Urea cycle disorder
Encyclopedia
An urea cycle disorder or urea cycle defect is a genetic disorder
caused by a deficiency of one of the enzyme
s in the urea cycle
which is 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 removed from the blood and converted to urea. Normally, the urea is transferred into the urine
and removed from the body. In urea cycle disorders, the nitrogen accumulates in the form of ammonia
, a highly toxic substance, and is not removed from the body.
Urea cycle disorders are included in the category of inborn errors of metabolism. There is no cure.
s. Because many cases of urea cycle disorders remain undiagnosed and/or infants born with the disorders die without a definitive diagnosis, the exact incidence of these cases is unknown and underestimated. It is believed that up to 20% of Sudden Infant Death Syndrome
cases may be attributed to an undiagnosed inborn error of metabolism such as urea cycle disorder. In April 2000, research experts at the Urea Cycle Consensus Conference estimated the incidence of the disorders at 1 in 10,000 births. This represents a significant increase in case diagnosis in the last two years.
s, hypotonia
(poor muscle tone), respiratory distress, and coma may occur. If untreated, the child will die. These symptoms are caused by rising ammonia levels in the blood. Acute neonatal symptoms are most frequently seen in, but not limited to, boys with OTC Deficiency
.
deficiencies may not show symptoms until early childhood, or may be diagnosed subsequent to identification of the disorder in a more severely affected relative or through newborn screening. Early symptoms may include hyperactive behavior, sometimes accompanied by screaming and self-injurious behavior, and refusal to eat meat
or other high-protein foods. Later symptoms may include frequent episodes of vomiting, especially following high-protein meals; lethargy and delirium
; and finally, if the condition is undiagnosed and untreated, coma and death. Children with this disorder may be referred to child psychologists because of their behavior and eating problems. Childhood episodes of hyperammonemia
(high ammonia levels in the blood) may be brought on by viral illnesses including chicken pox, high-protein meals, or even exhaustion. The condition is sometimes misdiagnosed as Reye’s Syndrome. Childhood onset can be seen in both boys and girls.
-like symptoms, episodes of lethargy, and delirium. These adults are likely to be referred to neurologist
s or psychiatrist
s because of their psychiatric symptoms. However, without proper diagnosis and treatment, these individuals are at risk for permanent brain damage, coma, and death. Adult-onset symptoms have been observed following viral illnesses, childbirth, and use of valproic acid
(an anti-epileptic drug).
Individuals with childhood or adult onset disease may have a partial enzyme deficiency. All of these disorders are transmitted genetic
ally as autosomal recessive
genes - each parent contributes a defective gene to the child, except for one of the defects, Ornithine Transcarbamylase Deficiency. This urea cycle disorder is acquired in one of three ways: as an X-linked trait from the mother, who may be an undiagnosed carrier; in some cases of female children, the disorder can also be inherited from the father's X-chromosome; and finally, OTC deficiency may be acquired as a "new" mutation
occurring in the fetus
uniquely. Recent research has shown that some female carriers of the disease may become symptomatic with the disorder later in life, suffering high ammonia levels. Several undiagnosed women have died during childbirth as a result of high ammonia levels and on autopsy were determined to have been unknown carriers of the disorder.
s responsible for cell growth and development, but not so much protein that excessive ammonia is formed. This protein restriction is used in conjunction with medication
s which provide alternative pathways for the removal of ammonia from the blood. These medications are usually given by way of tube feedings, either via gastrostomy
tube (a tube surgically implanted in the stomach) or nasogastric tube through the nose into the stomach. The treatment may also include supplementation with special amino acid formulas developed specifically for urea cycle disorders, multiple vitamin
s and calcium
supplements. Frequent blood tests are required to monitor the disorders and optimize treatment, and frequently hospitalizations are necessary to control the disorder.
At the most extreme end of the spectrum, a few liver transplants have been done successfully as a cure to the disorder. This treatment alternative must be carefully evaluated with medical professionals to determine if potential of success as compared to the potential for new medical concerns.
involving the connection between urea cycle disorders and other major diseases, such as cancer
, AIDS
, autism
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC551172/, and sickle cell anemia.
Researchers have found at least two major areas of interest in relation to urea cycle disorders. The first connection involves changes in urea cycle enzyme production in cancer patients with bone marrow
transplants undergoing chemotherapy
. Because the production of urea cycle enzymes takes place in the liver, drugs toxic to the liver
, such as those used in chemotherapy, are observed to be causing changes in the urea cycle. Thus, these bone marrow transplant patients are developing the same accumulation of ammonia (hyperammonemia
) seen in children with urea cycle disorders. Another study has found changes (polymorphisms) in these enzymes in large populations. This raises questions as to the significance of these variations on the overall health of the individual.The second connection relates to the drugs that were developed through the Orphan Drug Act for treating the children with of urea cycle disorders. These drugs, pioneered by children with urea cycle disorders, are now being used in Phase II clinical trial
s at major cancer research institutions across the nation. The drugs appear to halt the production of cancer cells in numerous cancers, including melanoma
and lymphoma
.
