The research was led by researchers from the Seaver Autism Center for Research and Treatment at Mount Sinai and published online in Human Genetics and Genomic Advances.
Ketamine was approved in the United States in 1970. Studies in animal models suggest that low-dose ketamine may be neuroprotective and increase the expression of the ADNP gene.
The ADNP gene affects brain formation, development, and function, and the protein produced from it control the expression of other genes. ADNP mutations are one of the most common single-gene causes of autism. The result from a small but unique research study suggested that a low dose of ketamine is safe and effective for treating children with ADNP syndrome (also known as Helsmoortel-VanDerAa syndrome).
“We were intrigued by the preclinical evidence suggesting that low-dose ketamine may increase levels of the ADNP protein and compensate for its loss in ADNP syndrome, so we designed this study to evaluate the safety, tolerability, and behavioral outcomes of low-dose ketamine in children with the syndrome,” says Alexander Kolevzon, MD, Clinical Director of the Seaver Autism Center. “We also sought to explore the feasibility of using electrophysiological biomarkers and computerized eye-tracking to assess sensitivity to treatment.”
To evaluate the effect of ketamine, the Mount Sinai research team used a single-dose (0.5mg/kg), open-label design, with ketamine infused intravenously over 40 minutes. Ten children with ADNP syndrome, ages six to 12 years, were enrolled.
The team found ketamine was generally well-tolerated, and there were no serious adverse events. The most common adverse events were elation/silliness (50 percent), fatigue (40 percent), and increased aggression (40 percent). Using parent-report instruments to assess treatment effects, ketamine was associated with improvements in a wide array of domains, including social behavior, attention deficit and hyperactivity, restricted and repetitive behaviors, and sensory sensitivities, a week after administration.
Results from the clinician-rated assessments indicated improvement based on the Clinical Global Impression-Improvement scale, a seven-point scale commonly used by clinicians to assess how much a patient’s illness has improved or worsened relative to a baseline state at the beginning of an intervention.
Importantly, results across clinician-rated and caregiver-rated assessments were largely consistent. The results also highlight the potential of assessing early changes in social attention with computerized eye-tracking and the electrophysiological measurement of a listening task known as an auditory steady-state response.
“We are encouraged by these findings, which provide preliminary support for ketamine to help reduce negative effects of this devastating syndrome,” Dr. Kolevzon says. “Future studies using a placebo-controlled design and studying the effects of repeated dosing over a longer duration of time and in a larger cohort of participants are needed before ketamine is used clinically, but our study is a promising first step in that process.”
Ongoing studies are using RNA sequencing to measure change in ADNP expression and other genes, as well as DNA methylation analysis, which has been previously described as relevant in ADNP syndrome.
DNA methylation regulates and silences the expression of genes and is vital for embryonic development. Increased occurrence of rare and extreme DNA methylation levels have been linked with neurodevelopmental disorders and congenital anomalies.
Parvathy Sukumaran 
