Argininosucciniclyase deficiency (ASLD) has been shown by the UCDC to have unique characteristics in clinical and physiologic behavior from the other urea cycle disorders. Accounting for around 15-20% of UCD disorders, ASLD patients have relatively worse cognitive outcomes, hepatic disorders, and vascular problems than other UCDs. Work by consortium members has clearly demonstrated a tissue and molecular specific role for ASL in the generation of nitric oxide (NO). As part of a substrate channeling complex involving ASS, ASL, and eNOS, we have shown that cells with defective ASL lose the ability to generate sufficient NO. This implies both a kinetic and structural role for the enzyme in NO production. This proposal will address the effect of bypassing this complex using a synthetic NO donor. We have also shown that in a hypertensive symptomatic patient that improvement in hypertension occurred and trends toward cognitive improvement occurred with NO donor treatment. Before this treatment would be accepted for widespread use in ASLD or other UCD patients an in depth double-blind placebo-controlled crossover study needs to be conducted. This proposed study will phenotype these patients in depth and study vaso-regulation on and off therapy as well as neurocognitive effects. If successful this would lead to a new tool for the treatment of patients with UCDs addressing some of the comorbidities identified by the UCDC longitudinal study and consortium members.

Public Health Relevance

This study seeks to correct a biochemical derangement in UCD which was previously unrecognized. It provides evidence of NO deficiency in ASLD and uses a novel therapy to correct the abnormality and hopefully ameliorate hypertension and cognitive deficits resulting from a distal block in the urea cycle. The approach of NO deficiency may be relevant to more common disorders.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZTR1-CI-8 (01))
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Children's Research Institute
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