Helsmoortel-Van Der Aa Syndrome

Results of a small but unique research study suggest that low-dose ketamine is generally safe, well-tolerated and effective to treat clinical symptoms in children diagnosed with ADNP syndrome (also known as Helsmoortel-VanDerAa syndrome), a rare neurodevelopmental disorder caused by mutations in the activity dependent neuroprotective protein (ADNP) gene. Results of a small, but unique research study, led by researchers from the Seaver Autism Center for Research and Treatment at Mount Sinai and published online in Human Genetics and Genomic Advances, suggest that low-dose ketamine is generally safe, well-tolerated and effective to treat clinical symptoms in children diagnosed with ADNP syndrome (also known as Helsmoortel-VanDerAa syndrome), a rare neurodevelopmental disorder caused by mutations in the activity dependent neuroprotective protein (ADNP) gene. The ADNP gene affects brain formation, development, and function, and the protein produced from it helps control the expression of other genes. ADNP mutations are one of the most common single-gene causes of autism. Ketamine was approved in the United States in 1970 and is used for anesthesia and pain management, and more recently as a treatment for depression. Studies in animal models suggest that low-dose ketamine may be neuroprotective and increase expression of the ADNP gene. "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." In order 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. They 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 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.

Researchers have associated gene mutations with certain neurological disorders, such as autism and schizophrenia. However, it wasn’t entirely clear how these mutations resulted in the disorders they were associated with. Now, new research has tied some of the mechanisms together. For that and more research news, continue reading. Mutational Mechanism in Different Genes Linked to Autism, Schizophrenia and More Researchers at Tel Aviv University have worked out a mechanism shared by mutations in the ADNP and SHANK3 genes, which cause autism, schizophrenia and other conditions. They also conducted assays using an experimental drug developed in Prof. Illana Gozes’ laboratory that is effective in laboratory models for the mutations. They believe it provides encouraging results for possible treatments for a range of diseases that impair brain functions and cause autism, schizophrenia, and neurodegenerative diseases such as Alzheimer’s. The research was published in Molecular Psychiatry. “Some cases of autism are caused by mutations in various genes,” said Gozes, who led the research. “Today we know of more than 100 genetic syndromes associated with autism, 10 of which are considered relatively common (though still extremely rare). In our lab we focus mainly on one of these, the ADNP syndrome, caused by mutations in the ADNP gene, which disrupt the function of the ADNP protein, leading to structural defects in the skeleton of neurons in the brain. In the current study, we identified a specific mechanism that causes this damage in mutations in two different genes: ADNP and SHANK3 — a gene associated with autism and schizophrenia. According to estimates, these two mutations are responsible for thousands of cases of autism around the world.” They found that when the ADNP protein is defective, it forms neurons with faulty microtubules, which impairs brain functions. Also, ADNP mutations take different forms, which can result in varying levels of damage. In some cases, a mutation added to the protein protects it and reduces the damage. That same control site is found on SHANK3. They also found that more sites on the ADNP protein can bond with SHANK3 and similar proteins. One of the sites is located on NAP, a section of ADNP that was developed into their experimental drug, davunetide. Gozes said, “We concluded that the ability to bond with SHANK3 and other similar proteins provides some protection against the mutation’s damaging effects.” Single Nucleotide Mutation Provides Insight into Epilepsy Researchers at Linkoping University found a previously unidentified mutation in a child with epilepsy. It involved a single nucleotide in the KCNA2 gene, which produces an ion channel protein. These proteins form pores in the cell surface membrane. In epilepsy, the balance in the brain between signals that increase cell activity and signals that suppress it is disturbed, and the nerve cells send signals in an uncontrolled fashion. In the patient, the mutated ion channel would typically have a calming effect on nerve signaling. The researchers noted that mutations in ion channels that increase function and others that decrease function have been linked to epilepsy. It appears that there needs to be just the right amount of activity. In the case of this patient, because he had one mutated copy and one normal, they would have expected 50% functional ion channels. But they found the channel activity in the laboratory was as low as 20% compared to normal. The mutation seemed to decrease the function of the normal proteins. Possible New Marker for Breast Cancer Patients Investigators from the University of Southampton identified “crown-like structures” surrounding breast tumors in overweight and obese patients that may inhibit their response to therapy. They believe this may eventually be used to enhance personalized treatments for patients with HER2-positive overexpressed breast cancer. The crown-like structures are formed from inflammatory immune cells called macrophages. This appears to cause an inflammatory environment in the breast, leading to the initiation and growth of new tumors. In the study, patients who were overweight or obese had significantly more of these structures in their fat tissue surrounding the tumor, which was associated with a faster shift to metastatic disease. They then identified a potential molecular biomarker, CD32B, on the surface of the macrophages in these structures. When CD32B was present in these patients, their response to trastuzumab therapy was worse. Preventing or Delaying Type 2 Diabetes The 21-year follow-up from the Diabetes Prevention Program Outcomes Study (DPPOS) was published in Circulation. The new findings describe the 21-year follow-up of more than 3,200 adults with prediabetes who participated in the original Diabetes Prevention Program trial. The study found that lifestyle changes or the use of metformin were effective long-term in preventing or delaying Type 2 diabetes in adults with prediabetes, but these changes didn’t appear to decrease the risk of heart attack, stroke or dying from cardiovascular disease compared to the standard care group. Almost 11% of the U.S. population has been diagnosed with Type 2 diabetes or more than 34 million people. It is caused by the body’s inability to efficiently utilize insulin manufactured in the pancreas. Adults with type 2 diabetes are twice as likely to die from cardiovascular disease than adults without T2D. People with T2D often have other risk factors, including overweight or obesity, high blood pressure or high cholesterol. “The fact that neither a lifestyle intervention program nor metformin led to a decrease in cardiovascular disease among people with prediabetes may mean that these interventions have limited or no effectiveness in preventing cardiovascular disease, even though they are highly effective in preventing or delaying the development of Type 2 diabetes,” Dr. Ronald B. Goldberg, M.D. said, chair of the writing group for the DPPOS and a professor of medicine, biochemistry and molecular biology in the division of diabetes, endocrinology and metabolism, and senior faculty member and co-director of the Diabetes Research Institute Clinical Laboratory at the University of Miami’s Miller School of Medicine in Miami, Florida. “It’s important to note that most study participants also received treatment with cholesterol and blood pressure medications, which are known to reduce CVD risk. Therefore, the low rate of development of cardiovascular disease found overall may have been due to these medications, which would make it difficult to identify a beneficial effect of lifestyle or metformin intervention. Future research to identify higher risk subgroups is needed to develop a more targeted approach to cardiovascular disease prevention in people with prediabetes and Type 2 diabetes.”