Hereditary orotic aciduria is a rare autosomal recessive genetic disorder characterized by the accumulation of orotic acid in the blood and urine. It is caused by a mutation in the UMPS gene resulting in a deficiency of the enzyme orotate phosphoribosyltransferase. This enzyme is critical for the biosynthesis of pyrimidine nucleotides like uracil, which are essential components of DNA and RNA. Without sufficient levels of this enzyme, orotic acid builds up in the body.

Symptoms of Hereditary Orotic Aciduria Industry

The accumulation of orotic acid typically leads to a constellation of symptoms affecting multiple organ systems. In infants and young children, the main symptoms include developmental delays, intellectual disability, seizures, and non-immune hydrops fetalis. Other common signs include hepatic dysfunction manifesting as jaundice, an enlarged liver and spleen, as well as Fanconi syndrome characterized by metabolic acidosis, aminoaciduria, and phosphaturia. Some patients may also experience megaloblastic anemia due to impaired DNA synthesis. The severity of symptoms can vary greatly even among individuals with the same genetic mutation.

Genetics and Inheritance Pattern

Hereditary Orotic Aciduria is inherited in an autosomal recessive pattern, which means an individual must inherit two copies of the defective UMPS gene - one from each parent - to be affected. Both parents are usually asymptomatic carriers with only one defective copy of the gene. Carrier testing and prenatal diagnosis are available if there is a family history. The defective UMPS gene has been mapped to chromosome 3p21.1. To date, over 30 different mutations have been identified as causal for the disorder.

Diagnosis and Testing

The diagnosis of hereditary orotic aciduria is made through a combination of clinical presentation, biochemical testing, and genetic analysis. Urine orotic acid levels are markedly elevated in affected individuals, often by 50-100 times the normal amount. Plasma orotic acid levels are also elevated but to a lesser degree. Additional tests may show low uracil and dihydrouracil levels in blood, implicating a pyrimidine biosynthesis defect. DNA-based genetic testing can confirm the presence of pathogenic mutations in the UMPS gene and aid in prenatal or carrier screening.

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