Glutaric acidemia type II is an inherited disorder that interferes with the body's ability to break down proteins and fats to produce energy. Incompletely processed proteins and fats can build up in the body and cause the blood and tissues to become too acidic (metabolic acidosis).

Glutaric acidemia type II usually appears in infancy or early childhood as a sudden episode called a metabolic crisis, in which acidosis and low blood glucose (hypoglycemia) cause weakness, behavior changes such as poor feeding and decreased activity, and vomiting. These metabolic crises, which can be life-threatening, may be triggered by common childhood illnesses or other stresses.

In the most severe cases of glutaric acidemia type II, affected individuals may also be born with physical abnormalities. These may include brain malformations, an enlarged liver (hepatomegaly), a weakened and enlarged heart (dilated cardiomyopathy), fluid-filled cysts and other malformations of the kidneys, unusual facial features, and genital abnormalities. Glutaric acidemia type II may also cause a characteristic odor resembling that of sweaty feet.

Some affected individuals have less severe symptoms that begin later in childhood or in adulthood. In the mildest forms of glutaric acidemia type II, muscle weakness developing in adulthood may be the first sign of the disorder.

Mutations in any of three genes, ETFA, ETFB, and ETFDH, can result in glutaric acidemia type II. The ETFA and ETFB genes provide instructions for producing two protein segments, or subunits, that come together to make an enzyme called electron transfer flavoprotein. The ETFDH gene provides instructions for making another enzyme called electron transfer flavoprotein dehydrogenase.

Glutaric acidemia type II is caused by a deficiency in either of these two enzymes. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are normally active in the mitochondria, which are the energy-producing centers of cells. These enzymes help break down proteins and fats to provide energy for the body. When one of the enzymes is defective or missing, partially broken down nutrients accumulate in the cells and damage them, causing the signs and symptoms of glutaric acidemia type II.

People with mutations that result in a complete loss of either enzyme produced from the ETFA, ETFB or ETFDH genes are likely to experience the most severe symptoms of glutaric acidemia type II. Mutations that allow the enzyme to retain some activity may result in milder forms of the disorder.

Glutaric acidemia type II is a genetic condition. Babies inherit it from their biological (birth) parents.

• Glutaric acidemia type II is an autosomal recessive condition. Babies inherit the condition when each parent passes down the same nonworking gene that causes glutaric acidemia type II (ETFA, ETFB, or ETFDH) to their baby. Only babies with two matching nonworking genes—for example, one nonworking ETFA from the mom and one nonworking ETFA from the dad—have this condition. Babies with two nonworking genes that do not match—for example, one nonworking ETFA from the mom and one nonworking ETFB from the dad—will not have this condition.
  • People with one working copy and one nonworking copy of the ETFA, ETFB, or ETFDH 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 ETFA, ETFB, or ETFDH gene, they have a 1 in 4 chance of having a child with glutaric acidemia type II.
  • Carriers for glutaric acidemia type II 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 glutaric acidemia type II.
  • Parents who already have a child with glutaric acidemia type II still have a 1 in 4 chance of having another child with glutaric acidemia type II. 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.

Newborn screening for glutaric acidemia type II is done using a small amount of blood collected from your baby’s heel. During screening, a special machine measures how much of certain substances (called acylcarnitines) are in your baby’s blood. Your body produces these substances when it makes energy from fats. Babies with high levels of these substances might have glutaric acidemia type II.

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

If your baby’s blood spot screening result for glutaric acidemia type II 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
• Small skin sample

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

False-positive newborn screening results for this condition can happen. Babies given carnitine may have out-of-range screening results.

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. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

It is important to talk to your health care provider about which treatment(s) are best for your baby. The goal of treatment is to prevent the health problems caused by this condition.

Treatments may include the following:

• Regular and frequent meals and snacks
• Diet high in carbohydrates and low in fat
• L-carnitine supplements to help the body break down fats (in some cases)
• Riboflavin (vitamin B-2) supplements (in some cases)
• Glycine supplements (in some cases)

Children who receive early and ongoing treatment for glutaric acidemia type II can have healthy growth and development. Treatments are not always successful in people with glutaric acidemia type II. Even with treatment, some people with glutaric acidemia type II may still experience learning disabilities. In very severe forms, treatment may not be able to help, especially if there are heart problems.

Glutaric acidemia type II is a very rare disorder; its precise incidence is unknown. It has been reported in several different ethnic groups.