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Dihydrolipoamide Dehydrogenase Deficiency, Genetic Testing

Dihydrolipoamide dehydrogenase deficiency (DLD deficiency), also known as maple syrup urine disease (MSUD) type III, is a rare genetic disorder affecting the metabolism of certain amino acids. It is inherited in an autosomal recessive manner, meaning an individual must inherit two copies of the mutated gene (one from each parent) to have the condition. The prevalence of DLD deficiency in the general population is less than 1 case per 1.000.000 inhabitants.

Dihydrolipoamide dehydrogenase deficiency genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximetaly 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).

Key points about DLD deficiency include:

  • Enzyme Deficiency: Dihydrolipoamide dehydrogenase is an enzyme involved in breaking down amino acids, particularly leucine, isoleucine, and valine. Deficiency of this enzyme can lead to the accumulation of these amino acids and their toxic byproducts in the body.
  • Symptoms: The symptoms of DLD deficiency can vary widely and may include developmental delays, intellectual disabilities, muscle weakness, seizures, and respiratory problems. The disorder can manifest in infancy or early childhood.
  • Maple Syrup Odor: The condition is sometimes called "maple syrup urine disease" due to the characteristic sweet odor of the affected individual's urine, which is caused by the buildup of certain amino acids.
  • Metabolic Crisis: Individuals with DLD deficiency may experience metabolic crises, during which their metabolic processes are disrupted, leading to a range of symptoms and potentially life-threatening complications.
  • Treatment: Management of DLD deficiency involves dietary restrictions to control the intake of certain amino acids, especially leucine, isoleucine, and valine. This may include a protein-restricted diet and the use of special medical formulas. Monitoring and management of metabolic crises are also essential components of care.
  • Genetic Counseling: As with many genetic disorders, genetic counseling is important for families affected by DLD deficiency. Understanding the genetic basis of the condition and the risk of passing it on to future generations is a key aspect of counseling.

Individuals with DLD deficiency must receive prompt diagnosis and appropriate medical management to minimize the risk of metabolic crises and associated complications. Treatment approaches may be tailored to each patient's needs, and a healthcare team specializing in metabolic disorders typically plays a central role in providing care and support.

The disease is caused by mutations in the DLD gene, which codes for the dihydrolipoamide dehydrogenase enzyme. This enzyme acts as a subunit (the E3 component) of several protein complexes involved in cellular energy production, such as BCKDH, αKGDH, and PDH. Pathogenic loss-of-function variants of DLD lead to variable dysfunction of these complexes. Their decreased activity produces a severe and variable phenotype in DLD deficiency.

About 40 pathogenic variants implicated in this syndrome have been described. The c.685G>T variant in the DLD gene is the most common, being especially prevalent in the Ashkenazi Jewish population (with a carrier frequency of 1:94). This variant causes alterations in the structure and function of the enzyme dihydrolipoamide dehydrogenase. Patients who manifest the disease early or late childhood are usually homozygous for c.685G>T. However, patients with a severe phenotype who were compound heterozygotes have also been observed.

In certain cases, the biochemical examination (lactate, pyruvate, amino acids in plasma, and organic acids in urine) is normal, and the differential diagnosis is only possible with genetic analysis, confirmed by the homozygous c.685G>T mutation in the DLD gene. Therefore, DLD deficiency should be considered in patients with Reye's syndrome or liver failure, even in the absence of biochemical findings. Screening for the c.685G>T variant is often advised among Ashkenazi Jewish couples, given the high frequency of carriers in this population.

The genetic test of dihydrolipoamide dehydrogenase deficiency analyzes the three most frequent pathogenic mutations of the DLD 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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