Urea cycle disorders are congenital diseases that are caused by a dysfunctional urea cycle. The genetics and biochemistry of these disorders have been extensively studied. They are the result of a deficiency of one of the six enzymes that catalyze the various biochemical reactions in the urea cycle which converts ammonia to urea for removal via urine.
Urea cycle disorders belong to inborn errors of metabolism that are associated with fatal brain damage and death in newborns.
Urea Cycle Disorders| Center for Rare Disease Therapy at UPMC Children's Hospital of Pittsburgh
Consequences of Urea Cycle Defects
When one of the urea cycle enzymes is absent or deficient, ammonia, which is a highly neurotoxic, is not eliminated from the body and accumulates, leading to elevated blood levels of ammonia called hyperammonemia. Excess ammonia in the blood stream enters the brain and causes irreversible damage, leading to coma or death. Untreated children experience retarded physical and mental development.
Different Disorders of the Urea Cycle
There are 8 urea cycle disorders based on the deficiency of different enzymes and transporter proteins that play key roles in the cycle.
N-acetylglutamate synthase (NAGS) deficiency – NAGS is essential for the functioning of the first enzyme in urea cycle, carbamoylphosphate synthetase I (CPS1). Lack of NAGS causes hyperammonemia symptoms similar to CPS1 deficiency, as CPS1 is inactivated in the absence of NAGS. It is the only defect in the urea cycle where hyperammonemia can be fully treated by using carglumic acid.
Carbamoylphosphate synthetase I (CPS1) deficiency – Complete lack of CPS1 causes hyperammonemia in newborns. It is a very severe urea cycle disorder and even after treatment and recovery, they are at chronic risk of bouts of hyperammonemia. Partial or mild CPS1 deficiency can cause symptoms at any stage of life, especially in response to stress or infection.
Ornithine transcarbamylase (OTC) deficiency – Lack of OTC can be as severe as CPS1 deficiency, and is more prevalent in males, as they have only one X chromosome which hosts the gene coding for OTC. Females are at lesser risk of OTC deficiency as they have 2 X chromosomes and chances of having one functional OTC gene are higher. Only about 15% of females show symptoms of OTC deficiency and develop hyperammonemia, necessitating chronic medical management.
Argininosuccinate synthase 1 (ASS1) deficiency or Citrullinemia type I – This defect results in severe hyperammonemia in affected individuals. They also have abnormally high levels of citrulline in blood. However, they can still channel some of the waste nitrogen into the urea cycle, making treatment relatively easy.
Citrin deficiency or Citrullinemia type II - Citrin is a transporter protein responsible for the transport of aspartate into the urea cycle. Deficiency of this protein causes hyperammonemia, leading to seizures and coma. This is more common in Asian populations where mutations in the Citrin gene are common.
Argininosuccinic lyase (ASL) deficiency – This disorder is characterized by rapid hyperammonemia in newborns. It causes chronic hepatic enlargement and increase in levels of transaminases. Enlarged hepatocytes may lead to fibrosis.
Arginase (ARG) deficiency – This defect does not cause rapid-onset hyperammonemia but some patients experience severe symptoms such as progressive spasticity and retarded growth.
Ornithine translocase deficiency - Ornithine translocase is another transport protein that carries ornithine and citrulline molecules within the urea cycle. Lack of this protein slows down the cycle and causes ammonia build up. Hyperammonemia, vomiting and coma are common symptoms.
Summary
Early diagnosis and advances in treatment methods have improved life expectancy in patients with urea cycle disorders. Although hyperammonemia is the primary cause of mortality and morbidity in these disorders, some of them point to unrelated pathophysiological processes.
There is no clarity regarding the exact incidence of these disorders, as many infants born with these defects die without a clear diagnosis or many cases are not diagnosed. According to researchers, the incidence of urea cycle disorders in newborns is 1 in 10,000 as of April 2000. This indicates a marked increase in the identification and diagnosis of these disorders in the recent years.
Currently, research studies are underway to precisely determine the incidence and prevalence of these disorders.
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Further Reading