About argininosuccinate lyase deficiency

What is argininosuccinate lyase deficiency?

Argininosuccinic aciduria is a rare inherited disorder characterized by deficiency or lack of the enzyme argininosuccinate lyase (ASL). Argininosuccinate lyase is one of six enzymes that play a role in the breakdown and removal of nitrogen from the body, a process known as the urea cycle. The lack of this enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood. Affected infants may experience vomiting, refusal to eat, progressive lethargy, and coma. Argininosuccinic aciduria is inherited as an autosomal recessive trait.

The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood.

What are the symptoms for argininosuccinate lyase deficiency?

Argininosuccinate lyase (ASL) catalyzes the lysis of arginine succinate into fumarate and arginine. This reaction replenishes arginine that initiates the urea cycle. ASL deficiency thus reduces the concentration of arginine and slows down the fixation of nitrogen into urea.

Symptoms of Argininosuccinate lyase Deficiency

  • Neonatal onset form is characterized by hyperammonemia within a few days after the birth. The manifestations of neonatal-onset form are tachypnoea leading to a central respiratory alkalosis, hypothermia, Seizures, Vomiting, and Lethargy. The affected children are born with brittle and dry hair.
  • In contrast, the manifestations of late-onset form range from episodic hyperammonemia to cognitive impairment, behavioral abnormalities, and learning disabilities.
  • While the secondary effects of hyperammonemia are common to other Urea cycle disorders, the incidence of hepatic cirrhosis, systemic hypertension, and trichorrhesis nodosa are unique to ASL deficiency.
  • In rare cases, a patient may develop renal diseases and abnormally rapid breathing.
  • ASL is the only enzyme that catalyzes the generation of arginine.
  • Hence in addition to the symptoms of other Urea cycle disorders, ASL deficiency causes chronic complications of tissue-specific deficiency of arginine and toxicity of elevated levels of arginine succinate.


Conditions
Developmental delay,Mental retardation,Progressive liver damage,Skin lesions,Brittle hair
Drugs
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,Hemodialysis
Symptoms
Abnormally diminished muscle tone (hypotonia),Poor feeding,Vomiting,Lethargy,Seizures

What are the causes for argininosuccinate lyase deficiency?

It is crucial to prevent the accumulation of undesirable by-products of various biochemical processes as they react with other biomolecules. Nitrogen, one such by-product, exists in the form of ammonia, which is a neurotoxin.

  • The urea cycle is a biochemical process that converts nitrogen into urea excreted through urine.
  • Argininosuccinate lyase deficiency (ASL) is one of the enzymes involved in the process.
  • The deficiency of the enzyme disrupts the urea cycle and builds up the concentration of nitrogen, in the affected individual.


Causes of Argininosuccinate lyase Deficiency
 

  • Argininosuccinate lyase is a protein; all the enzymes are proteins. Each protein, synthesized in the human body, is expressed by a stretch of DNA called a gene. Hence, every protein is a product of its corresponding gene.

What are the treatments for argininosuccinate lyase deficiency?

Argininosuccinate Lyase deficiency is an autosomal recessive disorder. Affected individuals have mutations in the gene coding for the enzyme argininosuccinate lyase (ASL), which is involved in the urea cycle.

Treatment of ASL deficiency involves two scenarios.

  • Rapid control of hyperammonemia during metabolic decompensations. The management of hyperammonemia includes discontinuing the oral protein intake, caloric supplementation with intravenous glucose and lipids with the initiation of intravenous nitrogen scavenging drugs.
  • Chronic management of ASL deficiency: This mode includes dietary restriction of protein and arginine supplementation. Patients who have had frequent metabolic decompensations or elevated ammonia are candidates for additional oral nitrogen scavenging therapy with either sodium benzoate or sodium phenylbutyrate
  • Dietary therapy, along with arginine supplements, has shown to reverse abnormalities of hair and improve cognitive outcomes, including reversal of abnormalities on EEG.
  • Orthotopic Liver Transplantation (OLT) offers long terms cure for the disease. However, OLT is recommended only for patients with recurrence of hyperammonaemia and metabolic decompensations, which are resistance to conventional treatment. OLT does not correct the abnormalities of deficiency of tissue-specific arginine and elevation of argininosuccinate.
  • Note: the ideal dosing of arginine and its utility is still unclear, as magnetic resonance spectroscopy of brains in the patients on arginine supplementation has shown elevation of guanidinoacetate.

Conditions
Developmental delay,Mental retardation,Progressive liver damage,Skin lesions,Brittle hair
Drugs
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,Hemodialysis
Symptoms
Abnormally diminished muscle tone (hypotonia),Poor feeding,Vomiting,Lethargy,Seizures

What are the risk factors for argininosuccinate lyase deficiency?

Argininosuccinic aciduria/argininosuccinate lyase deficiency is a rare genetic disorder characterized by deficiency or lack of the enzyme argininosuccinate lyase (ASL).

  • Genes: Argininosuccinate lyase deficiency is caused by mutations in the ASL gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When this is distrubed by a mutation, it may result in the protein product being inefficient or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
  • Inheritance: Argininosuccinate lyase deficiency is inherited in an autosomal recessive pattern. This means that both copies of the gene in each cell have mutations. If the individual's parents have autosomal recessive condition each carry one copy of the mutated gene. However, they typically do not show signs and symptoms of the condition.
  • When both parents are carriers, there is a 25% chance in each pregnancy for the child to have ASAL deficiency. There is a 50% chance for the child to be a carrier, just like the parents. And, there is a 25% chance for the child to have two working genes.


Conditions
Developmental delay,Mental retardation,Progressive liver damage,Skin lesions,Brittle hair
Drugs
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,Hemodialysis
Symptoms
Abnormally diminished muscle tone (hypotonia),Poor feeding,Vomiting,Lethargy,Seizures

Is there a cure/medications for argininosuccinate lyase deficiency?

The cure/medications for Argininosuccinic aciduria/argininosuccinate lyase deficiency include:

  • Patients with newly discovered hyperammonemia will need temporary withdrawal of protein.
  • To avoid catabolism of muscle protein for energy, the patient will need an increase nonprotein caloric sources.
  • Initial therapies include intravenous benzoate, arginine, and phenylacetate administration for hyperammonemia.
  • Arginine supplementation helps promote the excretion of nitrogen and in improving or reversing changes in the hair.
  • However, such combined therapy is appropriate only prior to a specific diagnosis.
  • Children with developmental disabilities may need occupational, speech-language, and physical therapies.
  • Genetic counseling is recommended for affected individuals and their families.
  • Dietary restrictions may be needed to limit the amount of protein intake to avoid the development of excess ammonia.
  • However, enough protein must be taken in by an affected infant to ensure proper growth.
  • High biological value natural protein like breast milk or cow’s milk formulate, an essential amino acid formula and a calorie supplement may be recommended.
  • Vitamins and calcium supplements may also be used in the treatment of argininosuccinate lyase deficiency.
  • Low protein foods that are rich in nitrite may be helpful for decreased production of nitric oxide in patients with argininosuccinate lyase deficiency.


Conditions
Developmental delay,Mental retardation,Progressive liver damage,Skin lesions,Brittle hair
Drugs
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,Hemodialysis
Symptoms
Abnormally diminished muscle tone (hypotonia),Poor feeding,Vomiting,Lethargy,Seizures

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