Arginosuccinate lyase deficiency
Arginosuccinate lyase deficiency
Description, Causes and Risk Factors:
Abbreviation: ASA lyase deficiency
Arginosuccinate lyase: An enzyme cleaving L-argininosuccinate nonhydrolytically to L-arginine and fumarate; a deficiency of this enzyme leads to argininosuccinoaciduria; a key step in the urea cycle. Arginosuccinate lyase deficiency deficiency was first described in 1958 by the British doctor JD Allan and his associates.
Argininosuccinate lyase deficiency is an inherited, congenital metabolic disease caused by a defect in the urea cycle. In this cycle a chain of enzymes in the liver converts ammonia into urea. Ammonia is produced when the body breaks down protein, and in high concentrations causes damage to the nervous system. If there is not sufficient argininosuccinate lyase in the body, as happens in the case of ASL deficiency, levels of ammonia rise.
The disease is caused by a total or partial absence of the enzyme argininosuccinate lyase, which is part of the urea cycle in the liver. The enzyme splits the molecule argininosuccinate into two substances, fumarate and arginine. The cause of the lack of the enzyme is a change or mutation in the arginosuccinate lyase deficiency gene which controls the formation of the enzyme's components. There are many known mutations associated with arginosuccinate lyase deficiency, and different mutations may have various effects on enzyme function. Certain individuals with arginosuccinate lyase deficiency deficiency may have no enzyme function, while others may have some residual functionality. This explains why the disease may give rise to different symptoms and have varying degrees of severity. The gene is located on chromosome 7, near the centromere, the place where the short and long arms meet (7cen-q11.2).
The inheritance pattern of arginosuccinate lyase deficiency deficiency is autosomal recessive. This means that two copies of the mutated gene are needed in order to develop the disease. If both parents have only one copy of the mutated gene they are called healthy carriers. Their children will have a 25 per cent risk of inheriting two mutated genes (one from each parent) and developing the disease. In 50 per cent of the cases the child will inherit only one copy of the mutated gene and become a healthy carrier. In 25 per cent of the cases the child will inherit two normal genes and will neither develop the disease nor pass it down.
The disease has different degrees of severity. In the neonatal phase symptoms may be life-threatening. It may develop gradually during the early years, presenting as feeding problems, slow growth and delayed development. Sometimes the diagnosis is first confirmed in adulthood. It is probable that there are a number of cases so mild that they are never diagnosed.
International medical literature usually gives the incidence of arginosuccinate lyase deficiency as one child per 70,000 births. This would indicate that in Sweden one or two children are born with the disease annually, but the actual figure is unknown.
Symptoms may include:
Heavy or rapid breathing.
Signs of severe hyperammonemia may be present.
Poor growth may be evident.
Tachypnea or hyperpnea may be present.
Apnea and respiratory failure may occur in later stages.
Neurologic symptoms may include:
Hypotonia or hypertonia.
Seizures and hypothermia.
Lethargy progressing to combativeness, obtundation, and coma.
Decorticate or decerebrate posturing.
It can be difficult to diagnose arginosuccinate lyase deficiency as the disease is unusual and has the same symptoms as other more common conditions. The diagnosis is confirmed by measuring the levels of ammonia (ammonium ions), argininosuccinate and amino acids in blood. If argininosuccinate is found in either blood or urine, the diagnosis is confirmed. Changes in amino acids in plasma, in particular raised citrulline levels, support the diagnosis. In very rare cases, where arginosuccinate lyase deficiency is mild, ammonia levels may be normal. The diagnosis is then based on the presence of argininosuccinate in blood and urine.
In arginosuccinate lyase deficiency, lack of the enzyme can be shown through an analysis of connective tissue (fibroblasts) or red blood cells, but normally such an analysis is not necessary for diagnosis. Instead, DNA analysis is currently used to establish a mutation in the ASL gene. If the mutation is known, DNA based prenatal testing is possible. If the mutation is not previously known, samples of amniotic fluid or cells from the placenta can be used for enzyme analysis or analysis of argininosuccinate levels.
Immediate temporary withdrawal of protein is indicated in all patients with newly discovered hyperammonemia. Increase nonprotein caloric sources to avoid catabolism of muscle protein for energy.
Intravenous benzoate, arginine, and phenylacetate administration may be indicated as initial therapy for hyperammonemia, but such combined therapy is appropriate only prior to specific diagnosis. Hemodialysis, if available, reduces the blood ammonia levels more efficiently and quickly.
Long-term therapy should involve a low-protein diet and arginine supplementation. This diet helps produce equivalent quantities of ornithine for enhancement of urea cycle activity up to the point of argininosuccinate (ASA) lyase and, thus, enhances waste nitrogen incorporation.
For several years, liver transplantation has been the accepted form of surgical treatment for urea cycle disorders. However, many patients have delayed development, physical debilitation, or both, disqualifying them from the procedure or greatly increasing the associated risks.
Donor cell engraftment has been reported to be an effective technique of reducing the acuity of the disease in patients with neonatal-onset ASA lyase deficiency. This modality may offer a safer approach to surgical treatment of urea cycle disorders in general and may reduce the need for patients to qualify for a place on a transplantation roster.
NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.
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