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Hereditary Orotic Aciduria


Hereditary orotic aciduria (HOA) is a rare metabolic disorder commonly associated with orotic acid crystalluria and megaloblastic anemia. Notwithstanding, few cases have been reported where hematological abnormalities could not be confirmed. This led to the definition of hereditary orotic aciduria without megaloblastic anemia (OAWA) as a separate entity. All types of HOA, including OAWA, are caused by deficiencies in the bifunctional enzyme uridine monophosphate synthase (UMPS), which is encoded for by the eponymous UMPS gene.


Microcytic, hypochromic megaloblastic anemia developing during the first months of life is the presenting symptom in most cases of HOA [1]. Affected individuals may appear pale, suffer from fatigue, lightheadedness, dizziness, and dyspnea. Glossitis may occur and result in feeding difficulties that, in turn, may be exacerbated by nausea and loss of appetite. Diarrhea has also been reported. Signs and symptoms don't improve with iron, vitamin B12, or folic acid supplementation.

Orotic acid crystalluria develops concomitantly but is not usually detected until urine analyses are carried out. OAWA patients are an exception to this rule: In the absence of megaloblastic anemia, it may well be the symptoms of obstructive uropathy that trigger further investigations [2].

Failure to thrive, growth retardation, developmental delay, and intellectual disability may ensue in patients who don't receive timely treatment with the pyrimidine precursor uridine [1]. Besides anemia, neutropenia may be detected in these individuals, and immunological deficiencies may arise.

Developmental Delay
  • Signs and symptoms include blood abnormalities such as decreased white blood cell count, urinary tract obstruction due to the formation of orotic acid crystals in the urinary tract, failure to thrive, and developmental delays.[specialtypharmacytimes.com]
  • Pyrimidine 5′-nucleotidase superactivity has been described in four unrelated patients with developmental delay and neurologic abnormalities. The patients were treated with uridine with good effect.[ommbid.mhmedical.com]
  • delay, dystonia, scoliosis Treatment: Not established Pyrimidine 5 ′ nucleotidase deficiency (266120) 5 ′ -Monophosphate hydrolase NT5C3 (7p15-p14)* Biochemical profile: No specific profile Clinical features: Hemolytic anemia, basophilic stippling Treatment[merckmanuals.com]
Multiple Organ Dysfunction Syndrome
Failure to Thrive
  • Signs and symptoms include blood abnormalities such as decreased white blood cell count, urinary tract obstruction due to the formation of orotic acid crystals in the urinary tract, failure to thrive, and developmental delays.[specialtypharmacytimes.com]
  • Signs and symptoms of the disease include blood abnormalities (anemia, decreased white blood cell count, decreased neutrophil count), urinary tract obstruction due to the formation of orotic acid crystals in the urinary tract, failure to thrive, and developmental[news-medical.net]
  • The inability to convert orotic acid results in the body being unable to normally synthesize uridine, a necessary component of RNA, which ultimately leads to a failure to thrive. 1 Hereditary orotic aciduria is a rare autosomal recessive disorder.[pharmacytimes.com]
  • Clinical features Delayed presentation (second year of life) Intermittent ataxia, sensorineural hearing loss Myoclonic seizures, developmental delay Skin rashes, alopecia Laboratory findings Organic aciduria (eg, elevated beta-hydroxyisovalerate, lactate[emedicine.medscape.com]
  • […] techniques and approaches with complete updates throughout 35 new chapters, including: Innovations in Addressing Child Health and Survival in Low Income Settings; Developmental Domains and Theories of Cognition; The Reggio Emilia Educational Approach Catatonia[books.google.es]


The microscopic examination of urine samples obtained from HOA patients reveals orotic acid crystalluria, and this finding should prompt further evaluation for a metabolic disorder. Enzyme activity measurements, urine analyses, and molecular biological studies are most effective to this end.

