Treatment of urea cycle defects Unfortunately, as with many other rare genetic diseases, there is no definitive therapy. Patients with this disorder are treated with a low protein diet (low protein) and with some drugs which favor the elimination of ammonium (called "scavengers").
Full Answer
What are the treatment options for urea cycle disorders?
OVERVIEW: The treatment of urea cycle disorders consists of dietary management to limit ammonia production in conjunction with medications and/or supplements which provide alternative pathways for the removal of ammonia from the bloodstream.
What is the urea cycle and what causes it?
The urea cycle genes and proteins form a metabolic pathway that begin with ammonia, and after a series of steps, produce urea, which can be safely excreted. Children’s National is considered the world leader in the diagnosis, treatment and research of urea cycle disorders with three renowned experts in this field.
What are urea cycle disorders (UCDs)?
Urea cycle disorders (UCDs) lead to the accumulation of ammonia in the blood and brain and resultant episodes of metabolic encephalopathy, with a great risk of morbidity and mortality.
What is the mainstay of long-term management of urea toxicity?
This mainstay of long-term management is based upon minimising the nitrogen load on the urea cycle. The amount of natural protein tolerated by each patient must be individually determined and by titration against ammonia.
What are some treatments for urea cycle disorders?
A liver transplant can reverse the symptoms of a urea cycle disorder....TreatmentDialysis to remove ammonia from their blood.Feeding them supplements of sugars, fats, and amino acids.Medicines to remove extra nitrogen.
What happens when urea cycle enzymes are genetically defective?
Urea cycle disorders are inborn errors of metabolism resulting from defects in one of the enzymes or transporter molecules involved in the hepatic removal of ammonia from the bloodstream. Removal of ammonia from the bloodstream normally occurs via its conversion to urea, which is then excreted by the kidneys.
How do you regulate urea cycle?
Glucagon, insulin, and glucocorticoids are major regulators of the expression of urea cycle enzymes in liver. In contrast, the "urea cycle" enzymes in nonhepatic cells are regulated by a wide range of pro- and antiinflammatory cytokines and other agents.
Why are genetic defects in the urea cycle life threatening?
In Urea cycle disorders, nitrogen builds up in the blood in the form of ammonia, a highly toxic substance, resulting in hyperammonemia (elevated blood ammonia). Ammonia then reaches the brain through the blood, where it can cause irreversible brain damage, coma and/or death.
What type of doctor treats urea cycle disorders?
Your UCD care team You may see a primary care doctor as well as a team of specialists at a metabolic center. These specialists may include a metabolic geneticist, a dietitian, nurses, a genetic counselor, a nurse practitioner, and a social worker. Metabolic geneticists are specialists who treat disorders like UCDs.
How can we remove urea from urine?
3:2715:09Extracting urea from my own pee - YouTubeYouTubeStart of suggested clipEnd of suggested clipProcess it to do this I transfer it all to a beaker. And start adding concentrated nitric acid thisMoreProcess it to do this I transfer it all to a beaker. And start adding concentrated nitric acid this reaction produces a lot of heat. And it can easily get out of control.
How is the urea cycle regulated quizlet?
Urea Cycle is primarily regulated by the availability of substrate. The higher the production rate of ammonia, the faster the cycle moves to excrete it. True.
What are the disorders of urea cycle?
Primary urea cycle disorders (UCDs) include carbamoyl phosphate synthase (CPS) deficiency, ornithine transcarbamylase (OTC) deficiency, argininosuccinate synthetase deficiency (citrullinemia), argininosuccinate lyase deficiency (argininosuccinic aciduria), arginase deficiency (argininemia), and N-acetylglutamate ...
What stimulates the urea cycle?
stimulated by N-acetyl-glutamate (a required allosteric activator), which is synthesized from acetyl CoA and glutamate; the synthesis of N-acetyl-glutamate is stimulated by arginine, the immediate precursor of urea in the urea cycle.
Why is arginine given in urea cycle disorder?
Common treatments for urea cycle disorders include a low-protein diet and arginine supplementation, which, when combined, help to decrease ammonia levels in the blood. Buphenyl-TM may aid in lowering ammonia and argininosuccinic acid levels.
How do you test for UCD?
