Markedly increased urinary levels of orotic acid are the most explicit sign of OAWA [1] [2] [3]. Developmental delays may also be noted and may present as growth failure, mental retardation, or motor disorders such as ocular motor dyspraxia [2] [3] [4] [5]. Hematological anomalies, as observed in orotic aciduria type 1, cannot be demonstrated.

Orotic acid crystalluria may manifest in different ways. The crystals may damage the mucous membranes lining the urinary tract, thereby provoking pain and hematuria [5] [6]. An obstruction of the urinary tract, either due to the accumulation of orotic acid crystals or inflammatory tissue swelling, seems conceivable but has not been described in OAWA patients. Neither has urolithiasis.

On the other hand, pyrimidine deficiency and/or excess orotic acid may trigger metabolic and/or neurological symptoms. Indeed, one of the more recently described patients initially presented with epilepsy [2]. When he was first examined for a prolonged generalized tonic-clonic seizure, his physical, motor, and mental development was appropriate to age - and it remained this way during the follow-up. No anomalies could be detected in magnetic resonance images, while electroencephalography revealed a permanent focal slowing in the left parieto-temporo-occipital region.

Electroencephalographic anomalies were also observed in a young girl who presented with cyclic vomiting and dehydration, and who was subsequently diagnosed with OAWA [3]. Here, generalized spike activity was described.

It remains to be seen whether or not additional features like strabismus, cardiac malformations, and immunodeficiency, which are occasionally observed in orotic aciduria type 1, may be present in OAWA. To date, they have not been observed in affected individuals.

• Developmental Delay

  Orotic aciduria is a rare hereditary disorder of pyrimidine metabolism whose predominant clinical features are orotic acid crystalluria, megaloblastic anemia, and developmental delays. [symptoma.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]

  Global developmental delay MedGen UID: 107838 •Concept ID: C0557874 • Finding A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social [ncbi.nlm.nih.gov]

  Some infants and children may have neurological problems including delays in reaching developmental milestones (developmental delays). There may also be delays or issues with intellectual development including mild intellectual disability. [rarediseases.org]

• Failure to Thrive

  It also can cause inhibition of RNA and DNA synthesis and failure to thrive. [checkorphan.org]

  Failure to thrive MedGen UID: 746019 •Concept ID: C2315100 • Disease or Syndrome Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm. [ncbi.nlm.nih.gov]

  Some infants fail to gain weight and grow as they normally would for their age and gender (failure to thrive), but others are normal. As all children grow older, height and weight appear to fall in the normal range. [rarediseases.org]

  Signs and symptoms[edit] Patients typically present with excessive orotic acid in the urine, failure to thrive, developmental delay, and megaloblastic anemia which cannot be cured by administration of vitamin B12 or folic acid.[3][2] Cause and genetics [en.wikipedia.org]

• Global Developmental Delay

  Global developmental delay MedGen UID: 107838 •Concept ID: C0557874 • Finding A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social [ncbi.nlm.nih.gov]

Urine analyses are the cornerstone of OAWA diagnosis:

• The macroscopic features of the patient's urine may or may not be altered; if detected, macroscopic anomalies are due to a the concomitant inflammation of the urinary tract. Orotic acid crystalluria alone does not alter the macroscopic properties of urine.
• The microscopic examination of urine samples reveals the presence of orotate crystals. They tend to agglomerate, assuming irregular shapes, and cannot be distinguished by their morphology. Depending on the degree of irritation of the urogenital mucosa, erythrocytes, leukocytes, and products of inflammation may also be observed.
• The diagnosis of orotic aciduria requires strong suspicion and the chromatographic measurement of urinary levels of metabolites of pyrimidine metabolism. Under physiological conditions, only traces of orotic acid and oritidine can be detected in urine. By contrast, two of the known OAWA patients excreted 0.18-0.60 mmol of orotic acid (per mmol of urinary creatinine), and 0.40-0.47 mmol of oritidine (per mmol of urinary creatinine) [1]; in the male patient with epilepsy, orotic acid and oritidine excretion amounted to 0.78 and 0.04 mmol, respectively [2], and in the young girl with metabolic symptoms, orotic acid and oritidine levels of 8.24 and 0.52 mmol, respectively, were measured [3]. These values correspond to ratios of urinary orotate to orotidine of 0.46-1.29, 19.38, and 15.84 respectively. For comparison: Patients diagnosed with classical orotic aciduria had orotate-to-orotidine ratios of 29-590 [1].

Additionally, the activities of OPRT and ODC may be assessed in erythrocytes, leukocytes, or fibroblasts [5] [6]. In OAWA patients, OPRT activity may be within or below the physiological range, while the level of ODC activity is always significantly reduced [1] [2]. For orotic aciduria type 1, it has been postulated that the complete absence of enzyme activity is incompatible with life [7]. It remains to be clarified if this hypothesis applies to type 3 disease, but residual activity of ODC may very well be detected.