The activity of the UMPS enzyme may be determined in erythrocytes, leukocytes, or fibroblasts. In HOA patients, it is to be expected to be <10%, whereby the complete absence of UMPS activity has never been reported and may be incompatible with life [3]. The individual measurement of OPRT and ODC activities poses a major challenge, though, which partially explains the lack of clarity regarding the biochemical background of distinct types of HOA. Another diagnostic tool was needed and finally found in urinary orotate and orotidine, which act as reporters of the intracellular amounts of orotic acid and orotidine-5'-monophosphate. To mention but a few specific numbers, HOA patients may excrete 0.18-8.93 mmol of orotic acid (per mmol of urinary creatinine), and 0.15-0.47 of oritidine (per mmol of urinary creatinine), whereby these statistics include all types of the disease [3]. Under physiological conditions, only traces of orotic acid and oritidine can be detected in urine samples.

Furthermore, the assessment of the urinary ratio of orotate to orotidine has been proposed as a means to test for particular types of enzyme defects. Bailey postulated that orotate-to-orotidine ratios of 7-42 were to be expected in patients with HOA type 1 and residual UMPS enzyme activity of 0.01-10%. By contrast, orotate-to-orotidine ratios close to 1 have been associated with OAWA [3]. The reliability of HOA typification on the basis of urinary orotate-to-orotidine ratios has recently been challenged, though, when values of about 15 and were reported for two individuals with OAWA [2] [4].

Of note, increased urinary orotate excretion is not a pathognomonic feature of HOA. Similar findings can be made in patients with urea cycle disorders ornithine transcarbamylase deficiency (hyperammonemia type 2), argininosuccinate synthetase deficiency (citrullinemia), argininosuccinate lyase deficiency, and arginase deficiency. And while these diseases are associated with a series of additional findings in blood and urine sample analyses, all diagnoses should be confirmed by genetic studies [5]. With regard to HOA, the underlying mutation of the UMPS gene should be identified not only to support the diagnosis but also to prepare the familial workup and prenatal diagnostics.

Macrocytic Anemia
  • […] blood or of typical megaloblasts in the marrow ) The nonmegaloblastic anemias (they simply represent macrocytic anemias in which DNA synthesis is unimpaired.[enotes.tripod.com]
  • The megaloblastic effect is characterized by an aregenerative macrocytic anemia with nuclear dysmaturity, where the nucleus appears immature relative to the cytoplasm because of impaired DNA synthesis. See image below.[emedicine.medscape.com]
  • B 12 deficiency - macrocytosis, hypersegmented neutrophils, low plasma vit. B12 level.[enotes.tripod.com]
  • Associated Infections; Intrapartum and Peripartum Infections; Bath salts and other drugs of abuse; Small Fiber Polyneuropathy; Microbiome; Kingella kingae; Mitochondrial Neurogastrointestinal Encephalomyopathy; Nonalcoholic Fatty Liver Disease; Plagiocephaly[books.google.es]
Megaloblastic Bone Marrow
  • Hereditary orotic aciduria was found in a 7-year-old girl who had anemia, leukopenia, a megaloblastic bone marrow, crystalluria, and normal growth and intelligence.[jamanetwork.com]


Therapeutic standards are established only for patients diagnosed with HOA type 1, who are to be treated with 50-300 mg of uridine per kg body weight and day [1]. Uridine is administered orally; it is converted to uridine monophosphate by uridine kinase, and thereby the enzyme defect can be bypassed [2]. The only patient ever reported to suffer from HOA type 2 responded well to uridine supplementation [6], and this same therapy has been proven effective in at least two of the children diagnosed OAWA [2] [4].


Oral uridine therapy leads to clinical and hematological remission in patients with HOA type 1 and OAWA [2] [4] [6]. Urinary orotate levels may be reduced but tend to remain above the reference range, which may predispose to urolithiasis and obstructive uropathy. Otherwise, no intellectual or physical handicap must arise from adequately treated HOA [4].


HOA has initially been related to deficiencies in orotate phosphoribosyltransferase (OPRT) and orotidine-5’-phosphate decarboxylase (ODC), and subtypes 1 and 2 have been defined accordingly [7]. Later studies revealed that OPRT and ODC activities were exerted by one and the same polypeptide, namely the bifunctional enzyme UMPS [3] [8]. This enzyme comprises two catalytical domains and is encoded for by the UMPS gene, located on the long arm of chromosome 3. In line with this, tests for mutations of the UMPS gene have been established as an essential part of the workup, and UMPS enzyme deficiency has become a synonym for HOA.

