Ornithine Transcarbamoylase Deficiency
Disease Details
Family Health Simplified
- Description
- Ornithine transcarbamoylase deficiency (OTC deficiency) is a genetic disorder that impairs the body's ability to eliminate ammonia, leading to toxic accumulation, particularly affecting the nervous system.
- Type
- Ornithine transcarbamoylase deficiency is an inherited disorder. It follows an X-linked recessive pattern of genetic transmission.
- 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. Ammonia is only toxic to the brain, other tissues can handle elevated ammonia concentrations without problems.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. These patients will often present with headaches, nausea, vomiting, delayed growth and a variety of psychiatric symptoms (confusion, delirium, aggression, or self-injury). A detailed dietary history of an affected individual with undiagnosed OTC deficiency will often reveal a history of protein avoidance.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. 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.
- 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.
- Onset
- Ornithine transcarbamoylase (OTC) deficiency typically presents during infancy or early childhood. In severe cases, symptoms can appear within the first few days of life. Milder forms may present later, sometimes not until adulthood.
- Prevalence
- Ornithine transcarbamoylase deficiency (OTC deficiency) is the most common urea cycle disorder. Its prevalence is approximately 1 in 80,000 to 1 in 250,000 live births.
- Epidemiology
- Ornithine transcarbamoylase deficiency (OTC deficiency) is a rare X-linked genetic disorder. Epidemiologically, its prevalence is estimated to be about 1 in 80,000 live births. Because it is X-linked, the condition predominantly affects males, though females can be carriers and sometimes exhibit symptoms due to X-inactivation. Cases have been reported worldwide, with no specific ethnic or geographical predilection.
- Intractability
- Ornithine transcarbamylase deficiency (OTC deficiency) is a genetic disorder that primarily affects the liver's ability to remove ammonia from the bloodstream. While it is a serious condition, it is not completely intractable. The disease can be managed with dietary modifications, medications, and in some cases, liver transplantation. Early diagnosis and ongoing medical care are crucial for improving outcomes and managing symptoms effectively.
- Disease Severity
- Ornithine transcarbamoylase deficiency (OTC deficiency) is a genetic disorder that affects the urea cycle, leading to the accumulation of ammonia in the blood. The disease severity can vary widely depending on the specific mutation and residual enzyme activity. It ranges from severe neonatal-onset forms, which can be life-threatening, to milder late-onset forms presenting in adulthood.
- Healthcare Professionals
- Disease Ontology ID - DOID:9271
- Pathophysiology
- Ornithine transcarbamylase (OTC) deficiency is an X-linked genetic disorder that disrupts the urea cycle. This cycle is essential for detoxifying ammonia in the liver by converting it into urea, which is then excreted in urine. In OTC deficiency, a mutation in the OTC gene results in a dysfunctional ornithine transcarbamylase enzyme. The impaired enzyme activity leads to an accumulation of ammonia, which is neurotoxic, and other intermediates like carbamoyl phosphate, causing severe metabolic disturbances. Elevated ammonia levels can result in encephalopathy, cerebral edema, and, if untreated, can be fatal.
- Carrier Status
- Ornithine transcarbamoylase (OTC) deficiency is an X-linked genetic disorder. Carrier status refers to individuals, typically females, who have one mutated copy of the OTC gene and one normal copy. Due to X-inactivation, carriers may or may not exhibit symptoms, which can range from mild to severe when present. Males with the mutation usually exhibit more severe symptoms because they have only one X chromosome. "Nan" could refer to "nanomoles" in a biochemical context, but without further information, it’s unclear what specific aspect you're referring to regarding OTC deficiency.
- Mechanism
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Ornithine transcarbamoylase (OTC) deficiency is a genetic disorder that affects the urea cycle, specifically disrupting the conversion of carbamoyl phosphate and ornithine into citrulline. This enzymatic defect leads to an accumulation of ammonia in the blood, which can be toxic, particularly to the brain.
**Mechanism:**
1. **Enzyme Deficiency:** OTC is an enzyme located in the mitochondria of liver cells. It plays a critical role in the urea cycle by catalyzing the reaction between carbamoyl phosphate and ornithine to form citrulline. A deficiency in OTC impairs this step, leading to disruptions in the urea cycle.
2. **Ammonia Accumulation:** Due to the defective urea cycle, ammonia (a byproduct of protein metabolism) is not efficiently converted to urea for excretion. This results in hyperammonemia, an excess of ammonia in the bloodstream.
