Hereditary orotic aciduria is a rare autosomal recessive genetic disorder caused by a mutation in the UMPS gene. This gene provides instructions for making an enzyme called orotate phosphoribosyltransferase. A mutation in this gene results in a deficiency or absence of this crucial enzyme. Orotate phosphoribosyltransferase is needed to break down orotic acid as part of the pathway that creates pyrimidine nucleotides, which are essential components of DNA and RNA. Without enough of this enzyme, orotic acid builds up in the blood and urine. This build up, known as orotic aciduria, is what gives the disorder its name.
Symptoms of Hereditary Orotic Aciduria Industry
The signs and symptoms of hereditary orotic aciduria typically appear within the first few months of life. Key symptoms include:
- Developmental delays and intellectual disabilities. This is due to deficiency in DNA and RNA synthesis.
- Seizures which can be severe and difficult to control.
- Lethargy and poor feeding.
- Vomiting and diarrhea.
- Liver enlargement (hepatomegaly).
- Kidney stones made of orotic acid.
If left untreated, additional complications can include chronic kidney disease and even premature death. However, early diagnosis and treatment substantially improve long-term outcomes.
Genetics and Inheritance Pattern
Hereditary Orotic Aciduria is an autosomal recessive disorder caused by mutations in the UMPS gene located on chromosome 3. This means an individual must inherit two copies of the mutated gene - one from each parent - to be affected. However, carriers who inherit one normal and one mutated copy do not experience any signs or symptoms.
When both parents are carriers, their children have a:
- 25% chance of inheriting two normal copies and being unaffected.
- 50% chance of inheriting one normal and one mutated copy and being a carrier like the parents.
- 25% chance of inheriting two mutated copies and being affected by the disorder.
Diagnosing Hereditary Orotic Aciduria
The diagnosis of hereditary orotic aciduria involves urine and blood tests to detect elevated levels of orotic acid. Newborn screening programs in some areas also test for elevated orotic acid. Genetic testing of the UMPS gene can confirm a diagnosis. Prenatal testing during pregnancy is possible if both mutations carried by the parents are known.
As symptoms may not appear until later infancy, some affected newborns are not diagnosed until they develop symptoms like developmental delays, seizures, or liver problems. A high index of suspicion from a healthcare provider can facilitate earlier diagnosis and treatment.
Treatment and Management
There is no cure for hereditary orotic aciduria, but treatment aims to manage symptoms and prevent complications. The primary treatment is a pyrimidine-free amino acid formula supplemented by a low-protein, high-calorie diet. This encourages use of alternative pathways to create pyrimidine nucleotides. Close monitoring for signs of liver or kidney damage is also important.
Additional medications may be used to control seizures, manage vomiting/diarrhea, or treat kidney stones. In severe cases, a liver transplant may be considered as the liver bears the brunt of orotic acid accumulation. With optimal treatment and management, most infants can expect relatively normal development and lifespans. However, lifelong management and clinical follow up are usually required.
Global Prevalence and Impact
Hereditary orotic aciduria is extremely rare, estimated to affect around 1 in 800,000 live births globally. However, prevalence may vary between populations and ethnic groups depending on founder mutations. For example, a Finnish population study reported a much higher rate of around 1 in 100,000.
Most cases are still discovered by chance as part of investigation into a child's developmental issues or unexplained illness. However, expanded newborn screening programs aim to catch more asymptomatic newborns to facilitate early diagnosis and optimal outcomes.
International cooperation is helping increase awareness and understanding of this rare disorder. Patient support groups also provide valuable community and resources for families. While always challenging a rare condition, ongoing research seeks better treatment protocols. Overall, proper diagnosis and management offer positive long-term prospects to those living with hereditary orotic aciduria worldwide.
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