preprints.org > medicine and pharmacology > pediatrics, perinatology and child health > doi: 10.20944/preprints202410.1499.v1 (registering DOI)

Preprint Article Version 1 This version is not peer-reviewed

Version 1 : Received: 18 October 2024 / Approved: 18 October 2024 / Online: 18 October 2024 (16:31:45 CEST)

October 17, 2024 Dear Prof. Dr. Rizzo and Dr. Oshiro, Prof. Dr. Rizzo: Editor-in-Chief of the Endocrinology section. Dr. Oshiro: Guest Editor of the “Advances in Clinical Diabetes, Obesity, and Metabolic Diseases” special Issue. I would like to submitt the manuscript entitled “Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome in Vietnamese Patients” by Khanh Ngoc Nguyen et al. to be considered for publication as an article in the “Advances in Clinical Diabetes, Obesity, and Metabolic Diseases” of the “Medicina” journal. This study included retrospective and prospective analyses of four unrelated Vietnamese children diagnosed with Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. HHH syndrome is one of the rarest urea cycle disorders and is characterized by failure of mitochondrial ornithine uptake, hyperammonemia, and accumulation of ornithine and lysine in the cytoplasm. Genetic analysis is key for diagnosis. In this study, we report the phenotype, genotype, treatment, and outcome of the four patients. To our best knowledge, this study is the first report of HHH patients in Vietnam. A diverse onset age and delayed diagnosis were observed. All four cases showed hyperornithinemia and prolonged prothrombin time. Three out of four cases presented with hyperammonemia, elevated transaminases, and uraciluria. No homocitrulline was detected in the urine. Genetic analyses identified three pathogenic variants in the SLC25A15 gene. The c.535C>T (p.Arg179*) variant is a common variant in Vietnamese patients. The c.562_564del (p.Phe188del) and c.408del (p.Met137Cysfs*10) variants were found in one case. The latter variant has yet been reported in the HHH patients in the literature. After intervention with a protein-restricted diet, ammonia-reducing therapy, and L-carnitine supplementation, no case had hyperammonemia and liver enzyme levels returned to normal range. Our results high-lighted clinical and biochemical heterogeneity of HHH syndrome and suggested that HHH syndrome should be considered when individuals present with hyperammonemia, elevated transaminase, and decreased prothrombin time. We believe these findings will be of interest to the readers of Medicina. We confirm that neither the manuscript nor any parts of its content are currently under consideration for publication with or published in another journal. All authors approved the final version of the manuscript and agree with its submission to Medicina. Thank you for your time and effort. We look forward to hearing from you regarding our submission. Yours sincerely, Chi Dung Vu (PhD., Assoc. Prof.) Center of Endocrinology, Metabolism, Genetic/Genomics and Molecular Therapy, Vietnam National Children’s Hospital, 18/879 La Thanh, Dong Da, Hanoi, Vietnam Email: dungvu@nch.gov.vn. Tel: +84-246-2747643

HHH syndrome; SLC25A15 variant; Vietnamese patients; p.Arg179*; p.Phe188del, p.Met137Cysfs*10

Medicine and Pharmacology, Pediatrics, Perinatology and Child Health

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