**Molecular Mechanisms:**
1. **Genetic Mutations:** OTC deficiency is caused by mutations in the OTC gene located on the X chromosome (Xp21.1). These mutations can include missense, nonsense, splice-site mutations, insertions, deletions, or large gene rearrangements. Because it is X-linked, males are typically more severely affected, while females may have milder symptoms due to random X-chromosome inactivation.
2. **Enzyme Dysfunction:** The mutations can result in an enzyme that is misfolded, unstable, or has reduced activity. This impairs the enzyme’s ability to catalyze the formation of citrulline, leading to a block in the urea cycle.
3. **Metabolic Consequences:** The biochemical blockade causes accumulation of upstream substrates, such as carbamoyl phosphate, which may be diverted to produce orotic acid (leading to orotic aciduria). Furthermore, the ineffective removal of ammonia from the body underlies the clinical symptoms of OTC deficiency, such as lethargy, vomiting, cerebral edema, and, if untreated, can lead to neurological damage or death.
Management of OTC deficiency typically involves dietary protein restriction to minimize ammonia production, medications to facilitate alternative pathways for ammonia excretion, and in severe cases, liver transplantation. - 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. Arginine is typically supplemented as well, in an effort to improve the overall function of the urea cycle. 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.Gene therapy had been considered a possibility for curative treatment for OTC deficiency, and clinical trials were taking place at the University of Pennsylvania in the late 1990s. These were halted after the death of Jesse Gelsinger, a young man taking part in a phase I trial using an adenovirus vector. Currently, the only option for curing OTC deficiency is a liver transplant, which restores normal enzyme activity. A 2005 review of 51 patients with OTC deficiency who underwent liver transplant estimated 5-year survival rates of greater than 90%. Severe cases of OTC deficiency are typically evaluated for liver transplant by 6 months of age.
- Compassionate Use Treatment
-
Ornithine transcarbamylase deficiency (OTC deficiency) is a genetic disorder that results in an impaired ability to eliminate ammonia from the body. Here are some treatments categorized as compassionate use, off-label, or experimental:
1. **Compassionate Use Treatment**:
- **Carglumic acid (Carbaglu)**: Used to treat acute hyperammonemia in certain urea cycle disorders. It may be provided under compassionate use for severe cases of OTC deficiency when standard treatments are insufficient.
2. **Off-label Treatments**:
- **Sodium benzoate and sodium phenylacetate**: These medications help to manage ammonia levels by providing an alternative pathway for nitrogen excretion.
- **L-arginine**: Helpful in detoxifying ammonia by promoting its conversion to urea, even though it's not specifically approved for OTC deficiency.
3. **Experimental Treatments**:
- **Gene Therapy**: Ongoing research is exploring methods to correct the underlying genetic defect. Early trials involve viral vectors to introduce functional OTC genes into liver cells.
- **mRNA-based Therapies**: These are designed to deliver the correct OTC gene sequence directly to cells, with some showing promise in preclinical studies.
- **Hematopoietic Stem Cell Transplantation**: Still largely experimental, it involves transplanting stem cells to potentially replace the defective gene, allowing for normal enzyme production.
Patients should consult with their healthcare providers to discuss appropriate treatments and access to experimental therapies. - Lifestyle Recommendations
-
For individuals with ornithine transcarbamoylase (OTC) deficiency, lifestyle recommendations primarily focus on managing ammonia levels to prevent hyperammonemia. Here are some key recommendations:
1. **Dietary Management:**
- **Low-Protein Diet:** Restrict intake of dietary protein to reduce ammonia production. Specific protein requirements should be determined by a dietitian.
- **Special Formulas:** Use special amino acid formulas that provide the essential amino acids without contributing to ammonia production.
- **Frequent, Small Meals:** Eating smaller, more frequent meals can help manage nitrogen balance.
2. **Regular Monitoring:**
- **Ammonia Levels:** Regular blood tests to monitor ammonia levels and amino acid profiles.
- **Liver Function:** Routine checks for liver function, as the liver plays a crucial role in detoxifying ammonia.
3. **Medication:**
- **Ammonia-Reducing Drugs:** Medications like sodium phenylbutyrate or glycerol phenylbutyrate can help reduce ammonia levels.
