Argininosuccinic aciduria

Last updated
Argininosuccinic aciduria
Other namesArgininosuccinic acidemia
Argininosuccinic acid.svg
argininosuccinate
Specialty Endocrinology   OOjs UI icon edit-ltr-progressive.svg

Argininosuccinic aciduria is an inherited disorder that causes the accumulation of argininosuccinic acid (also known as "ASA") in the blood and urine. Some patients may also have an elevation of ammonia, a toxic chemical, which can affect the nervous system. Argininosuccinic aciduria may become evident in the first few days of life because of high blood ammonia, or later in life presenting with "sparse" or "brittle" hair, developmental delay, and tremors.

Contents

An infant with argininosuccinic aciduria may seem lethargic or be unwilling to eat, have poorly controlled breathing rate or body temperature, experience seizures or unusual body movements, or go into a coma. Complications from argininosuccinic aciduria may include developmental delay and mental retardation. Progressive liver damage, skin lesions, and brittle hair may also be seen. Immediate treatment and lifelong management (following a strict diet and using appropriate supplements) may prevent many of these complications.

Occasionally, an individual may inherit a mild form of the disorder in which ammonia accumulates in the bloodstream only during periods of illness or other stress.

Signs and symptoms

Genetics

Mutations in the ASL gene cause argininosuccinic aciduria. Argininosuccinic aciduria belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions in the cells of the liver. It processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys.[ citation needed ]

In argininosuccinic aciduria, the enzyme argininosuccinate lyase, involved in the conversion of arginino succinate to arginine within the urea cycle, is damaged or missing. The urea cycle cannot proceed normally, and nitrogen accumulates in the bloodstream in the form of ammonia. Ammonia is especially damaging to the nervous system, so argininosuccinic aciduria causes neurological problems as well as eventual damage to the liver.[ citation needed ]

This condition is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder.

Diagnosis

Diagnosis is based mainly on clinical findings and laboratory test results. Plasma concentrations of ammonia (>150 μmol/L) and citrulline (200-300 μmol/L) are elevated. Elevated levels of argininosuccinic acid (5-110 μmol/L) in the plasma or urine are diagnostic. Molecular genetic testing confirms diagnosis. Newborn screening for ASA is available in the U.S. and parts of Australia, and is considered in several European countries[ citation needed ]

Treatment

During an acute hyperammonemic episode, oral proteins must be avoided and intravenous (I.V.) lipids, glucose and insulin (if needed) should be given to promote anabolism. I.V. nitrogen scavenging therapy (with sodium benzoate and/or sodium phenylacetate) should normalize ammonia levels, but if unsuccessful, hemodialysis is recommended. Long-term management involves dietary protein restriction as well as arginine supplementation. In those with frequent episodes of metabolic decompensation or with hyperammonemia even when following a protein-restricted diet, daily oral nitrogen scavenging therapy may be successful. Orthotopic liver transplantation offers long-term relief of hyperammonemia but does not seem to sufficiently correct neurological complications. Arterial hypertension can be treated by restoring nitric oxide deficiency

Prognosis

Due to the rarity of the disease, it is hard to estimate mortality rates or life expectancy. One 2003 study which followed 88 cases receiving two different kinds of treatment found that very few persons lived beyond age 20 and none beyond age 30. [1]

Incidence

Argininosuccinic aciduria occurs in approximately 1 in 70,000 live births. Many patients can now be detected on the newborn screen if their blood citrulline is elevated.

Related Research Articles

The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic.

<span class="mw-page-title-main">Ornithine transcarbamylase</span> Mammalian protein found in Homo sapiens

Ornithine transcarbamylase (OTC) is an enzyme that catalyzes the reaction between carbamoyl phosphate (CP) and ornithine (Orn) to form citrulline (Cit) and phosphate (Pi). There are two classes of OTC: anabolic and catabolic. This article focuses on anabolic OTC. Anabolic OTC facilitates the sixth step in the biosynthesis of the amino acid arginine in prokaryotes. In contrast, mammalian OTC plays an essential role in the urea cycle, the purpose of which is to capture toxic ammonia and transform it into urea, a less toxic nitrogen source, for excretion.

<span class="mw-page-title-main">Hyperammonemia</span> Medical condition

Hyperammonemia, or high ammonia levels, is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary.

<span class="mw-page-title-main">Ornithine transcarbamylase deficiency</span> Medical condition

Ornithine transcarbamylase deficiency also known as OTC deficiency is the most common urea cycle disorder in humans. Ornithine transcarbamylase, the defective enzyme in this disorder, is the final enzyme in the proximal portion of the urea cycle, responsible for converting carbamoyl phosphate and ornithine into citrulline. OTC deficiency is inherited in an X-linked recessive manner, meaning males are more commonly affected than females.

