Ornithine transcarbamylase deficiency
| Ornithine transcarbamylase deficiency | |
|---|---|
| Other names | OTC deficiency, Ornithine Carbamoyltransferase Deficiency Disease. |
urea cycle disorders, fulminant hepatitis, Citrin deficiency, and hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.[2] | |
| Treatment | Hydration, arginine, and hemodialysis.[1] |
| Prognosis | 50% of infants with OTC deficiency die.[1] |
| Frequency | 1 in 14,000 to 1 in 77,000 people.[3] |
Ornithine transcarbamylase deficiency also known as OTC deficiency is the most common
In severely affected individuals, ammonia concentrations increase rapidly causing ataxia, lethargy and death without rapid intervention. OTC deficiency is diagnosed using a combination of clinical findings and biochemical testing, while confirmation is often done using molecular genetics techniques.
Once an individual has been diagnosed, the treatment goal is to avoid precipitating episodes that can cause an increased ammonia concentration. The most common treatment combines a low protein diet with nitrogen scavenging agents. Liver transplant is considered curative for this disease. Experimental trials of gene therapy using adenoviral vectors resulted in the death of one participant, Jesse Gelsinger, and have been discontinued.
Signs and symptoms
As with several other metabolic conditions, OTC deficiency can have variable presentations, regarding age of onset and the severity of symptoms. This compounded when considering heterozygous females and the possibility of non-random X-inactivation. In the classic and most well-known presentation, a male infant appears well initially, but by the second day of life they are irritable, lethargic and stop feeding. A metabolic encephalopathy develops, and this can progress to coma and death without treatment.[4] Ammonia is only toxic to the brain, other tissues can handle elevated ammonia concentrations without problems.[5]
Later onset forms of OTC deficiency can have variable presentations. Although late onset forms of the disease are often considered milder than the classic infantile presentation, any affected individual is at risk for an episode of hyperammonemia that could still be life-threatening, if presented with the appropriate stressors.
The prognosis of a patient with severe OTC deficiency is well correlated with the length of the hyperammonemic period rather than the degree of hyperammonemia or the presence of other symptoms, such as seizures.[6] Even for patients with late onset forms of the disease, their overall clinical picture is dependent on the extent of hyperammonemia they have experienced, even if it has remained unrecognized.[5]
Genetics
OTC deficiency is caused by mutations in the
There are no common mutations that cause disease, however 10 - 15% of disease causing mutations are deletions.
Diagnosis
In individuals with marked hyperammonemia, a urea cycle disorder is usually high on the list of possible causes. While the immediate focus is lowering the patient's ammonia concentrations, identifying the specific cause of increased ammonia levels is key as well.
Diagnostic testing for OTC deficiency, or any individual with hyperammonemia involves plasma and urine amino acid analysis, urine organic acid analysis (to identify the presence or absence of orotic acid, as well as rule out an organic acidemia) and plasma acylcarnitines (will be normal in OTC deficiency, but can identify some other causes of hyperammonemia). An individual with untreated OTC deficiency will show decreased citrulline and arginine concentrations (because the enzyme block is proximal to these intermediates) and increased orotic acid.[4] The increased orotic acid concentrations result from the buildup of carbamoyl phosphate. This biochemical phenotype (increased ammonia, low citrulline and increased orotic acid) is classic for OTC deficiency, but can also be seen in neonatal presentations of ornithine aminotransferase deficiency.[4] Only severely affected males consistently demonstrate this classic biochemical phenotype.
Heterozygous females can be difficult to diagnose. With the rise of sequencing techniques, molecular testing has become preferred, particularly when the disease causing mutations in the family are known.
Treatment
The treatment goal for individuals affected with OTC deficiency is the avoidance of hyperammonemia. This can be accomplished through a strictly controlled low-protein diet, as well as preventative treatment with nitrogen scavenging agents such as sodium benzoate. The goal is to minimize the nitrogen intake while allowing waste nitrogen to be excreted by alternate pathways.[7] Arginine is typically supplemented as well, in an effort to improve the overall function of the urea cycle.[7] If a hyperammonemic episode occurs, the aim of treatment is to reduce the individual's ammonia levels as soon as possible. In extreme cases, this can involve hemodialysis.[4]
Prognosis
A 1999 retrospective study of 74 cases of neonatal onset found that 32 (43%) patients died during their first hyperammonemic episode. Of those who survived, less than 20% survived to age 14. Few of these patients received liver transplants.[11]
In pop culture
Ornithine transcarbamylase deficiency was the final
References
- ^ PMID 30725942. Retrieved October 22, 2023.
- PMID 24006547. Retrieved October 22, 2023.
- ^ "Ornithine transcarbamylase deficiency: MedlinePlus Genetics". MedlinePlus. October 1, 2017. Retrieved October 22, 2023.
- ^ PMID 11124797.
- ^ S2CID 25998574.
- ^ )
- ^ a b c d e f g "#311250 - Ornithine Transcarbamylase Deficiency, Hyperammonemia Due To". Johns Hopkins University. Retrieved 2014-01-01.
- ^ "Human ornithine transcarbamylase (OTC) mRNA, complete coding sequence". US National Library of Medicine.
{{cite web}}: Missing or empty|url=(help) - PMID 19773741.
- ^ S2CID 25787334.
- PMID 10064660.