WHAT IS CHD2?

CHD2 syndrome is a rare, genetic, neurologic disorder caused by a change, variation or mutation in the CHD2 gene. CHD2 was first discovered in 2013 by Dr. Gemma Carvill and Dr. Heather Mefford at the Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.

 

Basic Genetics

 

  • The human body is made up of trillions of cells. Most recent estimates put the number of cells at around 30 trillion.

  • Each cell contains 23 pairs of chromosomes (46 total, 23 from each parent).

  • Each chromosome contains hundreds to thousands of genes. 

  • Like chromosomes, genes come in pairs; we get one copy from each parent and they are made of strands of genetic material called DNA.

  • DNA is the code used to produce proteins. Proteins are used to build and regulate the body’s tissues and organs.

  • Genetic disorders are caused by one or more changes (variants or mutations) in the instruction code of a particular gene(s), preventing the gene(s) from functioning properly.

  • Genetic changes that are new in an individual, also called de novo mutations/variants, are not passed from generation to generation. Rather they occur as new mutations in the sperm or egg, or occasionally very early in human development.

  • Most CHD2 patients have de novo mutations, and would therefore not have a family history of this condition.

 

The main types of mutations found are:

 

  • Nonsense (also called a stop mutation or truncation)

  • Missense

  • Frameshift

  • Duplication

  • Deletion

 

For more information on these you can visit: 

https://ghr.nlm.nih.gov/primer/mutationsanddisorders/possiblemutations

 

The Role of CHD2

 

The CHD2 gene is located on Chromosome 15 at 15q26.1 and provides instructions for making a protein called chromodomain DNA helicase protein 2. 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 can 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. Chromodomain DNA helicase protein 2 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 nerve cells (neurons). The majority of known CHD2 mutations that cause CHD2-related neurodevelopmental disorders lead to non-functional protein (truncation of the protein), suggesting that when there isn’t enough chromodomain DNA helicase protein 2 in the body, this disorder occurs. See https://www.ncbi.nlm.nih.gov/books/NBK333201/

Clinical Characteristics

CHD2-related neurodevelopmental disorders can be characterized by early-onset developmental and epileptic encephalopathy (DEE). DEE are a group of disorders  with seizures that do not respond to anti-seizure medications and there is often learning and developmental impairment of regression. Seizure onset is typically between ages six months and four years. Seizure types typically include drop attacks, myoclonus, and a rapid onset of multiple seizure types associated with generalized spike-wave on EEG, atonic-myoclonic-absence seizures, and clinical photosensitivity. Intellectual disability and/or autism spectrum disorders are common. However, not all individuals with CHD2 mutations have the same clinical features and the full spectrum of features is yet to be defined (Carvill et al, 2005) https://www.ncbi.nlm.nih.gov/books/NBK333201/

 

What Are The Symptoms?

 

CHD2 is considered a spectrum disorder since patients are not all affected exactly the same way or with the same severity. It is not known yet what impacts the symptoms or their severity. The list below is a combination of the most commonly seen symptoms. CHD2 patients do not always present with all of these symptoms.

 

  • Epilepsy (subtle eyelid flutters, brief jerks, staring seizures and drop seizures)

  • Global developmental delays

  • Autism Spectrum Disorder or autistic features

  • ADHD, hyperactive behavior, or inattentive behavior

  • Intellectual disability (mild to severe) or learning disabilities

  • Behavioral problems including aggression

  • Developmental delay of speech

  • Motor delays

  • Regression (loss of milestones)

  • Hypotonia (low muscle tone)

  • Ataxia (lack of muscle control/coordination)

How Rare Is CHD2?


CHD2 mutations are thought to be the cause of 1% of developmental and epileptic encephalopathies. We currently have 139 diagnosed CHD2 patients in the world, but we know there are likely thousands more undiagnosed patients out there. Some are yet to be diagnosed for a few reasons:

 

  • Families receive a diagnosis like epilepsy, autism and/or intellectual disability and stop their search there.

  • Cost and access to genetic testing can be a barrier to getting a genetic explanation for all of the symptoms.

  • CHD2 as a disorder was only discovered in 2013, so all genetic tests done before 2013, and some for 3-4 years after would not have shown any CHD2 mutations, as it takes time for genes to be included on testing panels.

  • Some patients have a ‘variants of uncertain significance – VUS’ in CHD2. A VUS is when there is insufficient information about a variant to determine whether it is associated with the child’s symptoms, or not. There are now tests that look at the DNA methylation profile of a child with a CHD2 VUS and can determine if the DNA methylation is the same as patients with CHD2 mutations, if so, that CHD2 variant is the likely cause. If your child or family member had a VUS in CHD2 talk to your doctor or genetic counselor about ordering a DNA methylation test.

How Is It Diagnosed?

 

Not all genetic tests can identify CHD2 mutations. In some cases, Chromosome Microarray Analysis can show bigger deletions or duplications on chromosome 15, which may include the CHD2 gene; however the best way to diagnose CHD2 mutations is through an Epilepsy Panel, Exome, or Genome sequencing.

 

Is There A Treatment/Cure?

 

There is currently no cure or specific treatment for CHD2; however ASMs (Anti-Seizure Medications) can be used to help reduce the frequency and intensity of seizures. Therapy can help CHD2 patients improve their skills and reach milestones. The most common therapies are Physical Therapy, Occupational Therapy, Speech Therapy, Developmental Therapy and ABA Therapy.

 

CHD2 patients respond well to alternative therapies as well, including hippotherapy, aqua therapy, music therapy, PROMPT Therapy, etc.

 

CHD2 patients unfortunately will never catch up to their peers and always show delays, but they can continue to make progress and reach key milestones.


The Bright Side

 

As difficult as CHD2 is, most CHD2 patients are a joy to be around. They are happy, loving and full of life. Their laughter is contagious. They are very affectionate. Most CHD2 patients love water, music, animals and have a strong will, high pain tolerance and wonderful smiles.

After The Diagnosis

 

It is likely that as you read this you are looking for information on a condition that a loved one close to you has. The information in this document will assist your journey. While we are not medical professionals, we are a group of families who live with CHD2 daily. Other than our wonderful CHD2 children, we are the closest experts there can be to a full understanding of the CHD2 rare disease. This expertise, teamed with access to your local clinicians and intervention therapy providers, will support you and provide you with a full understanding of living with CHD2.

 

If you are new to the CHD2 world, we want to welcome you to our community. It will take time to accept the diagnosis but know that you are not alone. Since there are so few of us around the world, we are here to support each other.

​Please note that this information page was written by CHD2 parents, not medical professionals.