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Glutaric Acidemia Type 1, Genetic Testing

Glutaric acidemia type 1 (GA-1), known as glutaryl-CoA dehydrogenase deficiency, is a rare genetic disorder affecting particular amino acid metabolism. It is an autosomal recessive condition, meaning an individual must inherit two copies of the mutated gene (one from each parent) to develop the disorder. The worldwide prevalence of GA-1 is estimated to be 1 in 100.000 people.

Glutaric acidemia type 1 (GA-1) genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).

Critical features of Glutaric Acidemia type 1 include:

  • Metabolic Disorder: GA-1 is characterized by a deficiency of the enzyme glutaryl-CoA dehydrogenase, which plays a role in the breakdown of specific amino acids, including lysine, hydroxylysine, and tryptophan.
  • Accumulation of Metabolites: Due to the enzyme deficiency, there is an accumulation of specific metabolites, including glutaric acid, 3-hydroxyglutaric acid, and glutaconic acid, in the body.
  • Neurological Symptoms: The condition primarily affects the central nervous system, leading to neurological symptoms. This can include macrocephaly (enlarged head), hypotonia (low muscle tone), developmental delays, and an increased risk of acute encephalopathic crises.
  • Acute Episodes: Individuals with GA-1 are at risk of acute episodes triggered by illness, fever, or other stressors. These episodes can result in severe neurological damage and can be life-threatening.
  • MRI Findings: Imaging studies can show characteristic brain abnormalities, such as the widening of certain brain spaces (ventricles and cisterns) and damage to specific brain structures, especially during acute crises.

Diagnosis of Glutaric Acidemia type 1 is typically confirmed through biochemical testing, which may include measuring specific metabolites in blood and urine. Genetic testing can identify mutations in the GCDH gene, which produces the glutaryl-CoA dehydrogenase enzyme.

Management of GA-1 involves a specialized diet that restricts the intake of lysine, hydroxylysine, and tryptophan to minimize the production of toxic metabolites. Close monitoring, especially during illness or stressful situations, is essential to prevent and manage acute episodes. Some individuals with GA-1 may require medications and other supportive measures.

Early diagnosis and intervention are crucial for optimizing outcomes in individuals with Glutaric Acidemia type 1. Regular follow-up with a metabolic specialist and a multidisciplinary approach to care are typically recommended for individuals with this condition. Genetic counseling is essential for families with a history of GA-1 to understand the risk of having affected children and explore family planning options.

More Information

GA-1 is caused by mutations in the GCDH gene, located on 19p13.2. GCDH encodes for glutaryl-CoA dehydrogenase, a mitochondrial matrix enzyme made up of homotetramers involved in the catabolic pathways of L-lysine, L-hydroxylysine, and L-tryptophan.

GA-1 leads to the accumulation of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA), glutathione, and glutarylcarnitine (C5DC) in body fluids and tissues. This metabolic alteration induces neuronal death and affects neurotransmission, cerebral energy metabolism, and cerebral blood flow.

The disease follows an autosomal recessive pattern of inheritance, i.e., two copies of the pathogenic variant must be present for symptoms to manifest. However, it has been reported that pathogenic variants can produce symptoms if found in compound heterozygosis, i.e., the patient has one copy of a deleterious variant on one chromosome and another copy of a different deleterious variant on the other chromosome.

More than 200 pathogenic variants have been identified in the GCDH gene. The most frequent variant is c.1204C>T, also known as p.Arg402Trp or R402W, which is analyzed in this test. It results in substituting an amino acid arginine for tryptophan in the C region, which is the functional region of glutaryl-CoA dehydrogenase.

Glutaric acidemia type 1 (GA-1) genetic testing analyzes the 16 most frequent pathogenic mutations of the GCDH gene.

With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as e.g. next-generation sequencing (NGS).

Additional information
Results Time4 - 5 Weeks
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