During a genetic test, a doctor or nurse takes a sample of your DNA. This is usually done by drawing your blood or swabbing the inside of your mouth. Then, your sample is sent to a lab where doctors look at your DNA to see if they can find the defective gene that causes a UCD.
What is a urea cycle disorder?
A urea cycle disorder is a genetic disorder that results in a deficiency of one of the six enzymes in the urea cycle. These enzymes are responsible for removing ammonia from the blood stream. The urea cycle involves a series of biochemical steps in which nitrogen, a waste product of protein metabolism, is changed to a compound called urea and removed from the blood. Normally, the urea is removed from the body through the urine. In urea cycle disorders, nitrogen builds up in the blood in the form of ammonia, a highly toxic substance, resulting in hyperammonemia (elevated blood ammonia). Ammonia then reaches the brain through the blood, where it can cause irreversible brain damage, coma and/or death. The onset and severity of urea cycle disorders is highly variable. The severity correlates with the amount of urea cycle enzyme function. [1]
What is the FDA approved indication for urea cycle disorders?
FDA-approved indication: Use as a nitrogen-binding adjunctive therapy for chronic management of adult and pediatric patients at least 2 months of age with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone.
What is the NORD guide for urea cycle?
The NORD Physician Guide for Urea cycle disorders was developed as a free service of the National Organization for Rare Disorders (NORD) and it's medical advisors. The guides provide a resource for clinicians about specific rare disorders to facilitate diagnosis and treatment of their patients with this condition.
How does urea get out of the body?
Normally, the urea is removed from the body through the urine. In urea cycle disorders, nitrogen builds up in the blood in the form of ammonia, a highly toxic substance, resulting in hyperammonemia (elevated blood ammonia). Ammonia then reaches the brain through the blood, where it can cause irreversible brain damage, coma and/or death.
What is genetics materials for school success?
The Genetics Education Materials for School Success (GEMSS) aims to assure that all children with genetic health conditions succeed in school-life. Their Web site offers general and condition-specific education resources to help teachers and parents better understand the needs of students who have genetic conditions.
Who makes benzoate and phenylacetate?
Benzoate and phenylacetate (Brand name: Ucephan ) - Manufactured by Immunex Immunex. FDA-approved indication: For adjunctive therapy in the prevention and treatment of hyperammonemia in patients with urea cycle enzymopathy due to carbamylphosphate synthetase, ornithine, transcarbamylase, or argininosuccinate synthetase deficiency.
The Urea Cycle Disorders Consortium (UCDC)
The UCDC is an NIH-funded 16-site research consortium within the Rare Disease Clinical Research Network to investigate inborn errors of the urea cycle. These rare genetic disorders result from defects in any of the eight genes associated with this important metabolic cycle and have a combined prevalence of about 1 in 30,000.
Neuroimaging in Urea Cycle Disorders
Advanced neuroimaging technology, using diffusion tensor imaging, volumetric averaging, fMR and magnetic resonance spectroscopy, allows non-invasive investigations of the brain in complex conditions such as hyperammonemia in UCDs. Andrea Gropman, M.D., and her team, including John VanMeter, Ph.D.
Clinical Trials in Hyperammonemia
In an NIH-funded project, Mendel Tuchman, M.D., and Nicholas Ah Mew, M.D., demonstrated that an oral medication, N-carbamylglutamate, can correct the biochemical defect in patients with a UCD known as N-acetylglutamate synthase (NAGS) deficiency, thereby normalizing ammonia levels and restoring normal urea production.
Liver Transplant in the Urea Cycle Disorders
In a project funded by the Patient-Centered Outcomes Research Institute (PCORI), Nicholas Ah Mew, M.D., and Robert McCarter, Jr., Sc.D., are conducting a study to compare the outcome of liver transplantation with conservative management in urea cycle disorders.
Neuroprotection from Hyperammonemia
In addition to ammonia removal, a new therapeutic paradigm for treating hyperammonemia directly protects the brain. Ljubica Caldovic, Ph.D., and Hiroki Morizono, Ph.D., are screening chemicals as potential drugs that can protect the brain from the toxic effects of ammonia.
Gene Therapy for Urea Cycle Disorders
Hiroki Morizono, Ph.D., and Mark L.
Structural Biology of N-Acetylglutamate Synthase (NAGS) Deficiency
In another project funded by the NIH, Ljubica Caldovic, Ph.D., continued to investigate the structural biology of NAGS and CPS1 proteins of the urea cycle.
