What is argininosuccinic aciduria?
Argininosuccinic aciduria is a rare genetic disorder. People with this disorder are deficient in or missing an enzyme called argininosuccinate lyase or ASL. This enzyme has a job. It is part of the urea cycle. This cycle is series of biochemical reactions that occur in the body to help to break down (metabolize) and then remove excess nitrogen from the body. Nitrogen is obtained from the diet and is a normal waste product of the metabolism of protein. Through the urea cycle, nitrogen is broken down into a compound called urea that is passed from the body in the urine. Since people with argininosuccinic aciduria cannot properly break down nitrogen into urea, nitrogen (in the form of ammonia) build up in the body. When too much ammonia builds up, it is toxic to the body, particularly to the brain. The disorder is highly variable. This means how it affects one person can be very different from how it affects another person.
Argininosuccinic aciduria can be very severe right from birth, or there may be forms of the disorder that do not develop until after infancy; these are called late-onset forms. When the disorder occurs at birth, it can be severe and cause life-threatening problems. Infants may not eat well, may vomit, have irregular heartbeats, and be very tired (lethargic). If untreated, the disorder will worsen. Infants will become more lethargic, refuse to eat, can develop seizures, and may fall into coma. This called a metabolic crisis and occurs because of highly elevated ammonia levels. A metabolic crisis is a life-threatening complication that can be fatal.
The late-onset forms may have metabolic episodes similar to that seen in infants. Sometimes, symptoms may not occur unless something triggers an episode. This can include an infection, stress or when a child eats or drinks a lot of protein. Some children with late-onset forms develop intellectual disability, learning disabilities, seizures, and behavioral issues without any metabolic episodes. These problems can also develop in children who are treated from birth. Other problems may develop including liver damage, high blood pressure, and dry, brittle hair. The late-onset forms are quite variable. This means that can affect people very differently. For example, symptoms may not begin until childhood or the teen-age years. Sometimes, they don't develop until people are adults.
Researchers have shown that infants and children with argininosuccinic aciduria have fewer episodes of metabolic crisis than infants and children with other urea cycle disorders. However, they have the second highest frequency of cognitive issues among these disorders. Researchers believe that some symptoms including neurological symptoms do not develop solely because of elevated ammonia levels. Researchers are not sure what other factors contribute to these symptoms.
Argininosuccinic Aciduria. The National Organization for Rare Disorders website. Accessed July 1, 2017. https://rarediseases.org/rare-diseases/argininosuccinic-aciduria/
Nagamani SCS, Erez A, Lee B. Argininosuccinate Lyase Deficiency. GeneReviews website. Accessed July 1, 2017. https://www.ncbi.nlm.nih.gov/books/NBK51784/
Erez A. Argininosuccinic aciduria: from a monogenic to a complex disorder. Genet Med. 2013;15(4):251-7. https://www.nature.com/gim/journal/v15/n4/full/gim2012166a.html
Baruteau J, Jameson E, Morris AA, et al. Expanding the phenotype in argininosuccinic aciduria: need for new therapies. J Inherit Metab Dis. 2017;40(3):357-368. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393288/