Ethylmalonic encephalopathy is an inherited disorder that affects several body systems, particularly the nervous system. Neurological signs and symptoms include delayed development and the loss of previously acquired skills (developmental regression), weak muscle tone (hypotonia), seizures, and abnormal movements. The body's network of blood vessels (the vascular system) is also affected. Children with this disorder often develop rashes of tiny red spots (petechiae) caused by bleeding under the skin and blue discoloration in the hands and feet due to reduced oxygen in the blood (acrocyanosis). Chronic diarrhea is another common feature of ethylmalonic encephalopathy.

The signs and symptoms of ethylmalonic encephalopathy are apparent at birth or begin in the first few months of life. Problems with the nervous system typically worsen over time, and most affected individuals survive only into early childhood.

Ethylmalonic encephalopathy results from mutations in the ETHE1 gene. This gene provides instructions for making an enzyme that is active in mitochondria, which are the energy-producing centers in cells. The ETHE1 enzyme is part of a pathway that breaks down sulfide (H2S), a molecule that is critical at very low levels for normal cell functioning but is toxic at high levels. Excess sulfide interferes with numerous cell activities, including mitochondrial energy production.

Mutations in the ETHE1 gene lead to the production of a nonfunctional version of the enzyme or prevent any enzyme from being made. A shortage of functional ETHE1 enzyme prevents sulfide from being broken down, allowing this molecule to accumulate in cells. The buildup of sulfide interferes with the ability of mitochondria to produce energy and damages tissues and organs throughout the body. Researchers believe that the effects of excess sulfide in the brain, muscles, blood vessels, and lining of the intestines underlie most of the major features of ethylmalonic encephalopathy.

Normal Function

The ETHE1 gene provides instructions for making an enzyme that is active in mitochondria, which are the energy-producing centers in cells. The ETHE1 enzyme is part of a pathway that breaks down a molecule called sulfide (H2S) in mitochondria. Sulfide is produced in the body's tissues as part of normal cell processes, and it is also released by bacteria living in the gastrointestinal system (gut).

At low levels, sulfide is critical for normal cell functioning. However, this molecule becomes toxic at high levels, interfering with numerous cell activities. For example, excess sulfide interferes with mitochondrial energy production by blocking (inhibiting) an enzyme complex called cytochrome C oxidase (COX). This complex normally carries out one of the final steps in the process of energy production in mitochondria.

Health Conditions Related to Genetic Changes

Ethylmalonic encephalopathy

More than 30 mutations in the ETHE1 gene have been identified in people with ethylmalonic encephalopathy. This rare condition affects many parts of the body, including the nervous system, blood vessels, and intestines. Signs and symptoms include delayed development, abnormal movements, rashes of tiny red spots under the skin (petechiae), blue discoloration of the hands and feet (acrocyanosis), and chronic diarrhea.

Most of the mutations that cause ethylmalonic encephalopathy lead to the production of nonfunctional versions of the ETHE1 enzyme or prevent cells from making any of this enzyme. A shortage of functional enzyme prevents sulfide from being broken down normally, allowing this molecule to accumulate in cells. The buildup of sulfide inhibits the activity of COX, which disrupts mitochondrial energy production and damages tissues and organs throughout the body. Researchers believe that the effects of excess sulfide in the brain, muscles, blood vessels, and lining of the intestines underlie most of the major features of ethylmalonic encephalopathy.

Leigh syndrome

MedlinePlus Genetics provides information about Leigh syndrome

Other Names for This Gene

• ETHE1_HUMAN
• ethylmalonic encephalopathy 1
• Ethylmalonic encephalopathy protein 1
• hepatoma subtracted clone one
• HSCO
• YF13H12

Genomic Location

Ethylmalonic encephalopathy is a genetic condition. Babies inherit it from their biological (birth) parents.

• Ethylmalonic encephalopathy is an autosomal recessive condition. Babies inherit the condition when each parent passes down a nonworking ETHE1 gene to their baby. Only babies with two nonworking ETHE1 genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the ETHE1 gene are called carriers.
  • Carriers do not have or develop the condition. However, they may pass down a nonworking copy of the gene to their children.
  • If two parents are carriers of a nonworking copy of the ETHE1 gene, they have a 1 in 4 chance of having a child with Ethylmalonic encephalopathy.
  • Carriers for Ethylmalonic encephalopathy often do not know they are carriers before having a child with the condition. In most cases, families have no history of the condition until the birth of a child with Ethylmalonic encephalopathy.
  • Parents who already have a child with Ethylmalonic encephalopathy still have a 1 in 4 chance of having another child with Ethylmalonic encephalopathy. This 1 in 4 chance stays the same for all future children.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

The following list includes the most common signs and symptoms in people with ethylmalonic encephalopathy. These features may be different from person to person. Some people may have more symptoms than others and symptoms can range from mild to severe. This list does not include every symptom or feature that has been described in this condition.

Symptoms may include:

• Low muscle tone (hypotonia)
• Developmental delay
• Intellectual impairment that gets worse over time
• Injury to blood vessels
• Red spots on the skin (petechiae)
• Blue discoloration of the extremities (acrocyanosis)
• Chronic diarrhea
• Seizures

Symptoms of ethylmalonic encephalopathy are present from birth. The first symptom may be low muscle tone. Early development may be normal, but children with EE usually lose skills over time. Signs of blood vessel damage, such as red spots on the skin, usually appear in early childhood. People with EE develop spasms of the limbs and are often unable to walk without support. Swallowing difficulties and diarrhea lead to poor growth. Infectious illnesses can cause the neurological symptoms to get worse. Most people with EE die in childhood. EE is a variable disease and a few mild cases of this condition have been reported.

Newborn screening for Ethylmalonic encephalopathy requires collecting a small amount of blood from your baby’s heel. Screening measures how much of certain substances (called acylcarnitines) are in your baby’s blood. Babies with high levels of these substances might have Ethylmalonic encephalopathy.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for Ethylmalonic encephalopathy is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood and/or urine tests
• Genetic testing using a blood sample

You should complete any recommended follow-up testing as soon as possible. Babies with this condition can have serious health problems right away if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition can happen. Babies given carnitine might receive false-positive results. Babies with other conditions with high levels of C4 acylcarnitine may also be detected through this screening. Examples of other conditions that may be detected are short-chain acyl-CoA dehydrogenase deficiency and isobutyryl-CoA dehydrogenase deficiency.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps.

It is important to talk to your health care provider about which treatment(s) are best for your baby. While there are no treatment options available that can stop the progression of Ethylmalonic encephalopathy, there are treatments to help with some of the symptoms.

Treatments may include the following:

• Muscle relaxants
• Physical therapy
• Medications to help seizures

About 70 individuals with this condition have been identified worldwide, mostly in Mediterranean and Arab populations. Although ethylmalonic encephalopathy appears to be very rare, researchers suggest that some cases have been misdiagnosed as other neurological disorders.