Which are the causes of Argininosuccinic Aciduria?

Argininosuccinic aciduria is a rare genetic disorder that affects the metabolism of the amino acid arginine. It is caused by a deficiency of the enzyme argininosuccinate lyase (ASL), which is responsible for breaking down argininosuccinic acid into arginine and fumarate. Without this enzyme, argininosuccinic acid builds up in the body, leading to a range of symptoms and complications.

1. Genetic mutations: Argininosuccinic aciduria is an autosomal recessive disorder, meaning that both parents must carry a mutated gene for the condition to occur in their child. The ASL gene, located on chromosome 7, is responsible for producing the ASL enzyme. Mutations in this gene can disrupt the normal function of the enzyme, resulting in argininosuccinic aciduria.

2. Inherited from parents: When both parents carry a single copy of the mutated ASL gene, they are considered carriers. Carriers do not typically show symptoms of the disorder but can pass the mutated gene to their children. If both parents are carriers, there is a 25% chance with each pregnancy that their child will inherit two copies of the mutated gene and develop argininosuccinic aciduria.

3. Metabolic dysfunction: The deficiency of ASL enzyme in individuals with argininosuccinic aciduria disrupts the urea cycle, which is responsible for removing ammonia from the body. As a result, ammonia accumulates in the blood and other tissues, leading to hyperammonemia. This can cause severe neurological symptoms, such as seizures, lethargy, and developmental delays.

4. Variable severity: The severity of argininosuccinic aciduria can vary widely among affected individuals. Some individuals may have a milder form of the disorder with later onset symptoms, while others may experience life-threatening complications in infancy. The specific mutations in the ASL gene and other genetic and environmental factors can influence the severity of the condition.

5. Diagnosis: Argininosuccinic aciduria is typically diagnosed through newborn screening programs, which test for elevated levels of argininosuccinic acid and ammonia in the blood. Confirmatory diagnostic tests, such as genetic testing and enzyme activity assays, can be performed to identify the specific genetic mutations and enzyme deficiencies associated with the disorder.

6. Treatment: The management of argininosuccinic aciduria involves a combination of dietary restrictions and medications. A low-protein diet, supplemented with essential amino acids, helps to reduce the production of argininosuccinic acid and limit ammonia accumulation. Medications, such as nitrogen scavengers and ammonia-lowering drugs, may also be prescribed to further control ammonia levels.

7. Long-term outlook: With early diagnosis and appropriate treatment, individuals with argininosuccinic aciduria can lead relatively normal lives. However, the disorder requires lifelong management and close monitoring of ammonia levels to prevent metabolic crises. Regular follow-up with a metabolic specialist and adherence to the prescribed treatment plan are crucial for optimizing outcomes and minimizing complications.