100,858 research outputs found
Psychiatry and Neurocognition in Genetic Developmental Disorders: The Emblematic Case of Kleefstra Syndrome
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195502.pdf (Publisher’s version ) (Open Access)Radboud University, 05 oktober 2018Promotores : Egger, J.I.M., Bokhoven, J.H.L.M. van, Staal, W.G. Co-promotor : Kleefstra, T
Kleefstra syndrome: neuropsychiatric sequelae
No full textIntroductionSubmicroscopic deletions of the distal long arm of chromosome 9q are relatively common and give rise to a clinically recognizable phenotype referred to as the Kleefstra Syndrome [OMIM 610253]. It was shown that haploinsufficiency of the EHMT1 (Euchromatic Histone Methyltransferase 1) gene is responsible for the core phenotype by identifying cases with intragenic EHMT1 loss of function mutations. Key features of the syndrome are mental retardation, childhood hypotonia and facial dysmorphisms. Congenital heart and renal defects, microcephaly, epilepsy, and behavioural problems are frequently present.ObjectivesDescription of the developmental, behavioural and neuropsychiatric characteristics in 4 middle aged patients with recently diagnosed Kleefstra syndromeAimsContributing to the putative behavioural phenotype of Kleefstra syndrome.MethodsDetailed neuropsychiatric and neuropsychological assessment.ResultsIn the 4 patients, conventional cytogenetic investigation showed normal karyotypes. With routine subtelomeric MLPA and additional 9q regional specific MLPA tests, a submicroscopic deletion of the long arm of chromosome 9 (9q34.3) was found. Both deletions comprised the EHMT1 gene, in agreement with the diagnosis of Kleefstra syndrome. In all patients a severe apathy and a marked dyssomnia were present. Although some motor symptoms could be assessed with a catatonia rating scale, these have to be considered as a consequence of the apathy and belong therefore not to the catatonic spectrum.ConclusionsKleefstra syndrome is constituted, in addition to its distinct phenotypic features, by a specific behavioural phenotype that comprises, apart from the absence of speech development, a specific sleep disturbance and severe apathy from the third decade on.</jats:sec
Cognitive and psychopathological phenotyping of rare Mendelian disorders: Towards a neuropsychological algorithm
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227290.pdf (Publisher’s version ) (Open Access)Radboud University, 17 december 2020Promotor : Egger, J.I.M. Co-promotores : Kleefstra, T., Wingbermühle, P.A.M.170 p
Genetic elucidation of autosomal recessive intellectual disability
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111382.pdf (Publisher’s version ) (Open Access)Radboud Universiteit Nijmegen, 17 mei 2013Promotor : Bokhoven, J.H.L.M. van Co-promotores : Kleefstra, T., Brouwer, A.P.M. d
Histone Methylation by the Kleefstra Syndrome Protein EHMT1 Mediates Homeostatic Synaptic Scaling
No full textHomeostatic plasticity, a form of synaptic plasticity, maintains the fine balance between overall excitation and inhibition in developing and mature neuronal networks. Although the synaptic mechanisms of homeostatic plasticity are well characterized, the associated transcriptional program remains poorly understood. We show that the Kleefstra-syndrome-associated protein EHMT1 plays a critical and cell-autonomous role in synaptic scaling by responding to attenuated neuronal firing or sensory drive. Chronic activity deprivation increased the amount of neuronal dimethylated H3 at lysine 9 (H3K9me2), the catalytic product of EHMT1 and an epigenetic marker for gene repression. Genetic knockdown and pharmacological blockade of EHMT1 or EHMT2 prevented the increase of H3K9me2 and synaptic scaling up. Furthermore, BDNF repression was preceded by EHMT1/2-mediated H3K9me2 deposition at the Bdnf promoter during synaptic scaling up, both in vitro and in vivo. Our findings suggest that H3K9me2-mediated changes in chromatin structure govern a repressive program that controls synaptic scaling
Making headway with the molecular and clinical definition of rare genetic disorders with intellectual disability
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108606.pdf (Publisher’s version ) (Open Access)Radboud Universiteit Nijmegen, 17 oktober 2012Promotores : Hamel, B.C.J., Bokhoven, J.H.L.M. van, Schrojenstein Lantman-de Valk, H.M.J. van Co-promotor : Kleefstra, T
Twins with Kleefstra syndrome due to chromosome 9q34.3 microdeletion
