Deep brain stimulation for the obsessive-compulsive and Tourette-like symptoms of Kleefstra syndrome

Segar, David J; Chodakiewitz, Yosef; Torabi, Radmehr; Cosgrove, G. Rees

doi:10.3171/2015.3.focus1528

Cited by 25 publications

(18 citation statements)

References 25 publications

(50 reference statements)

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“…Nevertheless, Kleefstra is considered a rare single gene trait, although the incidence may likely be underestimated due to lack of genetic testing. In addition, published reports clearly demonstrate a spectrum of phenotypes (Chen et al 2014;Segar et al 2015;Hadzsiev et al 2016;Schmidt et al 2016), most likely due to complexity of modifier genes.…”

Section: Discussionmentioning

confidence: 99%

A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors

Mitra

Dodge

Ness³

et al. 2016

Molec Gen & Gen Med

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BackgroundKleefstra syndrome (KS) is a rare autosomal dominant developmental disability, caused by microdeletions or intragenic mutations within the epigenetic regulator gene EHMT1 (euchromatic histone lysine N‐methyltransferase 1). In addition to common features of autism, young adult regressive behaviors have been reported. However, the genetic downstream effects of the reported deletions or mutations on KS phenotype have not yet been completely explored. While genetic backgrounds affecting drug metabolism can have a profound effect on therapeutic interventions, pharmacogenomic variations are seldom considered in directing psychotropic therapies.MethodsIn this report, we used next‐generation sequencing (exome sequencing and high‐throughput RNA sequencing) in a patient and his parents to identify causative genetic variants followed by pharmacogenomics‐guided clinical decision‐making for making positive changes toward his treatment strategies. The patient had an early autism diagnosis and showed significant regressive behaviors and physical aberrations at age 23.ResultsExome sequencing identified a novel, de novo splice site variant NM_024757.4: c.2750‐1G>T in EHMT1, a candidate gene for Kleefstra syndrome, in the patient that results in exon skipping and downstream frameshift and termination. Gene expression results from the patient showed, when compared to his parents, there was a significant decreased expression of several reported gene variants associated with autism risk. Further, using a pharmacogenomics genotyping panel, we discovered that the patient had the CYP2D6 nonfunctioning variant genotype *4/*4 that results in very low metabolic activity on a number of psychotropic drugs, including fluvoxamine which he was prescribed. As reported here, a change in psychotropic drugs and intense behavior therapies resulted in a significant reversal of the regressive behaviors and physical aberrations.ConclusionThese results demonstrate an individualized approach that integrated genetic information and behavior therapies, resulting in a dramatic improvement in regressive behaviors associated with KS.

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Section: Discussionmentioning

confidence: 99%

A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors

Mitra

Dodge

Ness³

et al. 2016

Molec Gen & Gen Med

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“…After 24 months, SIB and core symptoms of autism spectrum in emotional, social, and cognitive domains were improved, although the scores relied on subjective day-to-day reports by the boy's parents. Segar, Chodakiewitz, Torabi, and Cosgrove, (2015) also reported beneficial effects of BLn DBS for a 24-year old patient with severe autism and Kleefstra syndrome, a rare genetic condition with TS and OCDlike symptoms. Three years after placement of the DBS devices, the patient continued to show improvements in her coprolalia, the involuntary and uncontrollable use of obscene language, social behaviour, and also her TS and OCD-like symptoms.…”

Section: Autismmentioning

confidence: 99%

The application of deep brain stimulation in the treatment of psychiatric disorders

Graat

Figee

Denys

2017

International Review of Psychiatry

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Deep brain stimulation (DBS) is a last-resort treatment for neurological and psychiatric disorders that are refractory to standard treatment. Over the last decades, the progress of DBS in psychiatry has been slower than in neurology, in part owing to the heterogenic symptomatology and complex neuroanatomy of psychiatric disorders. However, for obsessive-compulsive disorder (OCD) DBS is now an accepted treatment. This study first reviews clinical outcomes and mechanisms of DBS for OCD, and then discusses these results in an overview of current and future psychiatric applications, including DBS for mood disorders, Tourette's syndrome, addiction, anorexia nervosa, autism, schizophrenia, and anxiety disorders. In addition, it will focus on novel techniques that may enhance the application of DBS in psychiatry.ARTICLE HISTORY

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“…In a recent study published by the first author, volumes of tissue activated from the active contacts of the posteromedial hypothalamus, included the dorsal longitudinal fasciculum, the amygdala, and the MFB, although connectivity was not analysed before and after surgery [24]. Regarding studies specifically evaluating DBS for ASD, there are only 3, including 4 patients, among which 1 had Kanner autism [37] and another case, Kleefstra syndrome [38]. Except for the last case, DBS of the temporal amygdala and globus pallidum was successful in relieving the pathological aggressiveness [39].…”

Section: Discussionmentioning

confidence: 99%

Surgery and Radiosurgery in Autism: A Retrospective Study in 10 Patients

Torres

Martínez

Ríos-Lago

et al. 2021

Stereotact Funct Neurosurg

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Introduction: A subgroup of patients with autism spectrum disorder (ASD) show self or heteroaggression, dyscontrol episodes, and others are of obsessive-compulsive disorder (OCD) profile; some of them are resistant to medical and behavioural treatment. We describe the long-term outcome in a group of these patients, treated with radiofrequency brain lesions or combined stereotactic surgery and Gamma Knife (GK) radiosurgery. Methods: We reviewed the medical records of 10 ASD patients with pathological aggressiveness and OCD, who had undergone radiofrequency lesions and/or radiosurgery with GK in our institution. Results: The 10 patients had a significant reduction of their symptoms (PCQ 39.9 and 33, OAS 11.8 and 5, CYBOCS-ASD 30.4 and 20), preoperatively and in the last follow-up, respectively; p < 0.005 (in all cases), although all but 2 needed more than 1 treatment to maintain this improvement. Conclusions: We observed a marked improvement in behaviour, quality of life, and relationship with the environment in all our 10 patients after the lesioning treatments, without long-lasting side effects.

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Deep brain stimulation for the obsessive-compulsive and Tourette-like symptoms of Kleefstra syndrome

Cited by 25 publications

References 25 publications

A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors

A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors

The application of deep brain stimulation in the treatment of psychiatric disorders

Surgery and Radiosurgery in Autism: A Retrospective Study in 10 Patients

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