What Is Hereditary Orotic Aciduria?

Hereditary orotic aciduria: understanding a rare metabolic disorder

Hereditary Orotic Aciduria (HOA) is a rare genetic disorder that affects the metabolism of pyrimidines, a type of molecule essential for the synthesis of DNA and RNA. As of 2021, only twenty patients have been described as having the disorder. The condition is characterised by excess excretion of a compound called orotic acid in urine, which is a key diagnostic feature. Understanding HOA and its causes and symptoms can have a profound impact on affected individuals. Individuals with HOA can have a normal or near-normal life expectancy with proper diagnosis, treatment, and ongoing medical care.

Pyrimidines are a type of nucleotide base. These are what make up our DNA and RNA. DNA and RNA are built from a combination of the nucleotide bases - adenine, cytosine, guanine, thymine and uracil. Of these five bases, thymine, cytosine and uracil are pyrimidines, and problems in their synthesis can cause a plethora of difficulties in downstream processes in the body.

HOA is categorised as an inborn error of metabolism disorder, meaning that it is a rare disease caused by a defect in a single enzyme, a co-factor to an enzyme or a transport protein.¹ In the case of HOA, this is a mutation in the gene that encodes the uridine monophosphate synthase (UMPS) enzyme. These enzymes play an essential role in the de novo pyrimidine synthesis pathway, which is responsible for generating the pyrimidine nucleotides required for DNA and RNA construction.² Mutations in UMPS disrupt these pathways, leading to the accumulation of orotic acid in the body and a deficiency of pyrimidines.

Individuals with typically present with the following symptoms 

• Anemia
• Growth and developmental delays
• Enlarged liver and spleen
• Immunodeficiency
• Urinary symptoms

These symptoms will appear in infancy or early childhood, and the severity of the condition may vary. Research suggests that a combination of the symptoms of anaemia, developmental delay and immunodeficiency together in a child or infant is a good basis to test for HOA.³

Understanding HOA is essential for early diagnosis. Prompt identification allows healthcare professionals to initiate timely interventions that drastically improve the health and quality of life of those suffering from the disorder.

Clinical presentation and more about symptoms

Hereditary Orotic Aciduria presentation can vary among affected individuals. The age of onset for HOA is typically in infancy or early childhood. Symptoms often become apparent within the first few months of life.⁴ However, the exact age of onset can vary among individuals, and in some cases, particularly if symptoms are milder, it may go undetected until late childhood or adolescence.

Anaemia

Anaemia is a common feature of Hereditary Orotic Aciduria. It can be moderate to severe and is characterised by a reduced number of red blood cells or insufficient haemoglobin. Anaemia can lead to fatigue, weakness, and pallor. Red blood cells in HOA patients are differently sized, abnormally shaped and have less than typical levels of haemoglobin.⁵ Megaloblastic bone marrow is also typical in this disease, where blood cells are abnormally large due to impaired DNA synthesis and nuclear cell division. In HOA individuals, this type of bone marrow is known to be resistant to treatment using supplements (hematinic therapy).⁶

Growth and developmental delays

Infants with HOA will often experience poor growth compared to their peers. This is one of the earliest and most noticeable symptoms. Children with HOA may also experience delays in their developmental milestones, including delayed motor skills, speech and cognitive development.⁷ Similarly, sparse hair and nail growth may be observed, and the child may exhibit a failure to thrive in their environment without treatment.

Enlarged liver and spleen

Also known as hepatomegaly and splenomegaly, respectively, they are often observed in individuals with HOA.⁸ These abnormalities are related to the accumulation of orotic acid and the disruption of normal metabolic processes in the liver. Both these organs are engaged in producing and breaking down molecules in the body, so they have to work harder to cope with excess orotic acid and the lack of pyrimidine.

Immunodeficiency

Individuals with HOA will often exhibit fatal reactions to diseases, which can usually be overcome by the body. Reportedly, patients with HOA will have impaired T-cell function,  which means destroying intracellular pathogens such as virus-infected cells and intracellular bacteria.⁹ Antibody production, however, seems to be unaffected by HOA.

Urinary symptoms

Excessive orotic acid excretion in the urine is a hallmark of HOA. This may lead to crystalline deposits in the urinary tract and can contribute to urinary tract symptoms. Cloudy urine is usually observed in patients due to the orotic acid crystals. Continued excretion may lead to obstructions in the urinary pathway, which can cause kidney complications.

The severity of HOA can vary among affected individuals. The extent to which the Uridine Monophosphate Synthase (UMPS) enzyme is dysfunctional can influence the severity of the metabolic disturbances in HOA. Earlier diagnosis and prompt initiation of treatment can also mitigate the symptoms and drastically improve the overall prognosis.⁶

Causes and genetic mechanisms behind hereditary orotic aciduria

Mutations in urine monophosphate Synthase (UMPS), which disrupt the pyrimidine production pathway, are the cause of the disorder. UMPS mutations responsible for HOA are typically inherited in an autosomal recessive manner. So, the disorder only manifests if an affected individual carries two copies of the mutated gene (one from each parent). When both copies of the gene are mutated, the individual lacks functional enzyme activity, resulting in the metabolic disturbances seen in HOA. Parents with only one mutated copy, or carrier individuals, do not show any symptoms of HOA, as the one normal copy of the gene is enough to generate the necessary amount of enzyme. Offspring of two carrier individuals, therefore, have a 25% chance of inheriting both mutated copies of the gene. HOA is thought to be most commonly caused by a missense mutation.¹⁰ Missense mutations are those that cause a different amino acid to be encoded in the DNA.

