Argininosuccinate Lyase Deficiency - Clinical Presentation and Management

Introduction

Argininosuccinate lyase deficiency (argininosuccinic aciduria) is a rare, genetically inherited disorder that occurs due to the deficiency of the enzyme argininosuccinate lyase, which plays a vital role in the removal and breakdown of nitrogen from the body (urea cycle). It occurs in nearly 1 in 70,000 to 218,000 individuals.

Argininosuccinate lyase deficiency can be identified in the first few days after birth because of the elevated levels of ammonia in the blood. In later stages, the affected individuals show characteristic brittle or sparse hair with tremors and development delay. Children born with argininosuccinic aciduria may show unwillingness to eat, lethargy, poor breathing rate, unusual body movements, and seizures. In some cases, skin lesions, liver damage, mental retardation, and developmental delay are also seen.

What Is Argininosuccinate Lyase?

Argininosuccinate lyase (argininosuccinase) is a liver enzyme involved in the breakdown of argininosuccinate (ASA) into dicarboxylic acid fumarate and amino acid arginine. Argininosuccinate lyase acts as an intermediate enzyme in urea synthesis. Mutations in the argininosuccinate gene may cause alterations in the enzyme activity, leading to the accumulation of citrulline, ammonia, and argininosuccinate in the blood and side effects including vomiting, lethargy, hyperventilation (rapid breathing due to anxiety), abnormal hair growth, hepatomegaly (liver enlargement), hypothermia (drop in body temperature to dangerous levels), hepatic fibrosis (connective tissue accumulation in the liver), and developmental delay.

What Is Argininosuccinate Lyase Deficiency?

Argininosuccinate lyase deficiency (argininosuccinic aciduria) is a genetic disorder that results in high ammonia and argininosuccinic acid (ASA) levels in the body. It is characterized by a lack of the enzyme argininosuccinate lyase (ASL) that is part of the urea cycle. The lack of this enzyme causes nitrogen accumulation as ammonia in the blood. Excessive levels of ammonia in the body cause neurotoxicity and disrupt the normal functioning of the central nervous system. The affected infants may have lethargy, learning disability, vomiting, feeding refusal, and behavioral abnormalities.

What Are the Causes of Argininosuccinate Lyase Deficiency?

Mutations involving the argininosuccinate lyase (ASL) gene cause argininosuccinate lyase deficiency (argininosuccinic aciduria). This condition is included in genetic diseases and urea cycle disorders. The urea cycle consists of a sequence of reactions in the liver cells to convert nitrogen generated during protein breakdown into urea that is eliminated through the kidneys. In people with argininosuccinate lyase deficiency, the conversion of argininosuccinate to arginine is blocked, and thus the urea cycle is disrupted. Thus, excess nitrogen is accumulated in the blood as urea, causing liver damage and neurological problems. Argininosuccinate lyase deficiency is inherited as an autosomal recessive pattern. Thus the affected individuals have two copies of the altered gene in each cell. However, individuals with one normal gene and one altered gene will be considered carriers of the disease and usually do not show any symptoms of argininosuccinic aciduria.

What Are the Symptoms Associated with Argininosuccinate Lyase Deficiency?

The severity of the symptoms associated with argininosuccinate lyase deficiency varies from person to person. In severe form, there will be a complete lack of the enzyme, which occurs shortly after birth. Some individuals develop milder argininosuccinic aciduria during late infancy or adulthood due to a partial lack of argininosuccinate lyase enzyme. The symptoms associated with argininosuccinate lyase deficiency are:

• Lethargy.

• Lack of appetite.

• Vomiting.

• Refusal to eat.

• Irritability.

• Respiratory abnormalities.

• Cerebral edema (swelling in the brain).

• Seizures (fits or epilepsy).

• Hepatomegaly.

• Liver cirrhosis (liver healthy tissues replaced by scar tissues).

• Rapid breathing.

• Hair loss.

• Delayed developmental milestones.

• Cognitive impairment (trouble with learning, memory, decision making, etc.).

• Brittle hair.

• High blood pressure.

• Learning disabilities.

• Liver dysfunction.

• Ataxia (balance impairment).

• Intellectual disability.

How Can We Diagnose Argininosuccinate Lyase Deficiency?

Diagnosis of argininosuccinate lyase deficiency (argininosuccinic aciduria) can be made through specialized tests, detailed family history, and evaluation of characteristic findings.

The common diagnostic tests are :

• Plasma ammonia concentration greater than 150 micromoles per liter.

• Elevated argininosuccinic acid levels in the plasma or urine.

• Elevated citrulline levels.

• Molecular genetic testing.

• Gene-targeted testing.

• Comprehensive genomic testing (exome array and exome sequencing).

What Are Treatment Options for Argininosuccinate Lyase Deficiency?

• Dietary restriction of oral proteins.

• Intravenous administration of glucose, lipids, and insulin to promote anabolism (a metabolic pathway that makes complex molecules).

• Intravenous sodium phenylacetate or sodium benzoate ingestion to normalize ammonia levels (nitrogen scavenging therapy).

• Arginine base supplementation.

• Lifelong dietary management.

• Orthotopic liver transplantation.

• Use of calcium supplements.

• Hemodialysis (a blood purification process when an individual's kidney does not properly).

• Oral nitrogen scavenging therapy.

• Use of multivitamins.

• Physical, occupational, and speech therapies to improve developmental disabilities.

• Antihypertensive drugs and salt restriction to control high blood pressure.

• Electrolyte supplementation to manage hypokalemia (low potassium levels in the blood).

What Are the Complications of Argininosuccinate Lyase Deficiency?

• Neurocognitive Deficiencies - Individuals with argininosuccinate lyase deficiency have a higher incidence of neurological abnormalities and developmental delay. In severe cases, there will be neurological defects like behavioral abnormalities, learning disabilities, and seizures.

• Liver Disease - In severe cases of argininosuccinic aciduria, hepatomegaly, liver fibrosis, and liver damage will occur.

• Electrolyte Imbalance - Some patients develop electrolyte imbalance (hypokalemia) due to increased renal wasting.

• Trichorrhexis Nodosa - It involves nodular swellings in the hair shaft with loss of cuticle and frayed fibers. About 50 percent of the individuals with argininosuccinate lyase deficiency have brittle, dull hair and partial alopecia (hair loss).

• Hypertension - Argininosuccinate lyase deficiency results in hypertension and endothelial dysfunction.

Conclusion

Argininosuccinate lyase deficiency (argininosuccinic aciduria) is a genetic disorder that results in the accumulation of ammonia and argininosuccinic acid (ASA) in the body. It occurs due to the lack of the enzyme argininosuccinate lyase, which functions as an important enzyme in the urea cycle that promotes the conversion of excess nitrogen in the body to ammonia, excreted through urine.

Treatment of argininosuccinate lyase deficiency (argininosuccinic aciduria) aims to prevent the accumulation of excessive ammonia in the body and the resulting side effects. Excessive ammonia levels in the body result in neurologic complications such as mental retardation, seizures, and developmental disabilities. Argininosuccinate lyase deficiency may cause liver damage, respiratory difficulties, renal diseases, skin lesions, and hair loss. To reduce complications, long-term dietary restriction for proteins is done in individuals with argininosuccinate lyase deficiency.