Other large research institutions are now looking at urea cycle disorders, a previously limited disease, as a new key to developing treatments in other areas of medicine. This new interest will bring more resources to bear for urea cycle research, and our ultimate goal of a cure for the children suffering from these devastating disorders.
Recent advancements in technologies such as tandem mass spectrometry
have made it possible to screen all newborns for argininosuccinate synthetase deficiency (citrullinemia), argininosuccinate lyase, and arginase deficiency. Research into screens for OTC and CPS deficiencies has been initiated. We believe that comprehensive newborn screening will help prevent brain damage and other severe consequences of delayed diagnoses and save children’s lives.
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
caused by a deficiency of one of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s in the urea cycle
Urea cycle
The urea cycle is a cycle of biochemical reactions occurring in many animals that produces urea from ammonia . This cycle was the first metabolic cycle discovered , five years before the discovery of the TCA cycle...
which is responsible for removing ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
from the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
stream. The urea cycle involves a series of biochemical steps in which nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
, a waste product of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
, is removed from the blood and converted to urea. Normally, the urea is transferred into the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
and removed from the body. In urea cycle disorders, the nitrogen accumulates in the form of ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
, a highly toxic substance, and is not removed from the body.
Urea cycle disorders are included in the category of inborn errors of metabolism. There is no cure.
Incidence
Inborn errors of metabolism are generally considered to be rare but represent a substantial cause of brain damage and death among newborns and infantInfant
A newborn or baby is the very young offspring of a human or other mammal. A newborn is an infant who is within hours, days, or up to a few weeks from birth. In medical contexts, newborn or neonate refers to an infant in the first 28 days after birth...
s. Because many cases of urea cycle disorders remain undiagnosed and/or infants born with the disorders die without a definitive diagnosis, the exact incidence of these cases is unknown and underestimated. It is believed that up to 20% of Sudden Infant Death Syndrome
Sudden infant death syndrome
Sudden infant death syndrome is marked by the sudden death of an infant that is unexpected by medical history, and remains unexplained after a thorough forensic autopsy and a detailed death scene investigation. An infant is at the highest risk for SIDS during sleep, which is why it is sometimes...
cases may be attributed to an undiagnosed inborn error of metabolism such as urea cycle disorder. In April 2000, research experts at the Urea Cycle Consensus Conference estimated the incidence of the disorders at 1 in 10,000 births. This represents a significant increase in case diagnosis in the last two years.
The neonatal period
Children with very severe urea cycle disorders typically show symptoms after the first 24 hours of life. The baby may be irritable at first, followed by vomiting and increasing lethargy. Soon after, seizureSeizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
(poor muscle tone), respiratory distress, and coma may occur. If untreated, the child will die. These symptoms are caused by rising ammonia levels in the blood. Acute neonatal symptoms are most frequently seen in, but not limited to, boys with OTC Deficiency
Ornithine transcarbamylase deficiency
Ornithine transcarbamylase deficiency , the most common of the urea cycle disorders, is a rare metabolic disorder, occurring in one out of every 80,000 births...
.
Childhood
Children with mild or moderate urea cycle enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
deficiencies may not show symptoms until early childhood, or may be diagnosed subsequent to identification of the disorder in a more severely affected relative or through newborn screening. Early symptoms may include hyperactive behavior, sometimes accompanied by screaming and self-injurious behavior, and refusal to eat meat
Meat
Meat is animal flesh that is used as food. Most often, this means the skeletal muscle and associated fat and other tissues, but it may also describe other edible tissues such as organs and offal...
or other high-protein foods. Later symptoms may include frequent episodes of vomiting, especially following high-protein meals; lethargy and delirium
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
; and finally, if the condition is undiagnosed and untreated, coma and death. Children with this disorder may be referred to child psychologists because of their behavior and eating problems. Childhood episodes of hyperammonemia
Hyperammonemia
Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to encephalopathy and death. It may be primary or secondary....
(high ammonia levels in the blood) may be brought on by viral illnesses including chicken pox, high-protein meals, or even exhaustion. The condition is sometimes misdiagnosed as Reye’s Syndrome. Childhood onset can be seen in both boys and girls.
