Argininosuccinate Lyase Deficiency

Excerpt

Clinical characteristics: Argininosuccinate lyase deficiency (ASLD), an inborn error of urea synthesis, may present as a neonatal- or late-onset disease.

Neonatal-onset ASLD: Characterized by hyperammonemia within the first few days after birth that can manifest as increasing vomiting, lethargy, refusal to feed, tachypnea, and respiratory alkalosis. Absence of treatment leads to worsening lethargy, seizures, coma, and even death.

Late-onset ASLD: Manifestations range from episodic hyperammonemia triggered by acute infection or stress to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia.

Long-term manifestations of ASLD: Acute hyperammonemia and its associated complications; neurologic and neurocognitive features including attention-deficit/hyperactivity disorder, intellectual and developmental disabilities, learning disabilities, seizures, and abnormalities of motor functioning and coordination; liver disease, including hepatomegaly, hepatitis, steatosis, fibrosis, and cirrhosis; trichorrhexis nodosa (coarse, brittle hair that breaks easily); systemic hypertension; and hypokalemia.

Diagnosis/testing: The diagnosis of ASLD can be established by identification of increased argininosuccinate in plasma or urine; or identification of biallelic pathogenic variants in ASL by molecular genetic testing.

Management: Targeted therapies: Dietary treatment includes protein restriction, supplementation with non-protein-containing formulas to provide age-appropriate caloric requirements, and arginine base supplementation; nitrogen-scavenging medications are required in those with hyperammonemia or suboptimal metabolic control.

Treatment of metabolic decompensation: The focus for treatment of metabolic decompensation is to rapidly decrease blood ammonia. Treatment of acute hyperammonemic episodes involves temporary cessation of oral protein intake, intravenous lipids and/or glucose, and intravenous nitrogen-scavenging therapy. Treatment of severe hyperammonemia often requires kidney replacement therapy with hemodialysis or continuous venovenous hemofiltration.

Supportive care: Developmental and educational support; treatment of seizures per neurologist; treatment of abnormal motor functioning and coordination per neurologist, physical medicine and rehabilitation specialist, and physical and occupational therapists; orthotopic liver transplantation should be considered in individuals with recurrent hyperammonemia or metabolic decompensations that are resistant to conventional medical therapy; salt restriction, antihypertensive medications, and nitrites and nitrate-containing supplements for hypertension; potassium supplementation as needed; encourage medical alert bracelet; provide letters and written protocol for management in the setting of catabolic stressors; provide family with letters for optimizing social and school functioning; appropriate precautions should be taken during pre- and perioperative periods to prevent catabolic stress that could lead to hyperammonemia.

Surveillance: Assessment with metabolic dietitian and clinical biochemical geneticist including height, weight, body mass index, and laboratory indices of nutritional status; plasma ammonia and amino acids with frequency based on age and metabolic status; developmental, educational, and behavioral assessment annually; assess for seizures, abnormal motor function, and problems with coordination at each visit; ALT, AST, albumin, and INR every six to 12 months or as needed; consider liver ultrasound and noninvasive monitoring for hepatic fibrosis every one to two years; blood pressure measurement at each visit; plasma potassium levels at least annually.

Agents/circumstances to avoid: Excess protein intake; large boluses of protein or amino acids; less than recommended intake of protein; prolonged fasting or starvation; exposure to communicable diseases; valproic acid; oral or parenteral administration of corticosteroids; hepatotoxic drugs (in those with liver disease).

Evaluation of relatives at risk: For at-risk newborn sibs when prenatal testing was not performed: measure plasma amino acids (to specifically assess for argininosuccinate) and plasma ammonia immediately in the newborn period in parallel with newborn screening and molecular genetic testing for the familial ASL pathogenic variants (if known).

Pregnancy management: As pregnancy and the postpartum period pose significant stress in females in all urea cycle disorders, close monitoring and management is recommended for prevention of hyperammonemia.

Genetic counseling: ASLD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ASL pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the ASL pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.