No full textTwins with Kleefstra syndrome due to chromosome 9q34.3 microdeletion: Kleefstra or 9q subtelomeric deletion syndrome (9qSTDS) is a rare microdeletion syndrome. The most prominent phenotypic features include hypotonia, developmental retardation, as well as typical dysmorphic face. It has been shown that terminal deletions of the chromosome 9q34.3 region, or EHMT 1 gene mutations, lead to Kleefstra syndrome. We present 16-month-old twin sisters, one of whom had originally been referred for Down syndrome screening due to hypotonia, growth and development retardation, dysmorphic facial signs, and accompanying congenital heart disease. They were subsequently diagnosed as Kleefstra syndrome based on subtelomeric FISH analysis. In conclusion, Kleefstra syndrome should be considered in the differential diagnosis of Down syndrome because it presents with very similar phenotypic features
Neurocognition, adaptive functioning, and psychopathology in Kleefstra syndrome
No full textObjective: The diagnostic yield for rare genetic causes for ID has increased tremendously over the last years. Studies that focus on sub-cohorts with known underlying genetic causes may enable to define more specific profiles that potentially could guide tailor made management. In our present study we aimed to examine if EHMT1 gene defects, which are also known as Kleefstra Syndrome (KS) in human, are associated with specific profiles for adaptive and maladaptive functioning. Participants and Methods: In total we studied 58 subjects with ID (28 males, 30 females): 24 with Kleefstra Syndrome and 34 controls. They were examined with the Vineland Adaptive Behavior Scale, mini PAS-ADD interview, Autism Diagnostic Observation Schedule and the Cambridge Neuropsychological Test Automated Battery (CANTAB) to obtain measures of adaptive and maladaptive functioning. This study has an explorative nature and statistical analysis were used to contrast the results (Fisher's exact test for prevalences, Mann-Whitney tests for subscale scores). Results: KS-participants have low levels of adaptive functioning. Autism spectrum disorders are extremely prevalent (about 100%, p=0,001). There are also signifantly high prevalences and symptom scores for depressive episodes (41,6%, p=0,043), obsessive compulsive disorders (33,3%, p=0,03) and psychotic symptoms (29,2%, p=0,005). The performance and results at the CANTAB are discussed in line with these. All together this results in a discriminating neuropsychiatric picture in KS patients. Conclusions: KS patients are extremely vulnerable to develop neuropsychiatric disorders and should be carefully monitored for this
Kleefstra syndrome: Considerations about treatment strategy in 2 patients with a causative Ehmt1 mutation and apathy
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174237.pdf (Publisher’s version ) (Closed access)Introduction: Kleefstra syndrome [OMIM: 610253] is caused by a 9q34.3 micro-deletion or an intragenic mutation in the EHMT1 gene. Its core phenotype comprises intellectual disability, childhood hypotonia and distinct dysmorphisms. The syndrome can be associated with congenital anomalies, epilepsy, cardiac arrhythmias and a typical sleep pattern. Starting from adult age, a regressive phenotype may develop. Objectives: Further delineation of the neuropsychiatric phenotype. Aims: Formulating a comprehensive treatment approach. Methods: Detailed examination of two patients with EHMT1 mutation. Results: Patient 1, male aged 34 years, showed recurrent behavioral problems with aggression and self-injuries as well as obstipation. Elsewhere, a diagnosis of autism was established. Aged 24, he suffered from some epileptic seizures. Recently, paroxysmal atrial fibrillation was diagnosed. Neither treatment with pipamperone and risperidone nor with valproate was effective for behavioral control. Array analysis and metabolic screening did not reveal abnormalities. Whole exome sequencing revealed an intragenic EHMT1 mutation. Patient 2, female aged 53 years, was known with childhood epilepsy and developed gradual decline of general functioning with motor slowing from her third decade. In her thirties, a mood/anxiety disorder was suspected for which several antidepressants were given without any effect. Array analysis was normal. A pathogenic nucleotide deletion was identified resulting in a frame-shift in exon 21 of the EHMT1 gene. In both patients marked apathy was observed (AES = 62 and 64, respectively). Conclusions: Apathy syndrome in Kleefstra syndrome should be differentiated from depression and autism. Apart from treatment with selected psychotropics, individually targeted contextual measures should always be implemented.1 p
Update on Kleefstra syndrome
No full textKleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric featur
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