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D-Bifunctional Protein Deficiency, Genetic Testing

D-bifunctional protein (DBP) deficiency is a rare autosomal recessive genetic disorder that affects peroxisomal function. Peroxisomes are cellular structures involved in various metabolic processes, including the breakdown of fatty acids. DBP deficiency leads to impairment in the breakdown of specific fatty acids and, as a result, causes various health problems. DBP deficiency is a disorder of peroxisomal fatty acid beta-oxidation affecting the HSD17B4 gene and follows an autosomal recessive mode of inheritance. Its prevalence is estimated at 1 in 100.000 individuals. The pathology results in the accumulation of very long-chain fatty acids (VLCFA) and pristanic and phytanic acid in plasma.

D-bifunctional protein 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).

The critical points about D-bifunctional protein deficiency are:

Genetic Basis: DBP deficiency is caused by mutations in the HSD17B4 gene, which provides instructions for making the D-bifunctional protein. This protein is involved in two essential enzymatic activities within peroxisomes: enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase. Mutations in the gene result in a deficiency of functional D-bifunctional protein.

Enzymatic Activities: The two enzymatic activities of D-bifunctional protein are crucial for the breakdown of very long-chain fatty acids (VLCFAs) and branched-chain fatty acids. Deficiency in these activities leads to the accumulation of VLCFAs and branched-chain fatty acids, causing damage to various tissues and organs.

Clinical Features

  • Neurological Involvement: DBP deficiency often presents with neurological symptoms, including developmental delay, intellectual disability, and seizures.
  • Hepatic Dysfunction: Liver problems may occur, including hepatomegaly (enlarged liver).
  • Muscle Weakness: Weakness and hypotonia (reduced muscle tone) can be observed.
  • Vision and Hearing Impairment: Some individuals may experience vision and hearing problems.
  • Other Organ Involvement: Additional organ involvement can include cardiac, renal, and skeletal abnormalities.
  • Onset and Severity: The onset of symptoms and the severity of the disorder can vary widely among affected individuals. Some may experience symptoms in infancy, while others may not show signs until later in childhood.

Treatment: Currently, there is no cure for DBP deficiency. Treatment is mainly supportive and may include dietary management, physical and occupational therapy, and symptom-specific interventions. Management aims to alleviate symptoms and improve the individual's quality of life.

Prognosis: The prognosis for individuals with DBP deficiency varies, and the disorder can be life-limiting, particularly in severe cases. The degree of neurological impairment and the extent of organ involvement influence the overall prognosis. Given the complexity of DBP deficiency, a multidisciplinary medical team, including neurologists, geneticists, and other specialists, is typically involved in the care and management of affected individuals. Early diagnosis and intervention are crucial for optimizing outcomes.

Diagnosis involves biochemical testing to detect elevated levels of specific fatty acids in blood or urine samples. Genetic testing to identify mutations in the HSD17B4 gene confirms the diagnosis.

Peroxisomal disorders originate from defects in peroxisome biogenesis or are due to non-functional essential enzymes of peroxisome metabolism. D-bifunctional protein (DBP) deficiency belongs to this second category. A point mutation or deletion is typically found in the HSD17B4 gene encoding the D-bifunctional protein. D-bifunctional protein, also known as multifunctional enzyme type 2 (MFE-2), is responsible for the second and third reactions of fatty acid beta-oxidation occurring within peroxisomes. D-BP deficiency has been classified into three subtypes depending on the deficient enzyme activity (types I, II, and III).

The most common pathogenic variant is c.46G>A (p.Gly16Ser), associated with DBP deficiency (type III), followed by the variant c.1369A>T (p.Asn457Tyr), which causes DBP (type II).

The genetic test of D-Bifunctional Protein Deficiency analyzes the two most frequent pathogenic mutations of the HSD17B4 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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