2026-04-28 | Withania somnifera Withanolides for Neuroproteection in ASL Deficiency
Withanolide A and withanoside IV from Ashwagandha root cross the blood-brain barrier and activate Nrf2-ARE pathway, reducing oxidative stress from accumulated argininosuccinic acid. These compounds also modulate GABA-A receptors and reduce neuroinflammation through microglial M2 polarization, protecting against the cognitive impairment associated with chronic hyperammonemia.
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2026-03-19 | Impact of long-term nitrogen scavenger therapy on clinical outcome in individuals with urea cycle disorders.
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.
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2025-01-08 | Positive Clinical, Neuropsychological, and Metabolic Impact of Liver Transplantation in Patients With Argininosuccinate Lyase Deficiency.
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.
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