The role of the UMPS enzymes

The UMPS-encoded enzyme, Uridine Monophosphate Synthase, plays a central role in the development of Hereditary Orotic Aciduria. This enzyme is needed to produce both pyrimidine nucleotides and uridine monophosphate (UMP), which in turn serves as a precursor for the synthesis of the other pyrimidine nucleotides. The de novo pyrimidine synthesis pathway is one of the two major pathways for generating pyrimidine nucleotides (the other being the salvage pathway, where nucleotide bases from damaged DNA and RNA are recycled in the body). In this pathway, pyrimidines are synthesised from simple precursors. UMPS plays a critical role in this process, specifically in the conversion of orotic acid to UMP, which is used to make the pyrimidines in our body. UMPS is a bi-functional enzyme consisting of two domains: orotate phosphoribosyltransferase (OPRT) and orotidine-5'-monophosphate decarboxylase (OMPdase).¹¹ Both of these two activities within the enzyme molecule are essential for the conversion of orotic acid into UMP.

In the first step, UMPS functions as orotate phosphoribosyltransferase (OPRTase), catalysing the conversion of orotic acid to orotidine monophosphate (OMP). This step, also called ribosylation, involves the transfer of a phosphoribosyl group to the orotic acid. In the second step, UMPS acts as orotidine-5'-monophosphate decarboxylase (OMPdecase), catalysing the decarboxylation of OMP to finally produce UMP.¹¹

Mutations in the UMPS gene can impair one or both of the enzyme's activities, leading to a disruption in the de novo pyrimidine synthesis pathway. This usually causes decreased levels of the enzyme and an inability for the enzymes that are produced to efficiently bind to the substrate, which in this case is orotic acid.¹⁰ There are three sub-types of HOA, which are all caused by some form of mutation in the UMPS gene. Type 1 is where both activities of the UMP enzymes are non-functional, and types 2 and 3 are thought to be secondarily caused by the inactivation of OMPdecase.12 As a consequence, individuals with HOA are unable to efficiently convert orotic acid into UMP, which leads to the excessive accumulation of orotic acid in their urine and a deficiency of pyrimidines in their cells. The defective UMPS enzyme in HOA results in the clinical features of the condition and other symptoms related to the shortage of pyrimidine nucleotides necessary for normal DNA and RNA synthesis.

Diagnosis

Hereditary Orotic Aciduria (HOA) is diagnosed through a combination of clinical assessments, biochemical tests, and genetic testing. A thorough assessment of the patient’s symptoms and their onset, coupled with a physical examination, would be needed. Biochemical testing in the form of urine analysis will be able to detect elevated levels of orotic acid, which is a strong indicator of the condition. Blood may also be tested to check for abnormalities in blood cells, as well as pyrimidine levels in the blood.

The cornerstone and definitive method for diagnosing HOA, however, is molecular genetic testing. This would involve identifying mutations in the UMPS gene and whether or not both copies of the gene are affected. Additionally, understanding the specific mutations can be crucial for providing appropriate genetic counselling to affected families, as well as treatment for the patient. An early diagnosis of HOA is essential for initiating appropriate treatment and interventions, hence improving the chances of a better quality of life.

Treatment

Uridine Monophosphate Supplementation treatment involves providing exogenous uridine monophosphate (UMP) supplementation to combat the lack of it in the body. UMP supplements are typically administered orally as part of the daily treatment regimen. The supplementation helps to restore normal pyrimidine nucleotide levels in the body. UMP supplementation can lead to significant clinical improvements, including increased growth, reduced anaemia, and improved overall health. Uridine triacetate is often used as the supplement of choice.¹³

Individuals with HOA require ongoing monitoring to assess their response to treatment and to manage any potential complications. Regular blood tests, urine tests, and clinical assessments need to be conducted to evaluate the effectiveness of UMP supplementation and overall health. Treatment of symptoms (anaemia, immunodeficiency) needs to be maintained alongside UMP supplements. Furthermore, genetic counselling is also an essential component of HOA care, especially for affected individuals and their families. HOA is a lifelong condition, and treatment is typically required throughout an individual's life.

Summary

HOA is a rare genetic inherited disorder that is caused by an enzyme dysfunction. The UMPS enzyme, which produces vital DNA building blocks, is affected, and this can result in growth failure, anaemia and immunodeficiency. With proper treatment, this disorder is not fatal, and individuals may go on to live full lives as usual with some TLC.