The diagnosis of OAWA may be confirmed if molecular biological results are achieved that support the laboratory data. Also, the identification of the underlying mutation of the UMPS gene facilitates a possible familial workup and would add to the very narrow knowledge about this rare disease.

• Erythroblast

  Erythroblasts show a failure of nuclei maturation maintaining open or lax chromatin and normal mature cytoplasm. History and Physical Usually, anemia develops gradually, and symptoms are present only in severely anemic patients. [ncbi.nlm.nih.gov]

  Megaloblast an enlarged erythroblast ( erythrocyte precursor) with an enlarged nucleus, which arises in a background of vitamin b12 and/ or folic acid deficiency and is characterised by asynchronous nucleocytoplasmic development, and manifest by delayed [trephroda.duckdns.org]

  Substantial disintegration of erythroblasts occurs within the marrow sinuses sequel to undue prolonged detention of the erythroblasts with uncondensed nuclei wherein products of their disintegration are scanphage by macrophages. [intechopen.com]

In classical orotic aciduria, the dietary supplementation of uridine is the mainstay of treatment. Uridine is converted to uridine-5'-monophosphate by uridine kinase, so that a bypass effect is achieved with this kind of therapy. This strategy is primarily followed to relieve megaloblastic anemia, which is no burden to OAWA patients, but it has been proven effective in two of the children diagnosed with type 3 disease:

• The boy with OAWA and epilepsy was administered 75 mg/kg body weight, which caused a reduction of urinary orotic acid excretion by 77%. His epilepsy responded to the combined application of uridine and oxcarbazepine, and he did not experience further seizures after the cessation of anticonvulsive treatment, which was recommended four years later. Uridine therapy is continued throughout life [2].
• The girl who presented with metabolic symptoms received a total of 12 g uridine per day. Her condition improved considerably. She was able to compensate for her initial developmental deficits. There were no more seizures, but she still experienced tics, mainly facial. Contrary to the aforedescribed case, this girl's orotic acid crystalluria did hardly diminish under uridine therapy [3].
• In general, the daily dose of uridine should be adapted to decrease the urinary orotic acid level to a minimum.

The earlier case reports did not contain any information regarding the management of the disease [1].

Data regarding the course of the disease are available for two cases only.

• Urinary orotic acid levels could largely be reduced in the boy who suffered from OAWA and epilepsy, but they stayed above the reference range. The patient remained seizure-free during eight years of follow-up after the initial diagnosis. Later, he showed attention-deficit/hyperactivity disorder-like behavior, but a causal relation to OAWA has not been shown [2].
• OAWA-related symptoms could also be controlled in the girl who presented with vomiting and dehydration, who developed well after the initiation of treatment and did not experience additional seizures. Her urinary orotic acid excretion remained high ten years after the initiation of therapy [3].

Hereditary orotic aciduria is caused by mutations of the UMPS gene. This gene is located on the long arm of chromosome 3 and spans about 19 kb containing 6 exons. The N-terminal domain corresponds to OPRT, the C-terminal domain to ODC. The following mutations have been found in OAWA patients:

• c.254T>C (p.I85T)
• c.928T>G (p.F310V)
• c.1027C>A (p.H343N)

Both homozygosity and compound heterozygosity have been described [2] [4]. These findings and the results of genealogical analyses suggest an autosomal recessive pattern of inheritance.

Orotic aciduria type 1 may be considered a quantitative deficiency of UMPS. The ratio of OPRT activity to ODC activity does not differ from the wild-type enzyme, and percentages of residual enzyme activity are equal for both subunits. By contrast, OAWA-related UMPS may be qualitatively different from the physiological variant [1].

Little more than a dozen cases of orotic aciduria type 1 have been reported. This puts into perspective the small number of OAWA patients described in literature: Only four cases have been confirmed to date. One male patient was diagnosed at the age of 9 months, the other one during their second year of life [1]. The third patient experienced seizures from his third year of life but was not diagnosed with orotic aciduria until one year later [2]. The most recently described patient was female and presented with metabolic symptoms at the age of 9 years [3].

Before the advent of molecular biological studies, the activity levels of OPRT and ODC as well as urinary excretion profiles were the most reliable indicators of orotic aciduria. In detail, the urinary excretion of orotic acid/orotate and orotidine was (and still is) evaluated if an inborn error of pyrimidine metabolism is suspected. Such studies have also been the starting point for the definition of distinct types of orotic aciduria: The ratio of urinary orotate to orotidine has been observed to be >10 in patients with type 1 disease, but only about 1 in those with OAWA [1]. Although this hypothesis has recently been challenged [2] [3], it implies differences in the pathogenesis of both diseases.