- **Supplements:** Arginine or citrulline supplements may be recommended to support the urea cycle.
4. **Hydration:**
- **Adequate Fluid Intake:** Ensure proper hydration to help the kidneys excrete ammonia.
5. **Avoid Certain Substances:**
- **Avoid Alcohol:** Alcohol can affect liver function and exacerbate ammonia buildup.
- **Minimize Illness Exposure:** Infections and other stressors can increase protein catabolism, leading to higher ammonia levels.
6. **Emergency Plan:**
- **Action Plan:** Have an emergency plan in place for episodes of hyperammonemia, including knowing when to seek immediate medical attention.
7. **Education and Support:**
- **Educate Family and Caregivers:** Ensure that those around you understand the condition and how to manage it.
- **Support Groups:** Consider joining a support group for individuals with metabolic disorders for additional guidance and support.
Regular follow-up with healthcare providers specializing in metabolic disorders is crucial to manage OTC deficiency effectively. - Medication
-
Ornithine transcarbamoylase deficiency (OTC deficiency) is treated with a combination of dietary management and medications. Medications often used include:
1. **Ammonia-scavenging drugs:** These help reduce the levels of ammonia in the blood. Commonly used drugs include sodium phenylbutyrate (Buphenyl) and glycerol phenylbutyrate (Ravicti).
2. **Arginine or citrulline supplements:** These amino acids can help to stimulate the urea cycle and assist in the excretion of ammonia.
3. **Liver transplantation:** In severe cases, a liver transplant may be considered as it can provide a long-term solution to the enzyme deficiency.
Always consult with a healthcare professional for the most appropriate treatment plan. - Repurposable Drugs
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Ornithine transcarbamoylase deficiency (OTC deficiency) is a genetic disorder affecting the urea cycle, leading to hyperammonemia. Repurposable drugs for OTC deficiency primarily aim at reducing ammonia levels and managing symptoms.
1. **Sodium phenylbutyrate**: This drug helps to excrete excess nitrogen by conjugation with glutamine to form phenylacetylglutamine, which is then excreted in the urine.
2. **Arginine**: Supplementation with arginine hydrochloride can enhance the excretion of nitrogen and support the urea cycle.
3. **Carglumic acid**: Although primarily used for N-acetylglutamate synthase deficiency, it can help reduce ammonia levels in similar metabolic conditions.
Research is ongoing, and these medications are often used in conjunction with dietary management and other supportive therapies. - Metabolites
-
Ornithine transcarbamoylase deficiency (OTC deficiency) leads to an accumulation of ammonia and other toxic substances in the blood. Key metabolites affected include:
1. **Ammonia** - Elevated levels.
2. **Orotic acid** - Elevated in urine.
3. **Carbamoyl phosphate** - Elevated due to the block in the urea cycle.
4. **Glutamine** - Elevated in plasma.
5. **Citrulline** - Typically low to normal in plasma.
The deficiency disrupts the urea cycle, preventing the proper elimination of excess nitrogen. - Nutraceuticals
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Ornithine transcarbamoylase (OTC) deficiency is a urea cycle disorder that affects the body's ability to eliminate ammonia. Nutraceuticals, which are products derived from food sources with extra health benefits, may be considered as supportive care in managing some symptoms of OTC deficiency. However, evidence supporting their efficacy is limited. It's critical that any supplement or nutraceutical use be discussed with a healthcare professional.
The term "nan" often refers to "not a number" in data or computing contexts, or it might be a typo or abbreviation that is unclear in this context about OTC deficiency. Please specify if you have a different context or additional terms related to OTC deficiency for further clarification. - Peptides
-
Ornithine transcarbamoylase deficiency (OTC deficiency) is a genetic disorder that affects the urea cycle, leading to the accumulation of ammonia in the blood. This condition is caused by mutations in the OTC gene, which is responsible for producing the enzyme ornithine transcarbamoylase. Without this enzyme, the body cannot effectively eliminate ammonia.
The term "peptides, nan" seems unclear in this context. If you are asking about peptides related to OTC deficiency, it should be noted that proteins and peptides play various roles in metabolic pathways, and engineering peptides or nanotechnology-based treatments may be an area of research but are not directly linked to standard treatments for OTC deficiency. Current primary treatments focus on dietary management and medications to manage ammonia levels.
If you have a different context in mind for "peptides, nan," please provide additional details.