Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMGCS2D) is a rare metabolic disorder that impairs the body’s ability to produce ketone bodies and regulate energy metabolism. Diagnosing HMGCS2D is challenging because patients typically remain asymptomatic unless they experience fasting or illness. Due to the absence of reliable biochemical markers, genetic testing has become the definitive method for diagnosing HMGCS2D. This study included 19 patients from 14 unrelated families diagnosed with HMGCS2D in our department between October 2018 and October 2024. The clinical presentations, biochemical findings, molecular characteristics, and management strategies were systematically summarized and analyzed. Of the 19 cases studied, 16 were symptomatic, and 3 were asymptomatic. The onset of the first acute episode occurred between 10 days and 28 months of age. Triggers for the initial crisis in the symptomatic cases included poor feeding (93.8%), vomiting (56.3%), diarrhea (25.0%), and fever (18.8%). Clinical manifestations during the first episode were lethargy/coma (81.3%), rapid breathing (68.8%), hepatomegaly (56.3%), shock (37.5%), and seizures (18.8%). The biochemical abnormalities observed included elevated plasma transaminases (100%), metabolic acidosis (75%), hypoglycemia (56.3%), and elevated plasma ammonia levels (31.3%). Additionally, low free carnitine levels were found in seven cases, elevated C2 levels were found in one case, dicarboxylic aciduria was found in two cases, and ketonuria was found in two cases. Abnormal brain MRI findings were detected in three patients. Genetic analysis revealed seven HMGCS2 gene variants across the 19 cases. Notably, a novel variant, c.407A>T (p.D136V), was identified and has not been reported in any existing databases. Two common variants, c.559+1G>A and c.1090T>A (p.F364I), were present in 11 out of 19 cases (57.9%) and 10 out of 19 cases (55.5%), respectively. The implementation of a high glucose infusion and proactive management strategies—such as preventing prolonged fasting and providing enteral carbohydrate/glucose infusion during illness—effectively reduced the rate of acute relapses following accurate diagnosis. Currently, all 19 patients are alive, with ages ranging from 5 months to 14 years, and exhibit normal physical development. To the best of our knowledge, this study represents the first reported cases of HMGCS2D in Vietnamese patients. Our findings contribute to a broader understanding of the clinical phenotype and expand the known spectrum of HMGCS2 gene variants, enhancing current knowledge of this rare metabolic disorder.

Background and Objectives: Hyperornithinemia–hyperammonemia–homocitrullinuria syndrome (HHH; OMIM 238970) is one of the rare urea cycle disorders. Ornithine carrier 1 deficiency causes HHH syndrome, characterized by failure of mitochondrial ornithine uptake, hyperammonemia, and accumulation of ornithine and lysine in the cytoplasm. The initial presentation and time of diagnosis in HHH highly varies. Genetic analysis is critical for diagnosis. Materials and Methods: This study encompassed retrospective and prospective analyses of four unrelated Vietnamese children diagnosed with HHH syndrome. Results: The age of diagnosis ranged from 10 days to 46 months. All four cases demonstrated hyperornithinemia and prolonged prothrombin time. Three out of four cases presented with hyperammonemia, elevated transaminases, and uraciluria. No homocitrulline was detected in the urine. Only one case depicted oroticaciduria. Genetic analyses revealed three pathogenic variants in the SLC25A15 gene, with the c.535C>T (p.Arg179*) variant common in Vietnamese patients. The c.562_564del (p.Phe188del) and c.408del (p.Met137Cysfs*10) variants were detected in one case. The latter variant has yet to be reported in the literature on HHH patients. After intervention with a protein-restricted diet, ammonia-reducing therapy, and L-carnitine supplementation, hyperammonemia was not observed, and liver enzyme levels returned to normal. Conclusions: Our results highlighted the clinical and biochemical heterogeneity of HHH syndrome and posed that HHH syndrome should be considered when individuals have hyperammonemia, elevated transaminase, and decreased prothrombin time.

Background: Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMGCS2D) is a rare metabolic disorder that impairs the body's ability to produce ketone bodies and regulate energy metabolism. Diagnosing HMGCS2D is challenging because patients typically remain asymptomatic unless experiencing fasting or illness. Due to the absence of reliable biochemical markers, genetic testing has become the definitive method for diagnosing HMGCS2D. Methods: This study included 19 patients from 14 unrelated families diagnosed with HMGCS2D in our department between October 2018 and October 2024. The clinical presentations, biochemical findings, molecular characteristics, and management strategies were systematically summarized and analyzed. Results: Of the 19 cases studied, 16 were symptomatic and three were asymptomatic. The onset of the first acute episode occurred between 10 days and 28 months of age. Triggers for the initial crisis in the symptomatic cases included poor feeding (93.8%), vomiting (56.3%), diarrhea (25.0%), and fever (18.8%). Clinical manifestations during the first episode were lethargy/coma (81.3%), rapid breathing (68.8%), hepatomegaly (56.3%), shock (37.5%), and seizures (18.8%). Biochemical abnormalities observed included elevated plasma transaminases (100%), metabolic acidosis (75%), hypoglycemia (56.3%), and elevated plasma ammonia levels (31.3%). Additionally, low free carnitine levels were found in seven cases, elevated C2 levels in one case, dicarboxylic aciduria in two cases, and ketonuria in two cases. Abnormal brain MRI findings were detected in three patients. Genetic analysis revealed seven HMGCS2 gene variants across the 19 cases. Notably, a novel variant, c.407A>T (p.D136V), was identified and has not been reported in any existing databases. Two common variants, c.559+1G>A and c.1090T>A (p.F364I), were present in 11 out of 19 cases (57.9%) and 10 out of 19 cases (55.5%), respectively. Implementation of high glucose infusion and proactive management strategies—such as preventing prolonged fasting and providing enteral carbohydrate/glucose infusion during illness—effectively reduced the rate of acute relapses following accurate diagnosis. Currently, all 19 patients are alive, with ages ranging from five months to 14 years, and exhibit normal physical development. Conclusions: To the best of our knowledge, this study represents the first reported cases of HMGCS2D in Vietnamese patients. Our findings contribute to a broader understanding of the clinical phenotype and expand the known spectrum of HMGCS2 gene variants, enhancing current knowledge of this rare metabolic disorder.

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