Orotic aciduria is a rare autosomal recessive inborn error of pyrimidine metabolism resulting from mutations in the UMPS gene. This gene codes for the enzyme orotate phosphoribosyltransferase (OPRT), which plays a key role in the catabolism of uridine monophosphate (UMP). Deficiency of this enzyme leads to the accumulation and excessive excretion of orotic acid in the urine. If left untreated, the condition causes severe neurological impairment and developmental delay in affected individuals.

Genetic Basis

Uridine monophosphate synthase deficiency is caused by mutations in the UMPS gene located on chromosome 2q36-q37. This gene contains 10 exons and encodes OPRT, which catalyzes the conversion of orotic acid to orotidine monophosphate in the pyrimidine salvage pathway. To date, over 60 different mutations have been reported in UMPS, including missense, nonsense, and splicing variants. The most common mutation is c.209C>T, accounting for approximately 50% of mutant alleles in Caucasian populations. Other frequent mutations include c.424-1G>A and c.521C>T. Genetic testing of the UMPS gene is necessary to confirm a diagnosis of orotic aciduria at the molecular level.

Clinical Presentation

The clinical presentation of Hereditary Orotic Aciduria varies from asymptomatic to severe, depending on the residual enzyme activity. In the neonatal period, affected infants may present with nonspecific symptoms like lethargy, poor feeding, and vomiting. As the condition progresses, developmental delay, hypotonia, seizures, and ataxia often become apparent between 3-24 months of age if left untreated. Biochemically, elevated orotic acid is seen in the urine, plasma, and cerebrospinal fluid of patients. Urine orotic acid levels can range from 50-1000 times higher than normal. Some individuals may also exhibit Fanconi-like renal tubular dysfunction resulting in hypouricemia, metabolic acidosis, and aminoaciduria. Early diagnosis and intervention is key to prevent permanent neurological damage.

Diagnosis

The diagnosis of uridine monophosphate synthase deficiency is based on clinical presentation and biochemical findings. Urinary orotic acid quantification via organic acid analysis using gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS) confirms excessive excretion. Plasma orotic acid may also be measured through similar methods. Prenatal diagnosis is possible through analysis of fetal cells obtained by amniocentesis or chorionic villus sampling. Definitive diagnosis requires genetic testing of the UMPS gene to detect causative mutations. Enzyme activity assays using patient fibroblasts or lymphoblasts can also help establish the diagnosis. Differential diagnoses include diseases featuring increased orotic acid like orotic aciduria associated with liver disease.