While HOA type 1 is caused by combined deficiencies in OPRT and ODC activities, inactivity of the ODC domain has been proposed to cause HOA type 2 [7]. The hypothesis of an isolated ODC defect has later been doubted, though, and the mere existence of HOA type 2 has been questioned [3]. Be that as it may, both types 1 and 2 lead to the classical phenotype, including orotic aciduria and megaloblastic anemia responsive to dietary supplementation with uridine.

Interestingly, four cases have been documented to date where megaloblastic anemia could not be detected [4]. The respective variant has been referred to as OAWA and constitutes a third subtype of HOA. It has been speculated that OAWA may be the result of qualitative deficiencies of OPRT and ODC, i.e., the relative rates of transferase and decarboxylase activities differ from those of the wild-type enzyme. ODC deficiency seems to contribute to OAWA to a greater extent than dysfunctional OPRT [3] [9].

All subtypes of HOA are inherited in an autosomal recessive pattern, and both homozygous and compound heterozygous patients have been reported [3] [6]. Beyond that, heterozygosity for UMPS mutations has been shown to induce isolated orotic aciduria, while a possible predisposition of carriers to developmental delay remains to be confirmed [1] [10].


Disorders of pyrimidine metabolism are generally assumed to be underdiagnosed, which may put into perspective the low case numbers of HOA [6]. Little more than a dozen cases of HOA type 1 have been described in the literature; there is only one presumptive case of HOA type 2 and merely four patients have been diagnosed with OAWA [3] [4]. The majority of HOA patients has been diagnosed during their first two years of life. Yet, two had already reached school age at the time of diagnosis, and a single patient was 28 years old when their condition was recognized [3]. In this regard, no significant differences have been observed between those suffering from distinct subtypes of HOA.

Sex distribution
Age distribution


The UMPS enzyme catalyzes the final two steps of the pyrimidine biosynthesis. In detail, OPRT facilitates the conversion of orotic acid to orotidine-5'-monophosphate, and ODC is required for the decarboxylation of orotidine-5'-monophosphate, yielding uridine monophosphate. Accordingly, orotic acid or its salt, orotate, and orotidine-5'-monophosphate should accumulate inside the cell. While the former can cross the cell membrane and be excreted without further chemical modification, this does not apply to the latter. Orotidine-5'-monophosphate must be dephosphorylated and thus converted to orotidine before leaving the cell [3].

This allows for the following conclusions:

  • The uniform reduction of OPRT and ODC activities, as observed in HOA type 1, entails considerable limitations in the production of orotidine-5'-monophosphate and thus substrate shortage for ODC. Both urinary orotate and orotidine will rise, but orotidine levels will always remain below orotate excretion.
  • The selective loss of OPRT activity would result in orotic aciduria but oritidine could not be produced. Orotidine excretion thus assumes residual OPRT activity.
  • Sole ODC deficiency would lead to almost equal levels of urinary orotate and orotidine.
  • The ratio of orotate to oritidine excretion may provide valuable information as to the underlying enzyme deficiency.

The particular correlation of OPRT and ODC activities with megaloblastic anemia remains poorly understood, and no explanation can be provided to date for the absence of hematological abnormalities in OAWA patients [3]. In general, any reduction in the biosynthesis of pyrimidine nucleotides interferes with red cell stability. This is likely because of a reduced availability of pyrimidine nucleotide-lipid cofactors that are required for the build-up of erythrocyte membranes in the bone marrow [6].


Families known to harbor mutations of the UMPS gene may benefit from genetic counseling. Also, the prenatal diagnosis of the disease is feasible, and oral uridine therapy is indicated in all confirmed cases - both symptomatic and asymptomatic ones. The hypothesis of heterozygosity for UMPS mutations predisposing to developmental delay and intellectual disability, as proposed by Wortmann et al., may warrant prophylactic uridine supplementation in carriers, but therapy costs are definitely an issue [1] [10].


