An open-label study evaluating the safety, behavioral, and electrophysiological outcomes of low-dose ketamine in children with ADNP syndrome

Kolevzon, Alexander; Levy, Tess; Barkley, Sarah; Bedrosian‐Sermone, Sandra; Davis, Matthew M.; Foss‐Feig, Jennifer H.; Halpern, Danielle; Keller, Katherine; Kostić, Ana; Layton, Christina; Lee, Rebecca; Lerman, Bonnie; Might, Matthew; Sandin, Sven; Siper, Paige M.; Sloofman, Laura; Walker, Hannah E; Zweifach, Jessica; Buxbaum, Joseph D.

doi:10.1016/j.xhgg.2022.100138

Cited by 12 publications

(9 citation statements)

References 56 publications

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“…By applying precise phenotyping, Helsmoortel–Van der Aa syndrome may be clinically recognisable, but a “genotype-first” approach may be needed to establish the diagnosis of patients, which then may help patients and families obtain access to treatment options. In ANDP syndrome, promising results have been achieved with low-dose ketamine in a study of 10 patients, independent from their genotype [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Helsmoortel–Van der Aa Syndrome—Cardiothoracic and Ectodermal Manifestations in Two Patients as Further Support of a Previous Observation on Phenotypic Overlap with RASopathies

Szabó

Balogh

Újfalusi

et al. 2022

Genes

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The ADNP-gene-related neurodevelopmental disorder Helsmoortel–Van der Aa syndrome is a rare syndromic-intellectual disability—an autism spectrum disorder first described by Helsmoortel and Van der Aa in 2014. Recently, a large cohort including 78 patients and their detailed phenotypes were presented by Van Dijck et al., 2019, who reported developmental delay, speech delay and autism spectrum disorder as nearly constant findings with or without variable cardiological, gastroenterological, urogenital, endocrine and neurological manifestations. Among cardiac malformations, atrial septal defect, patent ductus arteriosus, patent foramen ovale and mitral valve prolapse were the most common findings, but other unspecified defects, such as mild pulmonary valve stenosis, were also described. We present two patients with pathogenic ADNP variants and unusual cardiothoracic manifestations—Bland–White–Garland syndrome, pectus carinatum superiorly along the costochondral junctions and pectus excavatum inferiorly in one patient, and Kawasaki syndrome with pericardiac effusion, coronary artery dilatation and aneurysm in the other—who were successfully treated with intravenous immunoglobulin, corticosteroid and aspirin. Both patients had ectodermal and/or skeletal features overlapping those seen in RASopathies, supporting the observations of Alkhunaizi et al. 2018. on the clinical overlap between Helsmoortel–Van der Aa syndrome and Noonan syndrome. We observed a morphological overlap with the Noonan-like disorder with anagen hair in our patients.

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Section: Discussionmentioning

confidence: 99%

Helsmoortel–Van der Aa Syndrome—Cardiothoracic and Ectodermal Manifestations in Two Patients as Further Support of a Previous Observation on Phenotypic Overlap with RASopathies

Szabó

Balogh

Újfalusi

et al. 2022

Genes

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“…The ketamine rationale is based on the finding that ketamine increased ADNP expression, however, the possibility of ketamine increasing mutated ADNP expression needs to be further investigated [ 140 – 142 ]. Meanwhile, an open label trial of a low doses of ketamine in ten individuals affected with the Helsmoortel–Van der Aa syndrome demonstrated that the drug is well tolerated and considered safe [ 143 ]. A nominal improvement in the Clinical Global Impressions—Improvement Scale, was reported, which according to the authors should be interpreted with care due to the study limitations of a small cohort size and the absence of a control group.…”

