尿素サイクル異常症

Objectives: To analyze the metabolomic profile of children with sleep disorders to understand whether there are distinct and specific metabolic patterns related to the severity and type of sleep disorders (neurological or respiratory). Materials and Methods: This is an observational pilot study. Patients referred to our department for sleep disorders-both neurological and breath-related sleep disturbances-were enrolled. All patients received an anamnestic interview, clinical evaluation, polysomnographic sleep study and urine collection for the metabolomic analysis. Results: Obstructive sleep apnea (OSA) patients were divided into mild and moderate while the third group was represented by patients with parasomnias. The oxalic acid and ribose increased in moderate OSA and pavor compared to mild patients, while 3-hydroxypropionic decreased. Furthermore, the pyroglutamic acid, aminomalonica acid, urea, p-cresol, glycine, 4-hydroxyphenyl acetate, citric acid and ethanolamine increased in moderate OSA patients with respect to mild ones. Finally, hippuric acid and glutamic acid decreased in moderate patients compared to mild ones. The enrichment analysis revealed that urea cycle, tryptophan metabolism, glucose-alanine cycle, glutathione metabolism and beta-alanine metabolism were the most significantly discriminant pathways between OSA patients, while the pentose phosphate pathway, propanoate metabolism, Warburg effect, citric acid cycle and transfer of acetyl group into mitochondria were the most significantly discriminant pathways between mild OSA and pavor patients. Conclusions: our data reveal interesting correlations between metabolomics and sleep disorders that deserve further investigations in larger cohorts of patients and the integration of different approaches to enhance our understanding of the field and guide clinicians toward precise and personalized patient management.

PURPOSE: Hyperammonemia is a serious metabolic disturbance characterized by elevated blood ammonia levels that can lead to severe neurological complications. This review aims to provide a comprehensive overview of inherited metabolic disorders associated with hyperammonemia and to evaluate the diagnostic role of whole-exome sequencing (WES), with particular attention to Iranian patient data. METHODS: A narrative literature search was performed in PubMed/MEDLINE and Google Scholar (1990-2024) using key terms related to hyperammonemia, its inherited etiologies, and whole-exome sequencing. RESULTS: Three major categories of inherited disorders associated with hyperammonemia were identified: urea cycle disorders (incidence 1:35,000), organic acidemias (incidence 1:3,600), and fatty acid oxidation deficiencies (incidence 1:9,000). WES has emerged as a powerful diagnostic tool enabling precise genetic diagnosis, as illustrated by several Iranian case reports with novel pathogenic variants. CONCLUSION: Early recognition and accurate genetic diagnosis of hyperammonemia are crucial for optimal patient outcomes. While challenges such as variant interpretation and accessibility remain, the integration of clinical, biochemical, and genetic data, particularly through WES, is essential for effectively diagnosing and managing these disorders.

Gene therapy encompasses the use of nucleic acids, including DNA and RNA, as therapeutic agents. This broad category includes approaches that permanently modify the genome to correct pathogenic variants, as well as strategies that restore gene expression without altering genomic DNA. In ornithine transcarbamylase (OTC) deficiency, the most common urea cycle disorder, the goal of somatic gene therapy is to restore hepatic expression of functional OTC enzyme and thereby reestablish urea cycle activity. Both viral and non-viral delivery platforms have been investigated in preclinical models and clinical studies to achieve therapeutic OTC expression. Despite contemporary medical therapy, individuals with OTC deficiency (OTCD) remain at risk for recurrent hyperammonemia which may result in neurocognitive impairment and reduced quality of life. Novel therapy that restores liver OTC expression and lessens chronic disease burden is highly desired. In this manuscript, we summarize the history of gene therapy development for OTC deficiency, spanning early preclinical investigations to contemporary clinical trials. Although a definitive cure through gene therapy has not yet been achieved, substantial progress has been made toward the development of safe and effective liver-directed nucleic acid therapeutics for this disorder.

OBJECTIVES: To review our use and outcomes of continuous renal replacement therapy (CRRT) for acute metabolic decompensation (hyperammonemia or hyperleucinemia) in infants and children with inborn errors of metabolism (i.e., M), and to identify factors associated with complications and mortality. DESIGN: Retrospective cohort identified using local clinical databases. SETTING: Single-center PICU and neonatal ICU in a tertiary pediatric center in Türkiye. PATIENTS: Thirty-eight children (with 49 CRRT sessions) for urea cycle disorders, organic acidemias, or maple syrup urine disease undergoing treatment between August 2014 and June 2025. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The median (interquartile range, IQR) age at CRRT initiation was 1.4 months (IQR 0.16-33.90); CRRT resulted in substantial metabolite reduction (mean change 87.6% for ammonia and 74.8% for leucine). Younger age was associated with more hemodynamic and metabolic complications. Overall mortality was 11 of 38 (28.9% [95% CI, 17-44.8%]). In the 11 episodes of CRRT that ended in death vs. 38 CRRT episodes with survival to discharge, there was a greater proportion with hypophosphatemia: 6 of 11 vs. 8 of 38, percentage difference 33.4% (95% CI, 2.8-59.6%), p value of equals to 0.03. Last, we failed to identify an association between episodes of CRRT by technique (continuous venovenous hemodiafiltration [CVVHDF] vs. dialysis) and mortality: 6 of 21 vs. 5 of 28, mean difference 10.7% (95% CI, -12.4 to 34.3%), p value of equal to 0.38. CONCLUSIONS: In our single-center 11-year experience of using CRRT for metabolic detoxification in critically ill young infants with inborn errors of metabolism, we have found that substantial reductions in ammonia and leucine can be achieved in severe biochemical derangement, irrespective of whether continuous venovenous hemodialysis or CVVHDF was used. Taken together, for us, these findings reinforce our continued practice of timely CRRT as a critical component of acute metabolic crisis management.

Sarcopenia is increasingly recognized in pediatric chronic diseases, yet its prevalence and determinants in children with intoxication-type inborn errors of metabolism (IEM) have never been investigated. This study aimed to evaluate sarcopenia in this population and to investigate associated metabolic alterations. We conducted a retrospective single-center study including 45 pediatric patients (0-18 years) with maple syrup urine disease (MSUD, 11 pts.), organic acidurias (OA, 22 pts.), or urea cycle defects (UCD, 12 pts.) considered for liver transplantation. Sarcopenia was defined as total psoas muscle area z-score ≤ -2 on CT scan. Anthropometric, dietary, and laboratory parameters were analyzed. Forty percent of patients exhibited sarcopenia, most frequently among OA (54.5%) and UCD (33.3%), and only occasionally in MSUD (18.2%). Sarcopenic children showed lower weight, height, and were more likely to require enteral nutritional support. Plasma levels of essential amino acids, particularly branched-chain amino acids (leucine, isoleucine, valine), histidine, and glutamine, were significantly reduced in sarcopenic patients. Leucine emerged as an independent predictor of sarcopenia (p = 0.016). FGF21 levels were elevated in sarcopenic OA and UCD patients, whereas MSUD patients with higher branched-chain amino acids levels showed lower FGF21, suggesting a role beyond mitochondrial stress signaling. Sarcopenia is common in pediatric patients with severe intoxication-type IEM and is closely linked to essential amino acid deficiencies and altered FGF21 signaling. These monogenic diseases provide unique pathophysiological models for better understanding of sarcopenia. Our findings highlight the need for targeted nutritional and metabolic strategies to preserve muscle mass in these vulnerable patients.