Uridine monophosphate synthetase deficiency

Uridine Monophosphate Synthetase Deficiency

Uridine monophosphate synthetase deficiency, also known as orotic aciduria, is a rare autosomal recessive metabolic disorder that affects the de novo synthesis of pyrimidines. This condition is characterized by an inability to properly synthesize uridine monophosphate (UMP) due to a deficiency in the enzyme uridine monophosphate synthetase (UMPS). This enzyme is responsible for the final two steps in the conversion of orotic acid to UMP, a precursor for the synthesis of RNA and DNA.

Pathophysiology

Uridine monophosphate synthetase is a bifunctional enzyme that catalyzes two sequential reactions in the pyrimidine biosynthesis pathway:

1. Orotate phosphoribosyltransferase (OPRT) activity: This reaction converts orotic acid to orotidine-5'-monophosphate (OMP) by transferring a ribose-phosphate group from phosphoribosyl pyrophosphate (PRPP). 2. Orotidine-5'-phosphate decarboxylase (ODC) activity: This reaction converts OMP to UMP by decarboxylation.

In individuals with UMPS deficiency, the accumulation of orotic acid occurs due to the impaired conversion to UMP. This leads to orotic aciduria, where excess orotic acid is excreted in the urine.

Clinical Presentation

Patients with uridine monophosphate synthetase deficiency typically present with:

- Megaloblastic anemia: Due to impaired DNA synthesis, red blood cells are larger than normal and fewer in number. - Growth retardation: Affected individuals may experience delayed growth and development. - Neurological symptoms: These can include developmental delay and intellectual disability.

Diagnosis

Diagnosis of UMPS deficiency is based on clinical presentation and laboratory findings, including:

- Urinary orotic acid levels: Elevated levels of orotic acid in the urine are indicative of the disorder. - Genetic testing: Identification of mutations in the UMPS gene confirms the diagnosis.

Treatment

The primary treatment for uridine monophosphate synthetase deficiency is oral uridine supplementation. Uridine bypasses the metabolic block and provides the necessary substrate for pyrimidine synthesis, alleviating symptoms such as anemia and growth retardation.

Prognosis

With early diagnosis and appropriate treatment, individuals with UMPS deficiency can lead relatively normal lives. However, untreated, the condition can lead to severe complications, including developmental delays and failure to thrive.

Also see

- Pyrimidine metabolism disorders - Megaloblastic anemia - Inborn errors of metabolism