Inborn errors involving enzymes essential for the ubiquitous pathways of pyrimidine metabolism may give rise to a broad spectrum of clinical manifestations, including hematological, neurological, and immunological symptoms [6]. Diagnostic delays are common and generally attributed to lack of awareness as well as genetic and phenotypic heterogeneity, which translate into ongoing changes of classification schemes [6]. The latter also applies for HOA, one of about a dozen currently recognized disorders of this group: Three subtypes of the disease have been described to date, but the existence of HOA type 2 has been questioned in recent years [3]. On the other hand, HOA is different from most other disorders of pyrimidine metabolism in one decisive respect: Effective treatment is available.

Patient Information

Pyrimidine metabolism plays an important role in human health, and there are several enzymes required for the synthesis, breakdown, and recycling of pyrimidines. Mutations of those genes that encode for these enzymes may result in specific hereditary diseases that interfere with development and growth, namely in inborn errors of pyrimidine metabolism. One of these enzymes is uridine monophosphate synthase, and the corresponding gene has been designated UMPS. Owing to characteristic clinical and laboratory findings, the respective patients are diagnosed with hereditary orotic aciduria (HOA).

Uridine monophosphate synthase catalyzes the conversion of orotic acid to uridine monophosphate. Accordingly, orotic acid accumulates in the cells of patients suffering from uridine monophosphate synthase deficiency, and it's excreted via urine. If urine samples are obtained from these individuals, orotic acid crystals can be observed and abnormally high concentrations of this compound can be measured. Enzyme activity measurements may be carried out to corroborate the suspected diagnosis, although the current gold standard of HOA diagnosis is the molecular biological confirmation of mutations of UMPS.

HOA patients may present with different signs and symptoms. Megaloblastic anemia is a frequent feature of HOA and may give rise to pallor, fatigue, lightheadedness, dizziness, nausea, and diarrhea. Some patients develop neurological symptoms, while others suffer from urinary tract obstruction. If adequate treatment is provided in a timely manner, the complete remission of symptoms may be achieved. Otherwise, irreversible damage and intellectual disability may ensue. Therapy is required throughout life; it consists in the administration of uridine, which is converted to uridine monophosphate, and thereby the enzyme defect can be bypassed. Uridine is taken orally.



  1. Wortmann SB, Chen MA, Colombo R, et al. Mild orotic aciduria in UMPS heterozygotes: a metabolic finding without clinical consequences. J Inherit Metab Dis. 2017; 40(3):423-431.
  2. Grohmann K, Lauffer H, Lauenstein P, Hoffmann GF, Seidlitz G. Hereditary orotic aciduria with epilepsy and without megaloblastic anemia. Neuropediatrics. 2015; 46(2):123-125.
  3. Bailey CJ. Orotic aciduria and uridine monophosphate synthase: a reappraisal. J Inherit Metab Dis. 2009; 32 Suppl 1:S227-233.
  4. Nyhan WL, Gangoiti JA. Hereditary Orotic Aciduria and the Excretion of Orotidine. Neuropediatrics. 2016; 47(6):408-409.
  5. Häberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012; 7:32.
  6. Balasubramaniam S, Duley JA, Christodoulou J. Inborn errors of pyrimidine metabolism: clinical update and therapy. J Inherit Metab Dis. 2014; 37(5):687-698.
  7. Fox RM, Wood MH, Royse-Smith D, O'Sullivan WJ. Hereditary orotic aciduria: types I and II. Am J Med. 1973; 55(6):791-798.
  8. Fallon HJ, Smith LH, Graham JB, Burnett CH. A Genetic Study of Hereditary Orotic Aciduria. N Engl J Med. 1964; 270:878-881.
  9. Besley GTN, Walter JH, Fairbanks LD, et al. Hereditary orotic aciduria without megaloblastic anemia. J Inherit Metab Dis. 2000; 23 Suppl 1:194.
  10. Imaeda M, Sumi S, Imaeda H, et al. Hereditary orotic aciduria heterozygotes accompanied with neurological symptoms. Tohoku J Exp Med. 1998; 185(1):67-70.

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Last updated: 2019-07-23 21:51