Mutations in the GCDH gene cause glutaric acidemia type I. The GCDH gene provides instructions for making the enzyme glutaryl-CoA dehydrogenase. This enzyme is involved in processing the amino acids lysine, hydroxylysine, and tryptophan.

Mutations in the GCDH gene prevent production of the enzyme or result in the production of a defective enzyme that cannot function. A shortage (deficiency) of this enzyme allows lysine, hydroxylysine and tryptophan and their intermediate breakdown products to build up to abnormal levels, especially at times when the body is under stress.

The intermediate breakdown products resulting from incomplete processing of lysine, hydroxylysine, and tryptophan can damage the brain, particularly the basal ganglia, causing the signs and symptoms of glutaric acidemia type I.

Normal Function

The GCDH gene provides instructions for making the enzyme glutaryl-CoA dehydrogenase. This enzyme is found in mitochondria, the energy-producing centers of cells. The GCDH enzyme is involved in the breakdown of the amino acids lysine, hydroxylysine, and tryptophan, which are building blocks of proteins.

Health Conditions Related to Genetic Changes

Glutaric acidemia type I

Mutations in the GCDH gene prevent production of the glutaryl-CoA enzyme, or result in the production of a defective enzyme that cannot fulfill its role in the breakdown of lysine, hydroxylysine, and tryptophan. This enzyme deficiency allows these amino acids and their intermediate breakdown products to build up to abnormal levels, which damages the nervous system, especially when the body is under stress.

More than 150 GCDH gene mutations that cause glutaric acidemia type I have been reported in populations around the world. Most of these mutations result in the substitution of one amino acid for another amino acid in the enzyme. In the Old Order Amish community, all known glutaric acidemia type I cases derive from the replacement of the amino acid alanine with the amino acid valine at position 421 (written as Ala421Val or A421V). A few specific mutations have been seen in certain Native American populations. Individuals with glutaric acidemia type I who belong to the Lumbee community of North Carolina have been found to have a mutation in which the amino acid glutamic acid is replaced with the amino acid lysine at position 414, written as Glu414Lys or E414K. A mutation that replaces a particular DNA building block (nucleotide) called guanine with the nucleotide thymine (written as IVS1, G-T, +5) is prevalent in the Ojibwa population of Canada. As a result of this mutation, an abnormally shortened version of the enzyme is produced. Many different mutations occur in other populations.

Other Names for This Gene

• ACAD5
• GCD
• GCDH_HUMAN
• glutaryl-CoA dehydrogenase, mitochondrial
• glutaryl-Coenzyme A dehydrogenase isoform a precursor
• glutaryl-Coenzyme A dehydrogenase isoform b precursor

Genomic Location

• 25% chance of having GA1
• 50% chance to be a carrier of GA1 like each parent
• 25% chance of not having GA1 and not being a carrier of GA1 (in other words, having two normal copies of the gene)

• 50% chance of having GA1
• 50% chance of being a carrier

Newborn screening for glutaric acidemia type I 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. The body makes these substances when it breaks down food. Babies with high levels of these substances might have glutaric acidemia type I.

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

If your baby’s blood spot screening result for glutaric acidemia type I 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 are rare.

Babies who received carnitine can have false-positive screening results for glutaric acidemia type I. Moms can also have glutaric acidemia type I without knowing it. Babies whose moms have this condition may have false-positive screening results for glutaric acidemia type I.

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:

• Diet of special formulas or foods
• Riboflavin (vitamin B-2) supplements (in some cases)
• L-carnitine supplements (in some cases)

Children who receive early and ongoing treatment for glutaric acidemia type I can have healthy growth and development.

Glutaric acidemia type I occurs in approximately 1 in 100,000 individuals. It is much more common in the Amish community and in the Ojibwa population of Canada, where up to 1 in 300 newborns may be affected.