Orotic Aciduria

Orotic aciduria is an extremely rare genetic disorder that can result in crystalluria, megaloblastic anemia, developmental delay, and failure to thrive. The disorder is caused by an enzyme deficiency in the pyrimidine synthesis pathway resulting in the accumulation of orotic acid. Depletion of nucleotides leads to the symptoms of the disease. Diagnosis is made with genetic sequencing as well as urine studies. Options for treatment include uridine monophosphate and uridine triacetate.

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Overview

Epidemiology

  • Rare disorder affecting men and women equally
  • Birth prevalence: < 1 in 1 million live births

Classification

Type I: 

  • Deficiency in both uridine monophosphate synthetase (UMPS) genes
  • More common than type II 

Type II:

  • Deficiency in orotidine 5’-phosphate decarboxylase (ODC) activity with increased activity of orotate phosphoribosyltransferase (OPRT)
  • Extremely rare

Etiology

  • Autosomal recessive inheritance
  • Mutations in uridine UMPS gene:
    • Found on the long arm of chromosome 3 (3q13)
    • Uridine monophosphate synthetase is a bifunctional protein product that has both OPRT and ODC actions.

Pathophysiology

  • UMPS gene mutation
    • Normal function of this gene product is an enzyme that catalyzes 2 consecutive metabolic reactions necessary for de novo pyrimidine biosynthesis.
    • Nonfunctional gene means that there is a low level of this enzyme and a buildup of orotic acid.
  • Excessive orotic acid is excreted in the urine, which leads to crystalluria.
  • Depletion of pyrimidine nucleotide leads to clinical symptoms.

Clinical Presentation

  • Hematologic: 
    • Anemia unresponsive to iron/folic acid therapy
  • Neurologic: 
    • Developmental delays
    • Mild intellectual disability
    • Seizures (epilepsy)
  • Systemic:
    • Failure to thrive
  • Genitourinary: 
    • Cloudy urine due to orotic acid crystals (crystalluria)
    • May lead to obstructive uropathy
  • Other reported symptoms:
    • Diarrhea
    • Congenital malformations
    • Inflammation of the mouth and lips (stomatitis)
    • Misalignment of the eyes (strabismus)
    • Congenital heart disease
Blood smear of megaloblastic anemia Orotic aciduria

Blood smear of megaloblastic anemia:
Megaloblastic anemia is seen on blood smear in patients with orotic aciduria because of decreased pyrimidine synthesis, which reduces the amount of nucleotide-lipid cofactors necessary for RBC membrane synthesis.

Image: “Bone marrow aspiration” by Turk J Haematol. License: CC BY 2.5

Diagnosis

  • Detailed patient and family history
  • Laboratory studies:
    • Blood chemistry:
      • Normal ammonia and BUN levels distinguish this condition from ornithine transcarbamylase (OTC) deficiency.
    • CBC:
      • Macrocytic hypochromic megaloblastic anemia due to marrow producing unusually large, structurally abnormal, immature RBCs (megaloblasts)
      • May have leukopenia 
    • Examination of the urine:
      • Elevated levels of orotic acid
  • Further confirmation through molecular genetic testing of the UMPS gene

Management

  • Uridine monophosphate supplementation 
  • Uridine triacetate (Xuriden): restores uridine monophosphate
  • Additional treatment targets specific symptoms that are present in each individual 
  • Genetic counseling can be beneficial
Uridine triacetate structure Orotic aciduria

Structure of uridine triacetate, an orally active prodrug of uridine that is used in the treatment of orotic aciduria

Image: “Uridine triacetate structure” by Vaccinationist. License: Public Domain

Differential Diagnosis

  • OTC deficiency: X-linked recessive condition that causes dysfunction within the urea cycle leading to inability to eliminate urea. This condition is rapidly fatal and causes a coma within the 1st days of life. OTC deficiency is similar to orotic aciduria, as both will elevate the level of orotic acid in the blood. Unlike orotic aciduria, OTC deficiency causes an elevation in ammonia and reduces the BUN. 
  • Lysinuric protein intolerance: autosomal recessive disorder that causes dysfunction in amino acid transit. Infants present with failure to thrive, GI disturbances (e.g., vomiting, diarrhea), hepatosplenomegaly, and osteoporosis. Patients are diagnosed on the basis of increased concentrations of lysine, arginine, and ornithine in the urine, with low concentrations of these amino acids in the blood. Appropriate treatment is with protein restriction and dietary supplementation. Unlike orotic aciduria, these patients will not have elevated orotic acid in the urine and genetic testing will not show UMPS gene mutation.
  • Galactosemia: autosomal recessive disorder caused by defects in galactose metabolism. Infants present with lethargy, nausea, vomiting, and jaundice. The diagnosis is confirmed through blood testing for genes that are required for galactose metabolism. Treatment is avoidance of lactose and galactose. Unlike orotic aciduria, patients will not have elevated levels of orotic acid in the urine.

References:

  1. Nyhan, W.L. (2018). Hereditary orotic aciduria. National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/hereditary-orotic-aciduria/
  2. Fox, R.F., Wood, M.H., Royse-Smith, D., O’Sullivan, W.J. (1973). Hereditary orotic aciduria: types I and II. American Journal of Medicine 55:791–798. https://pubmed.ncbi.nlm.nih.gov/4753642/
  3. Debnath, S., Aggarwal, A., Mittal, H. (2011). Megaloblastic anemia—a rare cause. Indian Journal of Pediatrics 78:1293–1295. https://pubmed.ncbi.nlm.nih.gov/21630071/

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