Etiological Diagnosis and Disease Course of Birk–Barel Syndrome in an Adult Woman with a KCNK9 Variant

Willem Verhoeven,1– 3 Ingrid Spee,4 Charlotte Wilhelmina Ockeloen,5 Rolph Pfundt,5,6 Jos Egger3,5,6 1Department of Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands; 2Centre for Consultation and Expertise, CCE, Utrecht, the Netherlands; 3Centre of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray, the Netherlands; 4Antroprosophic Institute for People with Intellectual Disabilities, Raphaelstichting Scorlewald, Schoorl, the Netherlands; 5Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; 6Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the NetherlandsCorrespondence: Willem Verhoeven, Centre of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Stationsweg 46, Venray, 5803 AC, the Netherlands, Tel +31 651 156 556, Email wmaverhoeven@planet.nlIntroduction: Birk-Barel syndrome (BIBARS), also known as KCNK9 imprinting syndrome, is an extremely rare genetic condition caused by pathogenic variants in the KCNK9 gene located on the long arm of chromosome 8 (8q24). This gene is paternally imprinted and therefore only expressed from the maternal allele. KCNK9 encodes for a member of the two-pore domain potassium channel (K2P) subfamily. BIBARS syndrome is characterized by congenital hypotonia and weakness of proximal muscles, intellectual disability, behavioural problems, dysmorphic features, feeding problems and epilepsy. The syndrome is implied in neurodevelopment, plays a role in various regulatory systems (eg, blood pressure maintenance, respiratory function, sleep, and cognitive function), and is associated with absence epilepsy.Methods: An institutionalized adult female patient with intellectual disability and challenging behaviours was presented whose history was carefully described and in whom extensive somatic, neurological, psychiatric and psychological investigation was performed, in addition to whole exome sequencing.Results: Intellectual disability, developmental delay with severe psychotrauma from early age on, as well as severe aggressive and self-injurious behaviours were established. Whole exome sequencing finally disclosed a pathogenic variant in the KCNK9 gene and an absence epilepsy in association with BIBARS was suspected. After treatment with valproic acid epileptic phenomena no longer occurred and behaviour and emotion regulation improved significantly.Discussion: A pathogenic heterozygous missense variant in the KCNK9 gene corresponding with a diagnosis of Birk-Barel syndrome was considered to be largely responsible for the severely disinhibited behaviours and causative for the absence epilepsy. For adequate diagnosis and treatment of neurodevelopmental disorders, this case clearly demonstrates the importance of adherence to clinical standards, in particular periodically renewed genetic analysis by means of WES/WGS.Keywords: KCNK9 imprinting syndrome, TASK3, Birk–Barel syndrome, BIBARS, absence epilepsy, potassium channel, channelopathies