Adulthood
Recently, the number of adult individuals being diagnosed with urea cycle disorders has increased at an alarming rate. Recent evidence has indicated that these individuals have survived undiagnosed to adulthood, probably due to less severe enzyme deficiencies. These individuals exhibit strokeStroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
-like symptoms, episodes of lethargy, and delirium. These adults are likely to be referred to neurologist
Neurologist
A neurologist is a physician who specializes in neurology, and is trained to investigate, or diagnose and treat neurological disorders.Neurology is the medical specialty related to the human nervous system. The nervous system encompasses the brain, spinal cord, and peripheral nerves. A specialist...
s or psychiatrist
Psychiatrist
A psychiatrist is a physician who specializes in the diagnosis and treatment of mental disorders. All psychiatrists are trained in diagnostic evaluation and in psychotherapy...
s because of their psychiatric symptoms. However, without proper diagnosis and treatment, these individuals are at risk for permanent brain damage, coma, and death. Adult-onset symptoms have been observed following viral illnesses, childbirth, and use of valproic acid
Valproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
(an anti-epileptic drug).
The six urea cycle disorders
There are six disorders of the urea cycle. Each is referred to by the initials of the missing enzyme.| Location | Abb. | Enzyme | Disorder | Measurements >- | Mitochondria |
NAGS | N-Acetylglutamate synthetase | N-Acetylglutamate synthase deficiency | Ammonia Ammonia Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or... >- | Mitochondria |
CPS1 | Carbamoyl phosphate synthetase I Carbamoyl phosphate synthetase I Carbamoyl Phosphate Synthetase I is a ligase enzyme located in the mitochondria involved in the production of urea. Carbamoyl Phosphate Synthetase I transfers an ammonia from glutamine to a molecule of bicarbonate that has been phosphorylated by a molecule of ATP. The resulting carbamate is... |
Carbamoyl phosphate synthetase I deficiency Carbamoyl phosphate synthetase I deficiency Carbamoyl phosphate synthetase I deficiency is an autosomal recessive metabolic disorder that causes ammonia to accumulate in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high... |
Ammonia Ammonia Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or... >- | Mitochondria |
OTC | Ornithine transcarbamylase Ornithine transcarbamylase Ornithine transcarbamoylase is an enzyme that catalyzes the reaction between carbamoyl phosphate and ornithine to form citrulline and phosphate... |
Ornithine transcarbamylase deficiency Ornithine transcarbamylase deficiency Ornithine transcarbamylase deficiency , the most common of the urea cycle disorders, is a rare metabolic disorder, occurring in one out of every 80,000 births... |
Ornithine Ornithine Ornithine is an amino acid that plays a role in the urea cycle.-Role in urea cycle:L-Ornithine is one of the products of the action of the enzyme arginase on L-arginine, creating urea. Therefore, ornithine is a central part of the urea cycle, which allows for the disposal of excess nitrogen.... , +Uracil Uracil Uracil is one of the four nucleobases in the nucleic acid of RNA that are represented by the letters A, G, C and U. The others are adenine, cytosine, and guanine. In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced by thymine.Uracil is a common and... , +Orotic acid >- | Cytosol Cytosol The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments.... |
ASS | Argininosuccinic acid synthetase | "AS deficiency" or citrullinemia Citrullinemia Citrullinemia, also called citrullinuria, is an autosomal recessive urea cycle disorder that causes ammonia and other toxic substances to accumulate in the blood.... |
Citrulline Citrulline The organic compound citrulline is an α-amino acid. Its name is derived from citrullus, the Latin word for watermelon, from which it was first isolated in 1930.It has the idealized formula H2NCNH3CHCO2H... >- | Cytosol Cytosol The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments.... |
ASL | Argininosuccinase acid lyase | "AL deficiency" or argininosuccinic aciduria Argininosuccinic aciduria Argininosuccinic aciduria, also called argininosuccinic acidemia, is an inherited disorder that causes the accumulation of argininosuccinic acid in the blood and urine. Some patients may also have an elevation of ammonia, a toxic chemical, which can affect the nervous system... (ASA) |
Citrulline Citrulline The organic compound citrulline is an α-amino acid. Its name is derived from citrullus, the Latin word for watermelon, from which it was first isolated in 1930.It has the idealized formula H2NCNH3CHCO2H... , +Argininosuccinic acid Argininosuccinic acid Argininosuccinic acid is a chemical compound that is a basic amino acid.-Reactions:Some cells synthesize argininosuccinic acid from citrulline and aspartic acid and use it as a precursor for arginine in the urea cycle or citrulline-NO cycle... >- | Cytosol Cytosol The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments.... |
ARG | Arginase Arginase Arginase is a manganese-containing enzyme. The reaction catalyzed by this enzyme is: arginine + H2O → ornithine + urea. It is the final enzyme of the urea cycle.- Structure and function :Arginase belong to the ureohydrolase family of enzymes.... |
"Arginase deficiency" or argininemia Argininemia Argininemia, also called arginase deficiency, is an autosomal recessive urea cycle disorder where a deficiency of the enzyme arginase causes a build up of arginine and ammonia in the blood.... |
+Arginine Arginine Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during... |
Individuals with childhood or adult onset disease may have a partial enzyme deficiency. All of these disorders are transmitted genetic
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
ally as autosomal recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
genes - each parent contributes a defective gene to the child, except for one of the defects, Ornithine Transcarbamylase Deficiency. This urea cycle disorder is acquired in one of three ways: as an X-linked trait from the mother, who may be an undiagnosed carrier; in some cases of female children, the disorder can also be inherited from the father's X-chromosome; and finally, OTC deficiency may be acquired as a "new" mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
occurring in the fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
uniquely. Recent research has shown that some female carriers of the disease may become symptomatic with the disorder later in life, suffering high ammonia levels. Several undiagnosed women have died during childbirth as a result of high ammonia levels and on autopsy were determined to have been unknown carriers of the disorder.
