Glutaric Acidemia Type I, Metabolic Disorder, Organic acid condition Screening -Infant

Glutaric Acidemia Type I, Metabolic Disorder, Organic acid condition Screening -Infant

Glutaric Acidemia Type I, Metabolic Disorder, Organic acid condition Screening

Summary of Recommendation and Evidence

Population

Recommendation

Grade
(What's This?)

Screening of both Genders

The genetic screening for Glutaric Acidemia Type I is recommended.

B

Glutaric acidemia type 1 (or "glutaric aciduria", "GA1", or "GAT1") is an inherited disorder in which the body is unable to break down completely the amino acids lysine, hydroxylysine and tryptophan. Excessive levels of their intermediate breakdown products (glutaric acid,  glutarylCoA,3 -hydroxyglutaric acid, glutaconic acid) can accumulate and cause damage to the brain (and also other organs), but particularly the basal ganglia, which are regions that help regulate movement. 

OVERVIEW

In glutaric acidemia type 1 (GA1), inadequate quantities of glutaryl-CoA dehydrogenase limit the ability to break down lysine, hydroxylysine, and tryptophan, leading to excessive levels of their intermediate metabolic products (glutaric and 3-OH-glutaric acid). These and other chemicals can then lead to brain injury, particularly in the basal ganglia. Mutations in the GCDH gene cause GA1.

SCREENING

Finding

Elevated C5-DC (glutaryl) carnitine

Tested By

Tandem mass spectrometry (MS/MS); sensitivity~90%; specificity=NA

PREVALENCE

Prevalence is about 1:40,000 Caucasian live births and 1:30,000 Swedish live births; n Old Amish and Ojibway populations, the incidence may be as high as 1:300.

INHERITANCE

GA1  is inherited in an autosomal recessive manner. It affects both boys and girls equally.

PRENATAL TESTING

DNA testing is possible by amniocentesis if both disease causing mutations of an affected family member have been identified.

CLINICAL CHARACTERISTICS

With treatment, normal outcome is possible. Without treatment, outcomes vary but many will have encephalitis-like crises that may result in developmental delay, neurologic deterioration, and spastic/dystonic cerebral palsy. Otherwise healthy newborns may have macrocephaly sometimes with hypotonia. Acute decompensation usually occurs between 6 and 18 months of age. Symptoms are usually triggered by illness (high fever, vomiting, dehydration). Children may be healthy until the first metabolic crisis. Profuse sweating may occur in some affected children. Acute decompensation has not been reported after 5 years of age, although some undiagnosed patients have presented with a leukoencephalopathy after this age. 

Initial symptoms/signs may include:

  • Macrocephaly
  • Failure to thrive
  • Metabolic ketoacidosis
  • Hypotonia
  • Dystonia and athetosis

EARLY SIGNS

At birth, you may not notice anything different about your baby, although some babies with glutaric acidemia, type 1 (GA-1) do have a larger than average head. 

Babies who are identified through newborn screening can begin treatment for the condition before signs of GA-1 start. 

A baby with GA-1 who has not been treated will start to show signs between 4 months and 2 years of age. These signs include:

  • Poor appetite
  • Sleeping longer or more often
  • Tiredness
  • Irritability
  • Twitches
  • Vomiting
  • Weak muscle tone (called hypotonia)
  • Fever
  • Delayed growth
  • Rigid muscles (known as spasticity)
  • Developmental delays
  • Excessive sweating

Many of these signs may occur when your baby eats foods that his or her body cannot break down. They can be triggered by long periods of time without eating, illnesses, and infections.

The severity of GA-1 varies highly for each individual. You may see many of these signs or none at all.

CAUSES

When we eat food, enzymes help break it down. Some enzymes help break down proteins into their building blocks, called amino acids. Other enzymes break down the amino acids. In glutaric acidemia, type 1 (GA-1) the enzyme “glutaryl-CoA dehydrogenase” is not working correctly.

This enzyme’s job is to break down the amino acids lysine, hydroxylysine, and tryptophan.

GA-1 occurs when your baby’s body either doesn’t make enough or makes malfunctioning glutaryl-CoA dehydrogenase enzymes. When your baby’s body cannot break down these substances, harmful substances build up in the body.

These harmful substances tend to accumulate in the basal ganglia, which are areas of the brain that control movement. This causes the neurological symptoms of GA-1.

GA-1 is an autosomal recessive genetic condition. This means that a child must inherit two copies of the non-working gene for GA-1, one from each parent, in order to have the condition. The parents of a child with an autosomal recessive condition each carry one copy of the non-working gene, but they typically do not show signs and symptoms of the condition. While having a child with GA-1 is rare, when both parents are carriers, they can have more than one child with the condition.

TREATMENT

Dietary Treatments

It is important to start treatment as soon as glutaric acidemia, type 1 (GA-1) is diagnosed to avoid many of the signs of GA-1 mentioned in the Early Signs section. Feeding your baby often and treating illnesses and infections can also help prevent these signs.

Your baby will also need a carefully planned diet in order to avoid the proteins your baby’s body is unable to break down but to still have enough nutrients for healthy growth. A dietician or nutritionist can help you manage your child’s diet.

Supplements and Medication

Your baby’s doctor might prescribe supplements like riboflavin. Riboflavin is a natural substance that helps the body break down proteins. It can also help reduce acid levels in your baby’s body. There is always some acid in the body, but very high levels can be toxic. GA-1 causes acid levels to increase.

L-carnitine is another natural supplement that your baby’s doctor might recommend. L-carnitine helps your baby’s body get rid of harmful wastes. Your baby’s doctor will need to write prescriptions for these supplements.

EXPECTED OUTCOMES

If glutaric acidemia, type 1 (GA-1) is treated early and throughout life, your baby can have healthy growth and development.

Some children have experienced signs of GA-1 even with treatment, but these tend to decrease with age. Many of these signs are very infrequent after age 6. These children can also develop intellectual disabilities.

It is important to screen for and treat GA-1 early. If GA-1 is untreated, it can lead to seizures, coma, or permanent brain damage.