Argininosuccinic aciduria: from identification to management of paucisymptomatic late onset forms

Background: Argininosuccinic aciduria, the second most common urea cycle disorder (UCD) is due to argininosuccinate lyase (ASL) deficiency. Neonatal onset forms are characterized by hyperammonemic comas. Late onset ASL patients exhibit variable symptoms ranging from intermittent hyperammonemia to unspecific psychomotor delay, behavioral and cognitive disturbances. Systemic hypertension, brittle hair or liver fibrosis are specific findings compared with other UCDs that can occur independently of hyperammonemia. Objective: To report two atypical late onset forms of argininosuccinic aciduria. Case reports: Patient 1 presented with myoclonic epilepsy and mild psychomotor delay at the age of 3. Clinical examination revealed hepatomegaly that prompted to perform a metabolic workup. The latter found argininosuccinic acid (ASA) accumulation in body fluids without hyperammonemia or liver dysfunction. ASA level in cerebrospinal fluid (CSF) was 3.6 fold higher than in blood. Patient 2 presented with acute episodes of apnea, cyanosis and hypertonia at age 3 months. Clinical findings revealed mild hepatomegaly and hypotonia. High ASA level was detected in blood and urine, without hyperammonemia. Low protein diet and arginine supplementation were introduced, resulting in decreased blood ASA levels in both patients who exhibited moderate neurodevelopmental delay. Discussion and conclusion: Nonspecific symptoms may occur in late onset ASL patients and time for metabolic screening is a challenge. In particular, myoclonic epilepsy is an unusual initial presentation. Increased ASA level in CSF combined with reported nitric oxide (NO) deficiency despite arginine supplementation may contribute to neurotoxicity. While protein restriction and arginine supplementation can decrease hyperammonemia if present and limit blood ASA accumulation, the impact of treatment on the neurological disease remains questionable. Recent data suggest that ASL patients might benefit from NO supplementation