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Glutaric Acidemia Type 2, Genetic Testing

Glutaric acidemia type 2, also known as multiple acyl-CoA dehydrogenase deficiency (MADD), is a rare inherited metabolic disorder that affects the breakdown of specific amino acids and fatty acids in the body. It is characterized by a deficiency of multiple acyl-CoA dehydrogenases, enzymes involved in processing these substances. The incidence of this metabolic deficiency is estimated at 1 in 250.000 people, with significant variations between countries and ethnic groups. It is most frequent in China where the presence of the c.250G>A variant has a frequency of 1.35% in the Han ethnic group.

Glutaric acidemia type 2 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 2 include:

  • Metabolic Dysfunction: Glutaric acidemia type 2 involves a dysfunction of enzymes that play a role in the oxidation of fatty acids and certain amino acids. As a result, the body cannot convert these substances into energy efficiently.
  • Variable Onset: Symptoms can vary widely and may present at different ages, from infancy to adulthood.
  • Neuromuscular Symptoms: Individuals with MADD may experience weakness, muscle pain, and other neuromuscular symptoms. These can lead to difficulty with movement and muscle coordination.
  • Hepatic Involvement: Liver involvement may lead to hepatomegaly (enlarged liver) and liver dysfunction.
  • Cardiac Involvement: In some cases, cardiac involvement may lead to cardiomyopathy and heart-related symptoms.
  • Triggers and Exacerbating Factors: Fasting, illness, or other stressors may trigger or exacerbate symptoms.

Diagnosis of Glutaric Acidemia type 2 involves biochemical testing, including blood and urine analyses to assess levels of specific metabolites. Genetic testing can confirm the diagnosis by identifying gene mutations associated with the disorder, such as ETFA, ETFB, and ETFDH.

Management of MADD typically involves dietary adjustments, including avoiding fasting and providing a carbohydrate-rich diet. Supplementation with specific cofactors and vitamins may also be recommended. In severe cases, treatment may include riboflavin (vitamin B2) supplementation.

The severity of symptoms and the course of the disorder can vary widely among individuals with Glutaric Acidemia type 2. Early diagnosis and appropriate management are essential for improving outcomes and preventing complications. Individuals with MADD often require coordinated care from a metabolic specialist, genetic counselor, and other healthcare professionals.

As Glutaric Acidemia type 2 is an inherited disorder, genetic counseling is essential for affected individuals and their families. It can provide information about the inheritance pattern, assess the risk of having affected children, and guide family planning decisions.

More Information

Glutaric acidemia type 2 or MADD differs from glutaric acidemia type 1 in that not only is an abnormal amount of glutaric acid produced, but other acids such as lactic, ethylmalonic, butyric, isobutyric, 2-methyl butyric, and isovaleric acids are also increased. MADD results from a deficiency in one of the 3 enzymes involved in electron transport in the mitochondria and the metabolism of acetyl-CoA and glutaric acid.

The three genes involved in MADD are ETFDH, ETFA, and ETFB. About 93% of the pathogenic variants related to MADD are found in ETFDH. Due to the different defects in each of the three genes, the clinical picture of MADD appears to be indistinguishable: mild to severe cases, presumably depending on the location and variant nature.

It should be noted that despite being an autosomal recessive disease (two copies of a pathogenic variant must be present to develop the disease), it can develop in compound heterozygosis (when one copy of a mutation is on one chromosome and another copy of a different mutation is on the other) in some cases.

Glutaric acidemia type 2 genetic testing analyzes the 11 most frequent pathogenic mutations of the ETFDH 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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