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Phenylketonuria, Genetic Testing

Phenylketonuria (PKU) is a rare genetic disorder that affects the metabolism of the amino acid phenylalanine. Phenylalanine is an essential amino acid found in protein-containing foods. In individuals with PKU, the enzyme needed to break down phenylalanine is either deficient or absent, accumulating this amino acid in the blood and body tissues. The prevalence of phenylketonuria is 1 case in 10.000 live births in Europe, with a higher rate in countries such as Ireland and Italy. The prevalence is exceptionally high in Turkey, where 1 in 4.000 births have phenylketonuria. The disorder is usually diagnosed through neonatal screening programs.

Phenylketonuria 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 Phenylketonuria include:

  • Inherited Metabolic Disorder: Phenylketonuria is an autosomal recessive genetic disorder, meaning that individuals with phenylketonuria inherit two mutated copies of the PAH gene, one from each parent. The PAH gene provides instructions for making the enzyme phenylalanine hydroxylase, which is essential for phenylalanine metabolism.
  • Elevated Phenylalanine Levels: The hallmark of phenylketonuria is increased phenylalanine concentration in the blood. High levels of phenylalanine can lead to intellectual disability and other neurological problems.
  • Neurological Impairment: Untreated phenylketonuria can cause intellectual disability, developmental delays, seizures, behavioral problems, and other neurological issues. These complications result from the toxic effects of elevated phenylalanine on the developing brain.
  • Newborn Screening: Many countries have established newborn screening programs to detect PKU early. Early diagnosis and dietary intervention can prevent or mitigate the disorder's neurological effects.
  • Dietary Management: The primary treatment for phenylketonuria involves a strict, lifelong low-phenylalanine diet. This typically includes a unique formula or medical foods that provide nutrients without excess phenylalanine. Individuals with PKU must carefully monitor their diet to avoid high-phenylalanine foods like meat, fish, dairy, and certain grains.
  • Special Diets During Pregnancy: Pregnant women with phenylketonuria need to maintain strict control of their phenylalanine levels, as elevated levels during pregnancy can harm the developing fetus. Medical supervision and dietary adjustments are crucial during pregnancy.
  • Monitoring and Support: Individuals with phenylketonuria require lifelong monitoring of phenylalanine levels and adherence to dietary restrictions. Regular follow-up with a metabolic specialist, dietitian, and other healthcare professionals is essential.

Advances in medical foods and treatments, such as sapropterin dihydrochloride (a medication that can help some individuals with phenylketonuria process phenylalanine), have improved the management of the disease. Ongoing research aims to develop new therapies and improve outcomes for individuals with this metabolic disorder.

Genetic counseling is recommended for families affected by phenylketonuria to understand the inheritance pattern, assess the risk of having affected children, and discuss available reproductive options. Early diagnosis and intervention are critical for the optimal management of PKU and the prevention of neurological complications.

More Information

Phenylketonuria is caused by a wide range of mutations in the PAH gene encoding phenylalanine hydroxylase. This enzyme, which catalyzes the conversion of the amino acid phenylalanine to tyrosine in a reaction requiring the co-substrate tetrahydrobiopterin (BH4), occurs mainly in the liver. The reaction also requires the action of the chaperone DNAJC12. In a minority of phenylketonuria cases, the gene affected is DNAJC12.

Phenylketonuria is genetically very heterogeneous. More than 1.000 pathogenic variants have been described in PAH, of which specific mutations are more prevalent in some geographic regions than others. Depending on the type of PAH mutation and its effect, the disease phenotype varies and can be classified into three primary forms: severe (classical form), moderate, or mild. Most patients with PKU are compound heterozygotes, i.e., they carry two different mutations in heterozygosis.

The c.1222C>T (p.Arg408Trp) variant is considered a severe pathogenic variant predominant in Celtic and Eastern European populations. Patients homozygous and compound heterozygous for c.1222C>T have classic phenylketonuria and have been associated with significantly reduced enzyme activity and the formation of high molecular weight aggregates, suggesting a severe defect in protein folding resulting in loss of protein function. In addition, patients with c.1222C>T are often unresponsive to BH4 therapy.

The typical variant in southern Europe, which mildly affects PHA, is c.782G>A (p.Arg261Gln). This mutation is associated with a broad spectrum of symptomatology, producing heterogeneity in the response to BH4.

Another frequent mutation is c.1066-11G>A (IVS10-11G>A), which produces classic and moderate PKU. The enzyme activity decreases to less than 5%. It has been detected mainly in the Mediterranean area.

Phenylketonuria genetic testing analyzes the 84 most frequent pathogenic mutations of the PAH gene.

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

Additional information
Results Time4 - 5 Weeks
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