Adaptive and maladaptive functioning in Kleefstra syndrome compared to other rare genetic disorders with intellectual disabilities

Abstract

Detailed neurobehavioural profiles are of major value for specific clinical management, but have remained underexposed in the population with intellectual disabilities (ID). This was traditionally classified based on IQ level only. Rapid advances in genetics enable etiology based stratification in the majority of patients, which reduces clinical heterogeneity. This paper illustrates that specific profiles can be obtained for rare syndromes with ID. Our main aim was to study (mal)adaptive functioning in Kleefstra Syndrome (KS) by comparing and contrasting our findings to three other subgroups: Koolen-de Vries Syndrome, GATAD2B-related syndrome, and a mixed control group of individuals with ID. In total, we studied 58 individuals (28 males, 30 females) with ID; 24 were diagnosed with KS, 13 with Koolen-de Vries Syndrome, 6 with the GATAD2B-related syndrome, and 15 individuals with undefined neurodevelopmental disorders. All individuals were examined with a Vineland Adaptive Behavior Scale, mini PAS-ADD interview, and an Autism Diagnostic Observation Schedule to obtain measures of adaptive and maladaptive functioning. Each of the three distinctive genetic disorders showed its own specific profile of adaptive and maladaptive functioning, while being contrasted mutually. However, when data of the subgroups altogether are contrasted to the data of KS, such differences could not be demonstrated. Based on our findings, specific management recommendations were discussed for each of the three syndromes. It is strongly suggested to consider the genetic origin in individuals with congenital neurodevelopmental disorders for individual based psychiatric and behavioral management.

Increased H3K9 methylation and impaired expression of Protocadherins are associated with the cognitive dysfunctions of the Kleefstra syndrome

“…Our epigenetic analysis disclosed the potential molecular mechanisms impaired in the Kleefstra syndrome. Interestingly Tdo2 , an enzyme indirectly involved in serotonin metabolism ( 46 ), is in our data up-regulated only in Ehmt1 +/− (2.2-fold H3K4me3, 1.7 RNA-seq plus changes in H3K4me1, H3K27ac, H3K36me3, DNA methylation), suggesting that serotonin deregulation could be one underlying cause of the depressive/mood disorders we observed in patients with Kleefstra syndrome ( 47 ). Also the Protocadherins ( Pcdhs ), cell-adhesion molecules that confer unique identities to individual neurons ( 30 , 31 ), appeared extensively repressed specifically in Ehmt1 +/− brain.…”

Neuropsychiatric decompensation in adolescents and adults with Phelan-McDermid syndrome: a systematic review of the literature

“…Kleefstra syndrome is caused by deletions or mutations of the EHMT1 gene, encoding a histone methyltransferase, and, like PMS, presents with ID, ASD, severe speech deficits, and hypotonia, in addition to distinctive facial features. At least six individuals with Kleefstra syndrome have been reported with severe behavioral regression developing during adolescence or adulthood, with periods of apathy and catatonia-like behaviors [62–64]. Individuals with Kleefstra syndrome also exhibit a high prevalence of depression, psychosis, and obsessive–compulsive disorder, with a general decline in functioning in all patients older than 18 years, usually preceded by severe sleep problems [65].…”

Intellectual disability and autism spectrum disorders ‘on the fly’: insights from Drosophila

“…Another disorder for which Drosophila contributed much of our current knowledge is Kleefstra syndrome. The disorder, caused by haploinsufficiency of the eukaryotic histone methyltransferase 1 gene ( EHMT1 ) (Kleefstra et al, 2010; Vermeulen et al, 2017), is characterized by ID, comorbid ASD in all patients reported so far (Vermeulen et al, 2017), behavioral problems and other clinical features, including recurrent infections and obesity (Kleefstra et al, 2012). Loss of Drosophila G9a , the ortholog of EHMT1 , only resulted in subtle anomalies of da neurons and did not show other detectable nervous system architecture anomalies (Kramer et al, 2011).…”