Rare Genetic Mutations Found in Up to 25% of Children With ADHD

The mutation-positive cohort was more likely to have issues with disruptive behaviors, anger control, and inappropriate movements compared with the mutation-negative cohort.

As of 2011, an estimated 11% of US children aged 4-17 years have been diagnosed with  attention-deficit/hyperactivity disorder (ADHD), and the numbers continue to increase.1 Findings presented in October at the 63rd Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) show that up to one-quarter of children with the disorder have rare genetic mutations.2

In a study sponsored by Medgenics, Inc., researchers investigated rates of mutations in glutamatergic network genes in 1,013 ADHD patients from 23 US centers. Participants were aged 6-17 and either had a preexisting ADHD diagnosis or met DSM-5 criteria for ADHD diagnosis at the time of the screening visit. The median age at diagnosis was 7 years.

The team was led by Josephine Elia, MD, a psychiatrist at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Delaware, and included researchers at The Children’s Hospital of Philadelphia. In a previous study, some of the same authors compared 3,500 ADHD patients with approximately 13,000 control subjects.3 They found that more frequent copy number variations (CNVs) affected specific metabotropic glutamate receptors (glutamate receptor metabotropic, GRM) and GRM family genes, and the ones linked with ADHD had large effect sizes (odds ratios >4). Some of the GRM network mutations were observed solely in the ADHD patients.

Expanding on these earlier findings, the team aimed to determine the prevalence of GRM network mutations in a population of ADHD patients by assaying 273 genes in the GRM network. Additionally, the previous study had revealed that some of the patients with GRM network mutations had a significant number of comorbid conditions, which indicates that there may be differentiating phenotypic traits between these patients and those without the mutations. As such, the researchers also sought to identify any such distinguishing traits in the present study.

GRM mutations were found in 22% of the overall sample and in 25% of patients aged 6-17. The mutation-positive cohort was more likely to have issues with disruptive behaviors, anger control, and inappropriate movements compared with the mutation-negative cohort. As with the general prevalence of ADHD, the mutation-positive cohort consisted of higher numbers of male patients.

These findings support a phase 2/3 interventional trial called SAGA, which will test the efficacy of a non-stimulant ADHD treatment called NFC-1 in mutation-positive adolescents.* “Our ultimate aim is to develop a genomically targeted, safe and superior product for this subpopulation of ADHD patients,” Liza Squires, MD, Vice President, Research and Development at Medgenics, Inc. said in a press release.4 “This would be the first such targeted therapy in any CNS disease and highlights the emergence of precision medicine in this therapeutic area.”

*More information about the SAGA trial can be viewed at https://clinicaltrials.gov/ct2/show/NCT02777931

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  1. Centers for Disease Control and Prevention. Attention Deficit/Hyperactivity Disorder (ADHD). Retrieved 11/7/16 from http://www.cdc.gov/ncbddd/adhd/data.html.

  1. Elia J, Glessner JT, Wang K, et al. Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat Genet. 2011; 44(1):78-84.

  2. Elia J, Kim C, Khan M, et al. Glutamatergic Network Gene Mutations in Adolescents and Children with Attention Deficit Hyperactivity Disorder (ADHD). Abstract presented at the American Academy of Child and Adolescent Psychiatry (AACAP) 63rd Annual Meeting; October 2016.

  1. Medgenics Presents New Data Showing Prevalence of Genetic Mutations in Pediatric Populations with Attention Deficit Hyperactivity Disorder. [press release]. Philadelphia, Pa. Medgenics. November 7, 2016.