THE SCIENCE OF CHD2
CHD2-related Neurodevelopmental Disorders
Individuals with CHD2-related neurodevelopmental disorders most commonly suffer from (1) refractory epilepsy and (2) developmental delays
Another clinical feature that may be unique to CHD2 disorders is photosensitivity epilepsy, which involves seizures caused by flashing lights.
What is CHD2?
The CHD2 gene is located on chromosome 15 at 15q26.1 and provides instructions for making a protein called chromodomain-DNA-helicase-binding protein 2, CHD2. This protein is found in cells throughout the body and regulates gene activity (expression) through a process known as chromatin remodeling. Chromatin is the complex of DNA and proteins that packages DNA into chromosomes. The structure of chromatin may be changed (remodeled) to alter how tightly DNA is packaged. When DNA is tightly packed, gene expression is less likely than when DNA is loosely packed. CHD2 appears to play an important role in the brain, although its function is not well understood. Research suggests that it may help control development or functioning of brain cells (neurons). The majority of known pathogenic (disease-causing) variants in the gene that cause CHD2-related neurodevelopmental disorders lead to non-functional protein (truncation of the protein), suggesting that when there isn’t enough CHD2 in the body, this disorder occurs. The clinical features of CHD2-related neurodevelopmental disorders includes, among other things, refractory or drug-resistant epilepsy.
What are other names for CHD2?
What types of seizures (and epilepsies) are associated with CHD2?
Seizure types associated with CHD2-related neurodevelopmental disorders typically include:
- tonic clonic seizures, which involve loss of consciousness, muscle rigidity and convulsions;
- myoclonic body jerks or involuntary muscle twitches;
- eyelid flutters/myoclonia;
- drop attacks;
- atonic-myoclonic-absence seizures;
- photosensitivity epilepsy caused by flashing lights; and
- a rapid onset of multiple seizure types associated with generalized spike-waves on an EEG.
CHD2-related neurodevelopmental disorders may be characterized by early-onset developmental and epileptic encephalopathy (DEE). DEE are a group of seizure disorders that do not respond to anti-seizure medications and are often associated with learning and developmental impairment and regression. The onset of seizures and other non-seizure type symptoms of CHD2-related neurodevelopmental disorders typically first present within the first five (5) years of life. The frequency of seizures may vary significantly from person to person, with some having multiple daily seizures, while others may have a seizure once a week, once a month or once a year, and others may have no seizures at all.
Epilepsies commonly associated with the CHD2 gene include:
- West Syndrome
What non-seizure symptoms are seen in CHD2?
Common non-seizure symptoms of CHD2-related neurodevelopmental disorders include:
- Intellectual disability (ID) ranging from mild to severe
- Autism spectrum disorders (ASD)
- Developmental delays
- Neuropsychiatric conditions, including bipolar disorder, psychosis, ADHD
- Low muscle tone
- Other challenging behaviors such as aggression
Not all individuals with CHD2 variants have the same clinical features and the full spectrum of features is yet to be defined.
How is CHD2 diagnosed?
A pathogenic variant in the CHD2 gene is identified by molecular genetic testing.
How is CHD2 treated?
While CHD2-related disorders are commonly associated with refractory or drug-resistant epilepsy, individuals suffering from these disorders have found some success in controlling the frequency of their seizures using the following anti-seizure medication (this list is not intended to be an exhaustive list): Lamotrigine, Clobazam, Epidiolex, Felbamate, Keppra, Zonisimide, Topirimate, Oxtellar, Clonazepam, Oxcarbazepine, and Depakote, among others.
There are no treatments or therapies specific to the CHD2 genetic disorder, but because a majority of individuals diagnosed with a CHD2 disorder have been diagnosed with autism spectrum disorders, intellectual disabilities and/or speech delays, therapies commonly used to treat these clinical features are commonly used to treat individuals with CHD2. These therapies include, but are not limited to, speech therapy, occupational therapy, physical therapy, behavioral therapy and psychological and developmental therapy. Specialists commonly seen include neurologists, orthopedists, dieticians, special needs dentists, cardiologists, gastroenterologists, geneticists and chiropractors.
How common is CHD2?
To date, there have been 205 patients diagnosed with a pathogenic variant in the CHD2 gene, but we know there are likely thousands more who have yet been diagnosed. Individuals with pathogenic CHD2 variants reside all over the world, and this condition presents about equally in males and females. For the moment, we do not have adequate data to be able to report comprehensively on the burden of this condition.
What is the outlook for CHD2?
Some individuals with the CHD2 disorder experience normal development prior to the onset of seizures, but once seizures occur, intellectual and developmental delays may become more prevalent and, in some cases, regression may occur. While some may outgrow their seizures, many will likely live with their seizures (although controlled to some degree for some) throughout their lifetime.
A number of researchers and pharmaceutical companies are either currently working on, or are considering working on or investing in, the development of drugs or precision therapies that may improve the lives of those living with CHD2, or that may even lead to a cure for this disorder.
A parent advocacy group known as Coalition to Cure CHD2 was organized in 2020, which has the mission of raising awareness of this disorder and raising funds to fund research to find a cure for the disorder.
To learn more about Coalition to Cure CHD2, see www.curechd2.org. As more is known about the disorder and the natural progression of the disorder, and as more individuals are tested for the disorder, the chances of finding a cure or treatments to help improve the lives of individuals living with CHD2 may increase exponentially.
Christine Salmi, Co-Founder and Co-President of Coalition to Cure CHD2, Inc.
Reviewed and Approved by: Dr. Gemma Carvill, Asst. Professor, Department of Neurology at Northwestern University Feinberg School of Medicine, Chicago, Illinois, and Dr. Heather Mefford, Center for Pediatric Neurological Disease Research, Department of Cell & Molecular Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee
The medical/clinical information included in this submission comes from presentations and webinars presented by Coalition to Cure CHD2's Chair of its Scientific Advisory Board, Dr. Gemma Carvill, who is an Assistant Professor in the Department of Neurology at Northwestern University Feinberg School of Medicine in Chicago, Illinois, and is a leader in the field of CHD2 research. Other clinical/medical information in this submission comes from a natural history study conducted of 59 CHD2 families in 2018, which was created and led by Dr. Anne Berg, Research Professor at the Ann & Robert H. Lurie Children's Hospital of Chicago and the Northwestern Feinberg School of Medicine. The results of Dr. Berg's natural history study can be found on Coalition to Cure CHD2's website, www.curechd2.org under the "Science" "Natural History Study" tabs.