitors; treatment; Urine; treatment; serotonin; MAO-A deficiency; diagnosis; autism spectrum disorder; Brunner syndrome; intellectual disability
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.12589

We report two families with Brunner syndrome living in one state of Australia. The first family had a predicted protein‐truncating variant of monoamine oxidase A (MAOA) (p.S251KfsX2). Affected males had mild intellectual disability (ID), obsessive behaviour, limited friendships and were introverted and placid during clinical interview. The family disclosed episodic explosive aggression after a diagnosis was made. The second family had a missense variant in MAOA (p.R45W). Affected males had borderline‐mild ID, attention deficit disorder and limited friendships. One had a history of explosive aggression in childhood and episodic symptoms of flushing, headaches and diarrhoea. Their carrier mother had normal intelligence but similar episodic symptoms. Characteristic biochemical abnormalities included high serum serotonin and urinary metanephrines and low urinary 5‐hydroxyindoleacetic acid (5‐HIAA) and vanillylmandelic acid (VMA). Symptomatic individuals in the second family had particularly high serotonin levels, and treatment with a serotonin reuptake inhibitor and dietary modification resulted in reversal of biochemical abnormalities, reduction of ‘serotonergic’ symptoms and behavioural improvement. Brunner syndrome should be considered as a cause of mild ID with paroxysmal behavioural symptoms. It can be screened for with serum/urine metanephrine and serotonin measurement. Cautious treatment with a serotonin reuptake inhibitor, dietary modifications and avoidance of medications contraindicated in patients on monoamine oxidase inhibitors can improve symptoms.