Principles of long-term medical management in individuals with urea cycle disorders (UCDs) encompass (1) a low protein diet, (2) supplementation of arginine and/or citrulline along with essential amino acids, nutrients, vitamins and trace elements, and (3) use of nitrogen scavenging agents to reduce recurrent hyperammonemic events (HAEs). These principles aim at providing metabolic stability, elimimation of chronic complications, and achievement of normal development as well as growth. A retrospective comparative analysis was performed by studying 138 individuals with male ornithine transcarbamylase deficiency (mOTC-D), citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) based on in vitro residual enzymatic activity for severity-adjustment. Results show that individuals with mOTC-D, CTLN1 and ASA are at risk of progressive linear growth impairment, recurrent annual HAEs and an unfavorable neurocognitive outcome despite being under long-term nitrogen scavenging pharmacotherapy. No overall superiority among existing nitrogen scavenging agents with regard to the individual's metabolic stability, linear growth impairment and poor neurocognitive outcome was observed. Novel therapeutic strategies are urgently needed to ultimately improve health outcomes in individuals with UCDs in order to sufficiently meet guideline-specific goals.

Argininosuccinate lyase deficiency (ASLD) is a rare autosomal recessive urea cycle disorder (UCD) resulting from mutations in the ASL gene. Previous studies of ASLD in patients from China have predominantly been limited to individual case reports, lacking comprehensive cohort study. This study aimed to systematically evaluate the clinical features, biochemical abnormalities, and genetic mutations of Chinese ASLD patients, thereby enhancing the understanding of the unique characteristics of this population. We conducted a retrospective analysis of clinical and genetic data from patients diagnosed with ASLD at Shanghai Xinhua Hospital between January 2011 and May 2024. The cohort consisted of 28 Chinese ASLD patients from Xinhua Hospital. The median age of symptom onset was 18 days (range: 2 days to 6 years). Five patients (17.9%) died within the first year, and 87.0% (20/23) of survivors exhibited developmental delay. Citrulline levels were elevated in all patients. 14 out of 16 (87.5%) who underwent platelet testing demonstrated elevated platelet counts. The median blood ammonia level was 172 µmol/L (range: 9-1911 µmol/L). Early-onset cases had significantly higher ammonia levels than late-onset cases ( P < 0.0001). Eight patients underwent liver transplantation, which normalized ammonia levels and liver function but did not prevent developmental delay. Genetic analysis identified 14 novel ASL variants. Our study represents the largest cohort of ASLD patients from China reported to date. Despite active interventions, including liver transplantation, the prognosis remains poor, with a high prevalence of developmental delays. The identification of 14 novel pathogenic variants significantly expands the known mutation spectrum of the ASL gene in this population.

Liver transplantation (LTx) is increasingly used in Urea Cycle Defects (UCDs) to prevent recurrent hyperammonemia and related neurological irreversible injury. Among UCDs, argininosuccinate lyase deficiency (ASLD) has a more complex phenotype than other UCDs, with long-term neurocognitive deficits. Therefore, the role of LTx in ASLD is still debated. The impact of LTx on nine patients with early-onset ASLD was assessed through pre- and post-LTx clinical, neuropsychological, MRI and biochemical evaluations. After LTx, no episodes of metabolic decompensations were reported. Neuropsychological evaluations documented significant improvement in cognitive/developmental functioning especially in patients transplanted in early childhood. Improvements were also highlighted in daily living skills and emotional-behavioral problems, with a reduction in attention disturbances and somatic complaints. Movement disorders resolved after LTx in patient transplanted in early childhood. Any patients developed epilepsy with stability of EEG alterations after LTx. A positive effect of LTx on other disease-related outcomes such as growth, diet, medications, hospitalizations, and long-term ASLD-related complications was highlighted. The primary biomarker argininosuccinic acid dramatically reduced in plasma after transplantation with a decreasing trend in CSF at long-term follow-up. Moreover, health-related quality of life improved after LTx, especially when assessed through MetabQoL, a tool designed for intoxication diseases such as ASLD. In conclusion, our study showed a global beneficial impact of LTx in early-onset ASLD patients to avoid episodes of hyperammonemia, and improve neurocognitive outcome, adaptive and behavioral deficits when performed in early childhood with a dramatic benefit in terms of quality of life.

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. 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. 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. 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.

Various forms of liver disease have been increasingly reported in individuals with urea cycle disorders (UCDs). In this study, we performed the first systematic and standardized histopathological assessment of the prevalence of fibrosis and steatosis in a large sample of hepatic explants and biopsies from individuals with UCDs at two liver transplantation centers. Sixty-seven hepatic tissue samples from 66 individuals with UCDs were staged by two pathologists for hepatic fibrosis and steatosis using standard scoring systems at two large liver transplantation centers in the United States. Histopathological findings were correlated with clinical parameters, including UCD type, laboratory parameters, and imaging findings. Overall, 23 % (n = 15) of individuals demonstrated clinically significant hepatic fibrosis (≥ F2 according to Metavir staging). Of these, 12 were diagnosed with argininosuccinate lyase deficiency (ASLD) leading to an 80 % prevalence of clinically significant fibrosis in this disorder in this cohort. Eighteen percent of the patients (n = 12) had microvesicular and/or macrovesicular hepatic steatosis. No clinical parameters including routine laboratory testing or imaging were significantly associated with clinically significant hepatic fibrosis in individuals with ASLD. In this large study of hepatic histopathology in UCDs, our findings demonstrate a high prevalence of clinically significant hepatic fibrosis in ASLD. These findings emphasize the importance of monitoring for liver disease and promoting liver health in UCDs and may have implications for long-term monitoring for individuals with ASLD.