Section: Candidate Drugs For the Helsmoortel–van Der Aa Syndromementioning

confidence: 99%

Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism

et al. 2023

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Background Individuals affected with autism often suffer additional co-morbidities such as intellectual disability. The genes contributing to autism cluster on a relatively limited number of cellular pathways, including chromatin remodeling. However, limited information is available on how mutations in single genes can result in such pleiotropic clinical features in affected individuals. In this review, we summarize available information on one of the most frequently mutated genes in syndromic autism the Activity-Dependent Neuroprotective Protein (ADNP). Results Heterozygous and predicted loss-of-function ADNP mutations in individuals inevitably result in the clinical presentation with the Helsmoortel–Van der Aa syndrome, a frequent form of syndromic autism. ADNP, a zinc finger DNA-binding protein has a role in chromatin remodeling: The protein is associated with the pericentromeric protein HP1, the SWI/SNF core complex protein BRG1, and other members of this chromatin remodeling complex and, in murine stem cells, with the chromodomain helicase CHD4 in a ChAHP complex. ADNP has recently been shown to possess R-loop processing activity. In addition, many additional functions, for instance, in association with cytoskeletal proteins have been linked to ADNP. Conclusions We here present an integrated evaluation of all current aspects of gene function and evaluate how abnormalities in chromatin remodeling might relate to the pleiotropic clinical presentation in individual“s” with Helsmoortel–Van der Aa syndrome.

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“…Ketamine’s effects – particularly its adverse events – are generally transient and, while there has been concern about a potential neurotoxic effect of ketamine administered at high doses, (40mg/kg), subclinical and subanesthetic are well tolerated and may, in fact, have neuroprotective effects (Jia & Hong, 2014; Acevedo-Diaz, et al, 2020). To this end, the first open-label safety and preliminary efficacy trial of intravenous ketamine was carried out in ADNP syndrome (Kolevzon, et al, 2022). This study was the first of its class for ADNP syndrome and provides preliminary clinical evidence for improvements in key domains of social communication, attention deficient and hyperactivity, restricted and repetitive behaviors, speech, and activities of daily living.…”

Section: Introductionmentioning

confidence: 99%

“…To build upon these recent efforts, we present complimentary molecular data from individuals with ADNP syndrome who participated in the ketamine trial (Kolevzon, et al, 2022). The primary goal of the current investigation was to examine the transcriptomic response to ketamine treatment in blood and in the immune milieu and to dissect its effects on ADNP-related biology.…”

Section: Introductionmentioning

confidence: 99%

Transient peripheral blood transcriptomic response to ketamine treatment in children with ADNP syndrome

Buxbaum Grice,

Sloofman,

Levy

et al. 2024

Preprint

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Activity-dependent neuroprotective protein (ADNP) syndrome is a rare neurodevelopmental disorder resulting in intellectual disability, developmental delay and autism spectrum disorder (ASD) and is due to mutations in the ADNP gene. Ketamine treatment has emerged as a promising therapeutic option for ADNP syndrome, showing safety and apparent behavioral improvements in a first open label study. However, the molecular perturbations induced by ketamine remain poorly understood. Here, we investigated the longitudinal effect of ketamine on the blood transcriptome of 10 individuals with ADNP syndrome. Transcriptomic profiling was performed before and at multiple time points after a single low-dose intravenous ketamine infusion (0.5mg/kg). We show that ketamine triggers immediate and profound gene expression alterations, with specific enrichment of monocyte-related expression patterns. These acute alterations encompass diverse signaling pathways and co-expression networks, implicating up-regulation of immune and inflammatory-related processes and down-regulation of RNA processing mechanisms and metabolism. Notably, these changes exhibit a transient nature, returning to baseline levels 24 hours to 1 week after treatment. These findings enhance our understanding of ketamine's molecular effects and lay the groundwork for further research elucidating its specific cellular and molecular targets. Moreover, they contribute to the development of therapeutic strategies for ADNP syndrome and potentially, ASD more broadly.

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An open-label study evaluating the safety, behavioral, and electrophysiological outcomes of low-dose ketamine in children with ADNP syndrome

Cited by 12 publications

References 56 publications

Helsmoortel–Van der Aa Syndrome—Cardiothoracic and Ectodermal Manifestations in Two Patients as Further Support of a Previous Observation on Phenotypic Overlap with RASopathies

Helsmoortel–Van der Aa Syndrome—Cardiothoracic and Ectodermal Manifestations in Two Patients as Further Support of a Previous Observation on Phenotypic Overlap with RASopathies

Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism

Transient peripheral blood transcriptomic response to ketamine treatment in children with ADNP syndrome

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