<span class="mw-page-title-main">Citrullinemia</span> Medical condition

Citrullinemia is an autosomal recessive urea cycle disorder that causes ammonia and other toxic substances to accumulate in the blood.

<span class="mw-page-title-main">Lysinuric protein intolerance</span> Medical condition

Lysinuric protein intolerance (LPI) is an autosomal recessive metabolic disorder affecting amino acid transport. It is characterised by the body's inability to properly digest and use certain proteins. This condition leads to various metabolic complications and is typically diagnosed in infancy or early childhood.

<span class="mw-page-title-main">Argininosuccinate synthase</span> Enzyme

Argininosuccinate synthase or synthetase is an enzyme that catalyzes the synthesis of argininosuccinate from citrulline and aspartate. In humans, argininosuccinate synthase is encoded by the ASS gene located on chromosome 9.

<span class="mw-page-title-main">Argininosuccinate lyase</span> Mammalian protein found in Homo sapiens

The enzyme argininosuccinate lyase (EC 4.3.2.1, ASL, argininosuccinase; systematic name 2-(N ω-L-arginino)succinate arginine-lyase (fumarate-forming)) catalyzes the reversible breakdown of argininosuccinate:

<span class="mw-page-title-main">Sodium phenylbutyrate</span> Chemical compound

Sodium phenylbutyrate, sold under the brand name Buphenyl among others, is a salt of an aromatic fatty acid, 4-phenylbutyrate (4-PBA) or 4-phenylbutyric acid. The compound is used to treat urea cycle disorders, because its metabolites offer an alternative pathway to the urea cycle to allow excretion of excess nitrogen.

<span class="mw-page-title-main">N-Acetylglutamate synthase deficiency</span> Medical condition

N-Acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder.

Carbamoyl phosphate synthetase I deficiency is an autosomal recessive metabolic disorder that causes ammonia to accumulate in the blood due to a lack of the enzyme carbamoyl phosphate synthetase I. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.

<span class="mw-page-title-main">Ornithine translocase deficiency</span> Medical condition

Ornithine translocase deficiency, also called hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, is a rare autosomal recessive urea cycle disorder affecting the enzyme ornithine translocase, which causes ammonia to accumulate in the blood, a condition called hyperammonemia.

<span class="mw-page-title-main">Orotic aciduria</span> Medical condition

Orotic aciduria is a disease caused by an enzyme deficiency, resulting in a decreased ability to synthesize pyrimidines. It was the first described enzyme deficiency of the de novo pyrimidine synthesis pathway.

<span class="mw-page-title-main">Citrin</span> Mammalian protein found in humans

Citrin, also known as solute carrier family 25, member 13 (citrin) or SLC25A13, is a protein which in humans is encoded by the SLC25A13 gene.

Organic acidemia is a term used to classify a group of metabolic disorders which disrupt normal amino acid metabolism, particularly branched-chain amino acids, causing a buildup of acids which are usually not present.

<span class="mw-page-title-main">Argininosuccinic acid</span> Chemical compound

Argininosuccinic acid is a non-proteinogenic amino acid that is an important intermediate in the urea cycle. It is also known as argininosuccinate.

<span class="mw-page-title-main">Argininemia</span> Medical condition

Argininemia is an autosomal recessive urea cycle disorder where a deficiency of the enzyme arginase causes a buildup of arginine and ammonia in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if levels become too high; the nervous system is especially sensitive to the effects of excess ammonia.

Transient hyperammonemia of the newborn (THAN) is an idiopathic disorder occasionally present in preterm newborns but not always symptomatic. Continuous dialysis or hemofiltration have proven to be the most effective treatment. Nutritional support and sodium benzoate have also been used to treat THAN.

<span class="mw-page-title-main">Homocitrulline</span> Chemical compound

L-Homocitrulline is an amino acid and can be detected in larger amounts in the urine of individuals with urea cycle disorders. At present, it is thought that the depletion of the ornithine supply causes the accumulation of carbamyl-phosphate in the urea cycle which may be responsible for the enhanced synthesis of homocitrulline and homoarginine. Both amino acids can be detected in urine. Amino acid analysis allows for the quantitative analysis of these amino acid metabolites in biological fluids such as urine or blood.

<span class="mw-page-title-main">Citrullinemia type I</span> Medical condition

Citrullinemia type I (CTLN1), also known as arginosuccinate synthetase deficiency, is a rare disease caused by a deficiency in argininosuccinate synthetase, an enzyme involved in excreting excess nitrogen from the body. There are mild and severe forms of the disease, which is one of the urea cycle disorders.

References

  1. Bachmann, Claude (2003-11-21). "Long-term outcome of patients with urea cycle disorders and the question of neonatal screening" (PDF). European Journal of Pediatrics. 162 (1): S29–S33. doi:10.1007/s00431-003-1347-z. ISSN   0340-6199. PMID   14634803. S2CID   24821261.

Literature