Long-term outcome of patients with argininosuccinate lyase deficiency diagnosed by newborn screening in Austria

Understanding the Role of Argininosuccinate Lyase Transcript Variants in the Clinical and Biochemical Variability of the Urea Cycle Disorder Argininosuccinic Aciduria

“…The clinical and biochemical phenotype of ASA is highly variable ranging from asymptomatic cases with only a biochemical phenotype (23)(24)(25), some of them diagnosed through newborn screening, to severe neonatal-onset hyperammonemic encephalopathy (26,27). The molecular basis for the diversity of ASA is not fully understood, and several explanations have been suggested, including tissue-specific ASL expression (27,28), genetic heterogeneity at the ASL locus (29), intragenic comple-mentation (7, 30 -32), different levels of residual ASL activity (33,34), the developmental control of the ASL gene by DNA methylation (35), and alternative splicing events at the ASL locus leading to frequent exon deletions (5,36,37).…”

Argininosuccinic aciduria: from a monogenic to a complex disorder

“…[11][12][13][14][15][16] Even subjects with milder forms of ASA who are diagnosed early in life by newborn screens can develop neurocognitive deficiencies, attention deficit/hyperactivity disorder, developmental disability, and seizures despite early treatment intervention. [17][18][19] Supporting this notion, hepatic disease and hypertension have been reported in patients with ASA who have good metabolic control. 13,15,[20][21][22] These data suggest that the complex phenotype observed in ASA involves mechanisms beyond the blockade in ureagenesis and that ASA could serve as an example of a complex IEM in which disease phenotype extends beyond the loss of the enzymatic function of ASL.…”

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“…There are 2 forms: the acute neonatal form presents with hyperammonemic coma within the first 2 days after birth; and the chronic late-onset form presents with hyperammonemia and vomiting episodes, abnormal hair, failure to thrive, hepatomegaly, and progressive hepatic fibrosis. [1][2][3] Though ASA has a lower 582…”

“…Over the past 40 years, argininosuccinate lyase deficiency has been included in some newborn screening programs in an attempt to prevent chronic complications by early diagnosis and treatment. 1,6 Mercimek-Mahmutoglu and associates 1 published the long-term outcome of patients diagnosed by newborn screening over 27 years and suggested that testing newborns for ASA is beneficial for the prevention of chronic neurologic and intellectual sequelae in late onset variants. The prognosis has improved significantly in the last 20 years.…”

“…The disease may present in an early form with severe neonatal hyperammonemia, which causes serious brain damage and death; or in subacute and late forms, with varying degrees of intellectual disability, failure to thrive, vomiting episodes, and hepatomegaly. [1][2][3] The long-term prognosis for patients with ASA under pharmacologic and dietary therapy remains poor. Liver transplant (LT) should be considered a treatment option in select cases.…”