Common Disorders Related to Nucleotide Metabolism
Orotic aciduria: Pathophysiology and impact on pyrimidine biosynthesis
Orotic aciduria is a rare genetic disorder affecting pyrimidine biosynthesis due to UMPS deficiency, leading to orotic acid accumulation and hematologic abnormalities.
Orotic Aciduria: Pathophysiology and Impact on Pyrimidine Biosynthesis
Orotic aciduria is a rare genetic disorder affecting nucleotide metabolism. It results from a deficiency in the enzyme uridine monophosphate synthase (UMPS), leading to excessive accumulation of orotic acid and impaired pyrimidine biosynthesis.
Pathophysiology
Orotic aciduria is primarily due to defects in the de novo pyrimidine synthesis pathway. UMPS is responsible for converting orotic acid to uridine monophosphate (UMP), a precursor in pyrimidine metabolism.
- Accumulation of orotic acid disrupts normal cellular function.
- Megaloblastic anemia is a common clinical manifestation.
- Neurological impairments and failure to thrive may occur in severe cases.
Impact on Pyrimidine Biosynthesis
The deficiency in UMP synthesis leads to reduced levels of uridine and cytidine nucleotides, essential for DNA and RNA synthesis. This disruption affects rapidly dividing cells, contributing to hematological abnormalities.
Clinical Presentation
Patients exhibit symptoms including:
- Megaloblastic anemia unresponsive to vitamin B12 and folate.
- Failure to thrive and developmental delays.
- Urinary excretion of orotic acid, often leading to crystalluria.
Diagnosis and Treatment
Diagnosis is established through urinary orotic acid quantification and genetic testing. Treatment involves oral uridine supplementation to bypass the metabolic block.
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