What is a urea cycle disorder?
A urea cycle disorder is a genetic disorder that results in a deficiency of one of the six enzymes in the urea cycle. These enzymes are responsible for removing ammonia from the blood stream. The urea cycle involves a series of biochemical steps in which nitrogen, a waste product of protein metabolism, is changed to a compound called urea and removed from the blood. Normally, the urea is removed from the body through the urine. In urea cycle disorders, nitrogen builds up in the blood in the form of ammonia, a highly toxic substance, resulting in hyperammonemia (elevated blood ammonia). Ammonia then reaches the brain through the blood, where it can cause irreversible brain damage, coma and/or death. The onset and severity of urea cycle disorders is highly variable. The severity correlates with the amount of urea cycle enzyme function. [6174]
How does urea get out of the body?
Normally, the urea is removed from the body through the urine. In urea cycle disorders, nitrogen builds up in the blood in the form of ammonia, a highly toxic substance, resulting in hyperammonemia (elevated blood ammonia). Ammonia then reaches the brain through the blood, where it can cause irreversible brain damage, coma and/or death.
What is the treatment for urea cycle disorder?
DIETARY MANAGEMENT: Treatment may include supplementation with special amino acid formulas (Cyclinex, EAA, Trio, UCD I&II), developed specifically for urea cycle disorders, which can be prescribed to provide approximately 50% of the daily dietary protein allowance.
What supplements can help with urea cycle?
Multiple vitamins and calcium supplements are also recommended. New research also suggests that antioxidants may be helpful in minimizing free radical damage to cells in tissue and brain. DRUG TREATMENT: Two forms of a drug, phenylbutyrate, are FDA approved for treatment of urea cycle disorders, sodium phenylbutyrate (trade name Buphenyl, ...
Why are amino acids reduced?
Branched-chain amino acids may be reduced as a result of treatment with ammonia scavenging medication (phenylbutyrate), triggering catabolism; therefore, frequent blood tests (serum ammonia, plasma quantitative amino acids) are required to monitor the disorders and are an important tool for optimizing treatment.
What is the term for a group of genetic conditions that result from genetic changes that disrupt the production of specific enzymes
For a group of genetic conditions called inborn errors of metabolism , which result from genetic changes that disrupt the production of specific enzymes, treatments sometimes include dietary changes or replacement of the particular enzyme that is missing.
What is gene therapy?
This experimental technique involves changing a person's genes to prevent or treat a disease. Gene therapy, along with many other treatment and management approaches for genetic conditions, are under study in clinical trials.
What is an example of an inborn error of metabolism?
An example of an inborn error of metabolism is phenylketonuria (PKU).
What are some examples of genetic changes?
One well-known example is familial breast cancer related to mutations in the BRCA1 and BRCA2 genes.
Can genetic disorders be cured?
As a result, these disorders often affect many body systems, and most cannot be cured. However, approaches may be available to treat or manage some of the associated signs and symptoms.
Treatment with Drugs
- Sodium phenylbutyrate or buphenyl is an ammonia scavenger that is widely used to treat UCDs. It provides alternative ammonia removal pathways and prevents hyperammonemia. Sodium benzoate is also used for continual ammonia removal from the bloodstream. Oral lactulose and …
Dietary Management
- Prevention or control of UCD symptoms can be achieved by dietary restrictions. Dietary protein is closely monitored and protein restriction is advised while balancing protein, fats and carbohydrates in the diet to make sure essential amino acids are adequately ingested and calorie intake matches the energy requirements of the body. Children are treated with a low protein and …
Genetic Counseling
- Except OTC deficiency, all other UCD are autosomal recessive disorders. OTC defect is X-linked and is found more in males. Females have 2 X chromosomes and hence most females affected by this gene mutation are carriers and are mostly asymptomatic. Only 15% of female carriers show symptoms especially during infection, after protein rich meals, post-partum, and with GI bl…
Parental Education
- Educating parents of children with this disorder is important for them to recognize the symptoms of hyperammonemia and to take extra care in case of infection and stress when ammonia production in the body is increased.
Respiratory Management
- In case of respiratory failure due to urea cycle disorder, mechanical ventilation is used to aid respiration.
References
Further Reading