Hereditary orotic aciduria is a rare inherited genetic disorder that affects pyrimidine nucleotide synthesis in the body. It is caused by a mutation in the UMPS gene that encodes for the enzyme orotate phosphoribosyltransferase (OPRT). This enzyme plays a vital role in the pyrimidine salvage pathway involved in the biosynthesis of uridine monophosphate (UMP), which is required for the formation of DNA and RNA. A deficiency of OPRT due to a mutation results in orotic acid accumulation in the blood and urine.

Symptoms of Uridine Monophosphate Synthase Deficiency

The symptoms of uridine monophosphate synthase deficiency usually present early in life and vary from mild to severe. Common symptoms include developmental delay, intellectual disability, seizures, microcephaly, and feeding difficulties in infants and children. Some patients may experience recurrent infections, vomiting, diarrhea, and failure to thrive. Facial dysmorphism with midface hypoplasia and epicanthal folds is also observed in many affected individuals. Symptom severity often correlates with the degree of enzymatic deficiency, however, significant variability exists even among individuals with the same mutation. Early diagnosis and treatment are crucial to prevent neurological complications.

Genetics and Inheritance Pattern

Hereditary Orotic Aciduria is inherited in an autosomal recessive manner. This means an individual must inherit two copies of the mutated UMPS gene - one from each parent - to be affected by the disorder. carriers who have only one copy of the mutated gene are usually unaffected but can pass the gene to their offspring. The estimated gene frequency of UMPS mutations varies in different populations worldwide. Consanguinity is frequently reported in families with multiple affected individuals, indicating parental relatedness increased the risk of offspring inheriting two recessive alleles. Prenatal diagnosis through molecular or enzymatic testing is possible for families with a previously identified mutation.

Pathophysiology and Biochemical Basis

The UMPS gene provides instructions for making the enzyme orotate phosphoribosyltransferase (OPRT), which plays a key role in the pyrimidine salvage pathway. This pathway helps recycle pyrimidine bases from nucleic acid degradation and provides an alternative to de novo pyrimidine biosynthesis. OPRT specifically catalyzes the conversion of orotic acid to orotidylic acid monophosphate in the presence of phosphoribosyl pyrophosphate (PRPP).