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At a glance

An inherited urea cycle disorders characterized by severe hyperammonemia. Affected infants present with vomiting, lack of appetite and failure to thrive, severe hypotonia, progressive lethargy, and coma.

Synonyms

Argininosuccinic Aciduria; Argininosuccinate Lyase Deficiency; ASL Deficiency; Argininosuccinase Deficiency; ASA Deficiency.

Incidence

The incidence is approximately 1:70,000 to 250,000 live births and ASLD is accounting for about 16% of all urea cycle disorder cases.

Genetic inheritance

Autosomal recessive inheritance and caused by mutations in the argininosuccinate lyase (ASL) gene, which is expressed predominantly in the liver and has been mapped to chromosome 7q11.21.

Pathophysiology

Argininosuccinate lyase is one of six enzymes in the urea cycle whose function is the detoxification of waste nitrogen into excretable urea and the de novo biosynthesis of arginine. ASL is required to cleave argininosuccinate to arginine and fumarate and considered the only enzyme in the body that can generate arginine. Thus, in ASLD arginine becomes an essential amino acid. Deficiency of ASL leads to accumulation of argininosuccinic acid in tissues and excretion of argininosuccinic acid in urine (Argininosuccinic Aciduria).

Diagnosis

In many countries, testing for ASLD is part of the routine newborn screening program. Besides the clinical findings, the biochemical diagnosis of ASLD is usually confirmed by elevated plasma citrulline concentrations in combination with increased argininosuccinic acid in the plasma or urine. Molecular genetic testing of ASL enzyme activity can be obtained for further final confirmation. Prenatal diagnosis by mutational analysis from chorionic villus samples or amniocytes as well as detection of elevated levels of argininosuccinic acid in the amniotic fluid can be used to reliably diagnose affected fetuses.

Clinical aspects

The severity varies considerably among patients and hyperammonemia is the main finding in this disease. The severe neonatal-onset form of the disorder, which is characterized by complete absence of the enzyme, typically presents in the first 24 to 72 hours after birth, usually once feeding has been established. This form of the disease is clinically characterized by refusal to eat, lethargy, vomiting, hypothermia, and neurologic irritability. Affected infants may experience respiratory alkalosis, hepatomegaly, seizures, cerebral edema, and hyperammonemic coma. Trichorrhexis nodosa (coarse and brittle hair) is an almost pathognomic finding for ASLD that is present in about half of these patients, but can easily be overlooked at that age. Left untreated for more than 72 hours, neurologic abnormalities (eg, severe developmental delay) are potential complications of surviving infants. Death is almost certain for those not treated in a timely fashion. The milder, late onset form of the disorder, characterized by partial absence of the enzyme, affects children later in infancy or early childhood. Clinically, symptoms include failure to grow and thrive, ataxia, lethargy, and vomiting. Additionally, dry, brittle hair may result in partial alopecia. ...

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