Orotic aciduria (AKA hereditary orotic aciduria) is a disease caused by an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

deficiency resulting in a decreased ability to synthesize

pyrimidine Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The other ...

s. It was the first described enzyme deficiency of the ''de novo'' pyrimidine synthesis pathway. Orotic aciduria is characterized by excessive excretion of

orotic acid Orotic acid is a pyrimidinedione and a carboxylic acid. Historically, it was believed to be part of the vitamin B complex and was called vitamin B13, but it is now known that it is not a vitamin. The compound is synthesized in the body via a mi ...

in urine because of the inability to convert orotic acid to UMP. It causes megaloblastic anemia and may be associated with mental and physical developmental delays.

Signs and symptoms

Patients typically present with excessive orotic acid in the urine, failure to thrive, developmental delay, and

megaloblastic anemia Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of DNA replication, DNA synthesis during red blood cell production. ...

which cannot be cured by administration of

vitamin B12 Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. It ...

folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...

Cause and genetics

This

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

disorder is caused by a deficiency in the

UMPS, a bifunctional protein that includes the enzyme activities of OPRT and ODC. In one study of three patients, UMPS activity ranged from 2-7% of normal levels. Two types of orotic aciduria have been reported. Type I has a severe deficiency of both activities of UMP synthase. In Type II orotic aciduria, the ODC activity is deficient while OPRT activity is elevated. As of 1988, only one case of type II orotic aciduria had ever been reported. Orotic aciduria is associated with megaloblastic anemia due to decreased pyrimidine synthesis, which leads to decreased nucleotide-lipid cofactors needed for erythrocyte membrane synthesis in the bone marrow.

Diagnosis

Elevated urinary orotic acid levels can also arise secondary to blockage of the

urea cycle The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic. The urea cycle converts highl ...

, particularly in

ornithine transcarbamylase deficiency Ornithine transcarbamylase deficiency also known as OTC deficiency is the most common urea cycle disorder in humans. Ornithine transcarbamylase, the defective enzyme in this disorder is the final enzyme in the proximal portion of the urea cycle, re ...

(OTC deficiency). This can be distinguished from hereditary orotic aciduria by assessing blood ammonia levels and

blood urea nitrogen Blood urea nitrogen (BUN) is a medical test that measures the amount of urea nitrogen found in blood. The liver produces urea in the urea cycle as a waste product of the digestion of protein. Normal human adult blood should contain 6 to 20 mg/dL ...

(BUN). In OTC deficiency,

hyperammonemia Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary. Ammonia is a substance that contains nitrogen. It i ...

and decreased BUN are seen because the urea cycle is not functioning properly, but megaloblastic anemia will not occur because pyrimidine synthesis is not affected. In orotic aciduria, the urea cycle is not affected. Orotic aciduria can be diagnosed through genetic sequencing of the UMPS gene.

Treatment

Treatment is administration of

uridine monophosphate Uridine monophosphate (UMP), also known as 5′-uridylic acid (conjugate base uridylate), is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid with the nucleoside uridine. UMP consists of the phosphate group, the pen ...

(UMP) or

uridine triacetate Uridine triacetate (INN), formerly known as vistonuridine, is an orally active tri-acetylated prodrug of uridine used: * in the treatment of hereditary orotic aciduria (brand name Xuriden ); * to treat people following an overdose of chemothe ...

(which is converted to UMP). These medications will bypass the missing enzyme and provide the body with a source of pyrimidines.

References

External links

{{Purine, pyrimidine, porphyrin, bilirubin metabolic pathology Autosomal recessive disorders Inborn errors of purine-pyrimidine metabolism