Orotic aciduria is related to deficiencies of UMPS and its two functional domains, OPRT and ODC. The aforedescribed results of urine analyses can be deduced from the functions of both subunits:

• Orotic acid is required for the production of oritidine monophosphate, which is catalyzed by OPRT.
• Oritidine monophosphate is converted to uridine by ODC. Otherwise, oritidine monophosphate is eventually dephosphorylated and excreted.

If both OPRT and ODC are defective, as in orotic aciduria type 1, the generation of oritidine monophosphate is severely limited, resulting in the accumulation of orotic acid and its salts. What's more, because pyrimidine nucleotides are the key mediators of negative feedback on the early reactions of their de novo synthesis, the interruption of this process during its final steps suspends that regulatory mechanism and further augments the production of orotic acid.

In OAWA, functional OPRT may allow for the first reaction to take place, but oritidine monophosphate is not processed to uridine. The accumulation of oritidine monophosphate would inhibit the conversion of orotic acid and would move the OPRT reaction towards equilibrium, so that diagnostic measurements yielded increased levels of both orotic acid and oritidine. According to steady-state modeling of the relative outputs of the enzymic products, the orotate-to-oritidine ratio to be expected in case of sole OCD deficiency was close to 1 [1]. It should be noted, though, that OAWA has been described in two cases with dysfunctional OPRT and ODC, and urinary orotate-to-orotidine ratios >10 [2] [3]. Possibly, the threshold orotate-to-orotidine ratio for the distinction of type 1 and type 3 disease needs to be redefined.

It has been speculated that any residual activity of UMPS may suffice to transmit negative feedback, to avoid the massive overproduction of orotic acid that is observed in type 1 disease, and to relieve potential anemia [1]. Still, this hypothesis is contradicted by the fact that neither OPRT nor ODC activity was detectable in samples obtained from the single boy diagnosed with OAWA and epilepsy [2]. No other explanation for the absence of megaloblastic anemia in OAWA has been provided, though.

Affected families may benefit from genetic counseling. OAWA may be diagnosed prenatally, either by assessing the concentrations of pyrimidine metabolites in amniotic fluid or by means of genetic studies [8]. Although the correlation between the outcome and the patient's age at the beginning of uridine supplementation has not yet been studied, early uridine therapy may possibly prevent irreversible disorders of development.

Orotic aciduria is a rare hereditary disorder of pyrimidine metabolism whose predominant clinical features are orotic acid crystalluria, megaloblastic anemia, and developmental delays. It is caused by mutations of the UMPS gene, which encodes for the eponymous enzyme. It has two functional domains, namely N-terminal OPRT and a C-terminal ODC. They catalyze the final steps in the de novo synthesis of uridine monophosphate. First, OPRT converts orotic acid to orotidine-5'-monophosphate. Second, uridine-5'-monophosphate is produced from orotidine-5'-monophosphate by ODC. These reactions are essential to the generation of uridine di- and triphosphate, which, in turn, serve as precursors in the synthesis of cytidine triphosphate and thymidine triphosphate. In patients with orotic aciduria, the inability to de-novo synthesize pyrimidines results in pyrimidine deficiency, reduced stability of red cell membranes, and megaloblastic anemia [4].

The aforementioned clinical hallmarks of orotic aciduria correspond to type 1 of the disease. Classical orotic aciduria, as it is also called, is related to functional deficiencies in both subunits of UMPS. By contrast, the specific inactivation of ODC had been assumed to be the cause of orotic aciduria type 2. A single case has been reported, and the clinical presentation of this variant of the disease was indistinguishable from orotic aciduria type 1. Indeed, further studies revealed that the activities of both OPRT and ODC were severely decreased in red cell extracts obtained from this patient, and urinary excretion profiles were in disagreement with a sole deficiency of ODC. Thus, it is debatable whether orotic aciduria type 2 should be considered a separate entity. Eventually, orotic aciduria type 3 has been described. It has been referred to as OAWA and may de facto be associated with dysfunctional ODC and intact OPRT [1]. However, OAWA may also be related to deficiencies of both OPRT and ODC [2].

Further research is required to improve the classification system of orotic aciduria and to determine the pathogenetic mechanisms underlying the development of megaloblastic anemia.

Hereditary orotic aciduria without megaloblastic anemia (OAWA) is a very rare genetic disorder, and only a handful of cases have been described to date. Orotic aciduria refers to the urinary excretion of orotic acid, which is the single most important sign of OAWA. It may manifest in hematuria and reflects an enzyme deficiency affecting pyrimidine metabolism. In detail, the patient's body is unable to complete the de novo synthesis of pyrimidines and thus eliminates metabolic intermediates such as orotic acid. Lack of pyrimidines may trigger metabolic and neurological symptoms, such as dehydration, vomiting, and epilepsy. OAWA patients may also present with growth failure, mental retardation, or motor impairment. Therapy consists in the replacement of pyrimidines and has been proven effective in some cases.

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