{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T20:20:41Z","timestamp":1789503641208,"version":"build-2803163510"},"reference-count":30,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T00:00:00Z","timestamp":1739491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Vietnam Ministry of Science and Technology","award":["DTDL.CN-133\/21"],"award-info":[{"award-number":["DTDL.CN-133\/21"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMGCS2D) is a rare metabolic disorder that impairs the body\u2019s 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&gt;T (p.D136V), was identified and has not been reported in any existing databases. Two common variants, c.559+1G&gt;A and c.1090T&gt;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\u2014such as preventing prolonged fasting and providing enteral carbohydrate\/glucose infusion during illness\u2014effectively 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.<\/jats:p>","DOI":"10.3390\/ijms26041644","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T11:14:41Z","timestamp":1739531681000},"page":"1644","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mitochondrial HMG-CoA Synthase Deficiency in Vietnamese Patients"],"prefix":"10.3390","volume":"26","author":[{"given":"Khanh Ngoc","family":"Nguyen","sequence":"first","affiliation":[{"name":"Center of Endocrinology, Metabolism, Genetic\/Genomics and Molecular Therapy, Vietnam National Children\u2019s Hospital, 18\/879 La Thanh, Dong Da, Hanoi 11512, Vietnam"},{"name":"Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tran Minh","family":"Dien","sequence":"additional","affiliation":[{"name":"Vietnam National Children\u2019s Hospital, 18\/879 La Thanh, Dong Da, Hanoi 11512, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1404-0328","authenticated-orcid":false,"given":"Thi Bich Ngoc","family":"Can","sequence":"additional","affiliation":[{"name":"Center of Endocrinology, Metabolism, Genetic\/Genomics and Molecular Therapy, Vietnam National Children\u2019s Hospital, 18\/879 La Thanh, Dong Da, Hanoi 11512, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bui Phuong","family":"Thao","sequence":"additional","affiliation":[{"name":"Center of Endocrinology, Metabolism, Genetic\/Genomics and Molecular Therapy, Vietnam National Children\u2019s Hospital, 18\/879 La Thanh, Dong Da, Hanoi 11512, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2504-4186","authenticated-orcid":false,"given":"Tien Son","family":"Do","sequence":"additional","affiliation":[{"name":"Center of Endocrinology, Metabolism, Genetic\/Genomics and Molecular Therapy, Vietnam National Children\u2019s Hospital, 18\/879 La Thanh, Dong Da, Hanoi 11512, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thi Kim Giang","family":"Dang","sequence":"additional","affiliation":[{"name":"Center of Endocrinology, Metabolism, Genetic\/Genomics and Molecular Therapy, Vietnam National Children\u2019s Hospital, 18\/879 La Thanh, Dong Da, Hanoi 11512, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ngoc Lan","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Center for Gene and Protein Research, Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Van Khanh","family":"Tran","sequence":"additional","affiliation":[{"name":"Center for Gene and Protein Research, Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuy Thu","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Center for Gene and Protein Research, Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tran Thi Quynh","family":"Trang","sequence":"additional","affiliation":[{"name":"Center for Gene and Protein Research, Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9557-9868","authenticated-orcid":false,"given":"Le Thi","family":"Phuong","sequence":"additional","affiliation":[{"name":"Center for Gene and Protein Research, Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phan Long","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Center for Gene and Protein Research, Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thinh Huy","family":"Tran","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Huu","family":"Tu","sequence":"additional","affiliation":[{"name":"Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0418-2613","authenticated-orcid":false,"given":"Chi Dung","family":"Vu","sequence":"additional","affiliation":[{"name":"Center of Endocrinology, Metabolism, Genetic\/Genomics and Molecular Therapy, Vietnam National Children\u2019s Hospital, 18\/879 La Thanh, Dong Da, Hanoi 11512, Vietnam"},{"name":"Hanoi Medical University, 1st Ton That Tung Street, Hanoi 11521, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1203\/00006450-200103000-00005","article-title":"Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency: Clinical Course and Description of Causal Mutations in Two Patients","volume":"49","author":"Bouchard","year":"2001","journal-title":"Pediatr. 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