Hereditary orotic aciduria is very rare form of genetic disorder, which affects people from birth. Untreated, infants are at risk of megaloblastic anemia, poor weight gain as a sign of failure to thrive, recurrent infections and formation of orotic acid crystals in the urine or crystalluria. Some effects on the brain have been reported, although this incidence is not as frequent anymore because there is treatment available. 

Unfortunately, due to the limited number of patients who have been   Na12diagnosed with this disorder the information about the hereditary orotic aciduria is still incomplete. It is known to be caused by mutations in the UMPS gene. In 2015, the FDA approved a drug, Xuriden (Uridine triacetate) to treat this disorder. 

This disorder affects both sexes. Only about 20 cases pertaining to this disorder have been described in medical reviews. The incidence of birth is less than one in ten lakh live births. The rarity of the diseases themselves and misdiagnosis make it highly difficult to truly determine their frequency within the general population. 

This is a very rare metabolic disorder that results from mutations of the UMPS gene encoding for the enzyme uridine monophosphate synthase, a critical moiety in the synthesis of pyrimidines, which constitute the basic building blocks of nucleic acids such as RNA and DNA. The pathophysiology of HOA includes an enzyme deficiency, a block in pyrimidine synthesis, orotic aciduria, megaloblastic anemia, failure to thrive, and increased susceptibility to infection. This in turn results in a deficiency of UMP and hence pyrimidine nucelotides, which inhibits RNA and DNA synthesis. The latter, particularly in rapidly diving cells such as those in the bone marrow, has serious consequences. Defective pyrimidine synthesis hence will have far-reaching consequences at the cellular level. Affected infants will fail to thrive, with stunted growth and an increased susceptibility to infections. Inherent in the development and function of the nervous system, the basic role played by pyrimidines may result in neurological impairment. Uridine triacetate is a bypassing therapy, which avoids the metabolic block by providing an exogenous source of uridine that may then be directly phosphorylated to UMP. The FDA already approved it for the aforementioned conditions. Hence, with the help of early diagnosis and proper treatment, these serious consequences can be avoided. 

It is a genetic disorder that is caused by variants in uridine monophosphate synthetase gene. The UMPS gene encodes for a specialized enzyme called uridine 5’- monophosphate synthase that ccan catalyze two metabolic reactions converting orotic acid into other substances. A mutation in the UMPS gene leads to low amounts of this enzyme needed for breakdown of orotic acid so it accumulates within the body. This excess is excreted through urine and may also enhance the metabolism of folic acid and vitamin B12 and may play a role in gene transcription. 

The exact cause of buildup of orotic acid and deficiency of uridine monophosphate synthase is not well understood. The basis for genetic diseases is the combination of genes for some particular trait on chromosomes received from the father and mother. Recessively inherited disorders are those in which the patient inherits the same variant gene for the same trait from each parent. When one receives a normal gene and a disease gene, he or she will be a carrier of the disease but usually does not show symptoms. For each pregnancy, the child has a 25% chance of being affected because of having received a defective gene from both parents, another 50% because of having received one carrier gene counterpart from each parent, and 25% because of receiving the normal form of both genes. 

This rare genetic disorder is caused by UMPS gene mutations, which encode the bifunctional enzyme uridine monophosphate synthase. It can cause severe clinical symptoms in infancy or early childhood, and developmental delays. Early diagnosis and treatment are crucial for effective management. Uridine supplementation, which bypasses the metabolic block, can lead to significant clinical improvement, resolution of anemia, and improved growth and development. With treatment, the prognosis is generally good, but without treatment, severe complications may occur.  

Megalobalstic anemia, a condition causing abnormal red blood cell production, is common in affected infants. Neurological issues and delayed cognitive development, seizures, and failure to thrive may also occur. Hereditary orotic aciduria can cause cloudy urine and obstructive uropathy, leading to blood in urine. Symptoms include congenital malformations, diarrhea, inflammation of lips and mouth, and misaligned eyes. Some infants may also have CHD, including defects in septum. These conditions can lead to developmental delays, intellectual disabilities, seizures, and abnormalities in the urinary tract.

General appearance:  

Assessment of growth parameters including weight, height, and BMI, and developmental milestones, such as motor skills and speech delays should be carried to ensure a healthy growth environment. 

Skin and Mucus membranes 

Look for signs of anemia using the following, pallor of the skin, mucous membranes and jaundice in severe cases. 

Cardiovascular system 

Monitor for tachycardia and irregular heartbeats, which can be a result of anemia, and auscultate for abnormal heart sounds, which might indicate severe cardiac complications resulting from anemia. 

Respiratory system 

Observe for signs of respiratory distress which can be a consequence of sever anemia leading to increased breathing. 

Abdomen palpitation 

Check for hepatomegaly or splenomegaly, though these are less common in this disease. 

Neurological examination: 

Assess motor delays or coordination issues. Observe for delayed development or any signs of intellectual disability. 

• Megalobalstic anemia 
• Delayed development and growth 
• Learning disabilities 
• Bone marrow dysfunction 
• Immunological impact 
• Hepatic issues 

Xuriden was approved by FDA in 2015. This is the drug used for treating this condition. This is a hereditary problem which makes uridine monophosphate not to be produced. Clinical trials have revealed improvements in anemia, lowered levels of orotic acid in urine as well as megaloblastosis. However, the long-term outcomes remain unknown. Other treatments should target specific symptoms while genetic counseling can help both the patients and their families. 

Hematology

Community resources 

Link to groups and services that offer support for rare genetic disorders and their management. Partner with advocacy organizations to further support. 

Lifestyle modifications 

Encourage regular physical activity to promote health and well-being, keeping in mind the limitations that come with age. Provide a daily routine to create stability and predictability. 

Hematology

Uridine: This can be observed in CSF and plasma in higher concentrations than remaining nucleosides. This helps to maintain homeostasis of uridine which plays a crucial role in the maintenance of normal metabolism and basic functions. 

Hematology

Xuriden: This is used as a replacement therapy for uridine. It is indicated in the treatment of HOA in pediatric and adult patients. Being an acetylated uridine, this will be deacetylated to uridine with nonspecific esterases which leads to an increase in the concentration of circulating uridine which is particularly useful in patients who cannot produce sufficient amounts of uridine.  

Hematology

HOA is a condition characterized by anemia and developmental delays. It is managed through a multi-phase process, including diagnosis, initial assessment, clinical evaluation, diagnostic testing, immediate management, ongoing monitoring, supportive care, and long-term follow-up. The very first step is the multi-dimensional, clinical evaluation aimed at the establishment of diagnosis and evaluation of the patient’s condition. Urine analysis, genetic testing, and the responses of the blood tests, and evaluation of comorbidities form part of diagnostic tests. The administration of uridine, which is done to reduce orotic acid levels and correct anemia, is the treatment starting point in phase two. This period is meant for the ongoing management and monitoring of patients with all the care they need. Supportive care includes but not limited to psychosocial support and developmental assistance which make it an integral part of every patient’s life journey. Finally, it also entails long-term follow up and evaluation in respect of resources provision as well as evaluating the effectiveness of the treatment given.