Treatment
The treatment of urea cycle disorders consists of balancing dietary protein intake in order that the body receive the essential amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s responsible for cell growth and development, but not so much protein that excessive ammonia is formed. This protein restriction is used in conjunction with medication
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
s which provide alternative pathways for the removal of ammonia from the blood. These medications are usually given by way of tube feedings, either via gastrostomy
Gastrostomy
Gastrostomy refers to a surgical opening into the stomach. Creation of an artificial external opening into the stomach for nutritional support or gastrointestinal compression....
tube (a tube surgically implanted in the stomach) or nasogastric tube through the nose into the stomach. The treatment may also include supplementation with special amino acid formulas developed specifically for urea cycle disorders, multiple vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...
s and calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
supplements. Frequent blood tests are required to monitor the disorders and optimize treatment, and frequently hospitalizations are necessary to control the disorder.
At the most extreme end of the spectrum, a few liver transplants have been done successfully as a cure to the disorder. This treatment alternative must be carefully evaluated with medical professionals to determine if potential of success as compared to the potential for new medical concerns.
Research
In 2003, the National Institutes of Health began a research initiative including the creation of a Rare Diseases Clinical Research Network, including 10 consortia studying more than 50 rare diseases. The Urea Cycle Disorders Consortium, under the direction of Mark Batshaw, M.D. at Children's National Medical Center, and in combination with eight other academic centers, began longitudinal studies of the urea cycle disorders. There has also been a recent explosion of researchResearch
Research can be defined as the scientific search for knowledge, or as any systematic investigation, to establish novel facts, solve new or existing problems, prove new ideas, or develop new theories, usually using a scientific method...
involving the connection between urea cycle disorders and other major diseases, such as cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
, autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC551172/, and sickle cell anemia.
Researchers have found at least two major areas of interest in relation to urea cycle disorders. The first connection involves changes in urea cycle enzyme production in cancer patients with bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
transplants undergoing chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
. Because the production of urea cycle enzymes takes place in the liver, drugs toxic to the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, such as those used in chemotherapy, are observed to be causing changes in the urea cycle. Thus, these bone marrow transplant patients are developing the same accumulation of ammonia (hyperammonemia
Hyperammonemia
Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to encephalopathy and death. It may be primary or secondary....
) seen in children with urea cycle disorders. Another study has found changes (polymorphisms) in these enzymes in large populations. This raises questions as to the significance of these variations on the overall health of the individual.The second connection relates to the drugs that were developed through the Orphan Drug Act for treating the children with of urea cycle disorders. These drugs, pioneered by children with urea cycle disorders, are now being used in Phase II clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s at major cancer research institutions across the nation. The drugs appear to halt the production of cancer cells in numerous cancers, including melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
and lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
.
Other large research institutions are now looking at urea cycle disorders, a previously limited disease, as a new key to developing treatments in other areas of medicine. This new interest will bring more resources to bear for urea cycle research, and our ultimate goal of a cure for the children suffering from these devastating disorders.
Recent advancements in technologies such as tandem mass spectrometry
Tandem mass spectrometry
Tandem mass spectrometry, also known as MS/MS or MS2, involves multiple steps of mass spectrometry selection, with some form of fragmentation occurring in between the stages.-Tandem MS instruments:...
have made it possible to screen all newborns for argininosuccinate synthetase deficiency (citrullinemia), argininosuccinate lyase, and arginase deficiency. Research into screens for OTC and CPS deficiencies has been initiated. We believe that comprehensive newborn screening will help prevent brain damage and other severe consequences of delayed diagnoses and save children’s lives.
External links
- Overview at Indiana State UniversityIndiana State UniversityIndiana State University is a public university located in Terre Haute, Indiana, United States.The Princeton Review has named Indiana State as one of the "Best in the Midwest" seven years running, and the College of Education's Graduate Program was recently named as a 'Top 100' by U.S...
- GeneReviews/UW/NIH entry on Urea cycle disorders