Argininosuccinate lyase deficiency: Longterm outcome of 13 patients detected by newborn screening

Abstract

Argininosuccinate lyase deficiency is a urea cycle disorder which can present in the neonatal period with hyperammonemic encephalopathy, or later in childhood with episodic vomiting, growth and developmental delay. Abnormal hair, hepatomegaly, and hepatic fibrosis are unique features of this disorder. Twelve patients with argininosuccinate lyase deficiency were ascertained between 4 and 6 weeks of age by urine amino acid screening. One infant in a previously identified family was diagnosed shortly after birth. Diagnosis was confirmed by enzyme assay in red blood cells and/or skin fibroblasts. At the time of last follow-up, patients had been followed for 13-33 years. All patients were asymptomatic at detection, 7 had slightly increased blood ammonia, and all were initially treated with low-protein diet. Utilization of 14 C-citrulline by intact skin fibroblasts measured by 14 C incorporation into macromolecules was 74-135% of the control mean for 7 of the 8 patients studied. Nine patients had normal development, 4 had learning disability, 6 had EEG abnormalities, 3 had seizure disorder. None had any episodes of hyperammonemic coma. None had hepatomegaly. Patients detected by screening had higher enzyme activity measured by the 14 C-citrulline incorporation assay than comparison groups of patients with neonatal onset and with late onset detected by clinical disease. The ability to utilize 14 C-citrulline by intact fibroblasts seems to correlate with clinical outcome and may have prognostic value. It is likely that early diagnosis and treatment contributed to the relatively mild clinical course of the study group.

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.…”

“…A number of studies have attempted to draw a correlation between the genotype, which determines the level of ASL enzyme activity, and the phenotype severity of patients with ASA, with limited success. 18 These difficulties suggest that the phenotype observed in ASA may result in part from the substrate accumulation (argininosuccinate) upstream of the enzymatic blockade, the deficiency of the metabolites downstream of the blockade, and their interactions with other metabolic cycles.…”

The Ketogenic Diet Is Well Tolerated and Can Be Effective in Patients with Argininosuccinate Lyase Deficiency and Refractory Epilepsy

“…Patients with ASL deficiency may present with either a severe neonatal form or a late onset form (Erez et al 2011. Epilepsy is a frequent complication of ASL deficiency, both in patients with a clinical presentation and in those detected with newborn screening (Ficicioglu et al 2009;Grioni et al 2011).…”