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Expanding phenotypic and mutational spectra of mitochondrial HMG-CoA synthase deficiency.
Eur J Med Genet. 2020 Dec; 63(12):104086.EJ

Abstract

Mitochondrial 3-hydroxy-3 methylglutaryl-CoA synthase-2 deficiency (HMGCS2D) is a rare autosomal recessive inborn error of hepatic ketogenesis, caused by mutations in HMGCS2. As its clinical and laboratory manifestations resemble many other metabolic disorders, HMGCS2D definite diagnosis presents a challenge, frequently requiring molecular tests. Only 26 patients with HMGCS2 mutations have been previously described, and this study reports the first two unrelated Thai patients, a 9-month-old male and an 8-month-old female, with HMGCS2D. During acute episodes, steatorrhea and dyslipidemia occurred, both previously unreported. Increased serum levels of triglycerides, very low density lipoproteins (VLDL), and low density lipoproteins (LDL), along with a decreased serum level of HDL were found. Both patients had hypophosphatemic encephalopathy, and the female had metabolic acidosis without hypoglycemia. Trio whole-exome sequencing (WES) revealed that the male harbored two HMGCS2 mutations, a novel c.1480C>T (p.Arg494*) and a previously reported c.1502G>C (p.Arg501Pro), while the female was compound heterozygous for the c.1502G>C (p.Arg501Pro) and a previously reported mutation, c.520T>C (p.Phe174Leu). Interestingly, c.1502G>C (p.Arg501Pro) was not only found in both of our patients but also detected heterozygously in 9 out of 1081 unrelated individuals (allele frequency of 9/2162; 0.42%) in our in-house Thai exome database. Discovery of this common mutation suggests there could be about 14 babies with HMGCS2D within 800,000 newborns in Thailand annually. Therefore, awareness of HMGCS2D among medical personnel in Thailand should be raised.

Authors+Show Affiliations

Department of Pediatrics, Faculty of Medicine, Thammasat University, Pathumthani, 12120, Thailand.Department of Pediatrics, Faculty of Medicine, Thammasat University, Pathumthani, 12120, Thailand.Department of Pediatrics, Faculty of Medicine, Thammasat University, Pathumthani, 12120, Thailand.Department of Pediatrics, Faculty of Medicine, Thammasat University, Pathumthani, 12120, Thailand.Department of Pediatrics, Faculty of Medicine, Thammasat University, Pathumthani, 12120, Thailand.Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand; Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, 10330, Thailand.Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand; Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, 10330, Thailand.Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand; Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, 10330, Thailand.Genomics and Precision Dentistry Research Unit, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, 10330, Thailand.Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand; Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, 10330, Thailand.Genomics and Precision Dentistry Research Unit, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, 10330, Thailand. Electronic address: thantrira.p@chula.ac.th.Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand; Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, 10330, Thailand.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33045405

Citation

Rojnueangnit, Kitiwan, et al. "Expanding Phenotypic and Mutational Spectra of Mitochondrial HMG-CoA Synthase Deficiency." European Journal of Medical Genetics, vol. 63, no. 12, 2020, p. 104086.
Rojnueangnit K, Maneechai P, Thaweekul P, et al. Expanding phenotypic and mutational spectra of mitochondrial HMG-CoA synthase deficiency. Eur J Med Genet. 2020;63(12):104086.
Rojnueangnit, K., Maneechai, P., Thaweekul, P., Piriyanon, P., Khositseth, S., Ittiwut, C., Chetruengchai, W., Kamolvisit, W., Theerapanon, T., Suphapeetiporn, K., Porntaveetus, T., & Shotelersuk, V. (2020). Expanding phenotypic and mutational spectra of mitochondrial HMG-CoA synthase deficiency. European Journal of Medical Genetics, 63(12), 104086. https://doi.org/10.1016/j.ejmg.2020.104086
Rojnueangnit K, et al. Expanding Phenotypic and Mutational Spectra of Mitochondrial HMG-CoA Synthase Deficiency. Eur J Med Genet. 2020;63(12):104086. PubMed PMID: 33045405.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Expanding phenotypic and mutational spectra of mitochondrial HMG-CoA synthase deficiency. AU - Rojnueangnit,Kitiwan, AU - Maneechai,Parisa, AU - Thaweekul,Patcharapa, AU - Piriyanon,Punnapat, AU - Khositseth,Sookkasem, AU - Ittiwut,Chupong, AU - Chetruengchai,Wanna, AU - Kamolvisit,Wuttichart, AU - Theerapanon,Thanakorn, AU - Suphapeetiporn,Kanya, AU - Porntaveetus,Thantrira, AU - Shotelersuk,Vorasuk, Y1 - 2020/10/09/ PY - 2019/12/25/received PY - 2020/09/09/revised PY - 2020/10/04/accepted PY - 2020/10/13/pubmed PY - 2020/10/13/medline PY - 2020/10/12/entrez KW - HMGCS2 KW - Hepatomegaly KW - Hypertriglyceridemia KW - Hypoglycemia KW - Hypophosphatemia SP - 104086 EP - 104086 JF - European journal of medical genetics JO - Eur J Med Genet VL - 63 IS - 12 N2 - Mitochondrial 3-hydroxy-3 methylglutaryl-CoA synthase-2 deficiency (HMGCS2D) is a rare autosomal recessive inborn error of hepatic ketogenesis, caused by mutations in HMGCS2. As its clinical and laboratory manifestations resemble many other metabolic disorders, HMGCS2D definite diagnosis presents a challenge, frequently requiring molecular tests. Only 26 patients with HMGCS2 mutations have been previously described, and this study reports the first two unrelated Thai patients, a 9-month-old male and an 8-month-old female, with HMGCS2D. During acute episodes, steatorrhea and dyslipidemia occurred, both previously unreported. Increased serum levels of triglycerides, very low density lipoproteins (VLDL), and low density lipoproteins (LDL), along with a decreased serum level of HDL were found. Both patients had hypophosphatemic encephalopathy, and the female had metabolic acidosis without hypoglycemia. Trio whole-exome sequencing (WES) revealed that the male harbored two HMGCS2 mutations, a novel c.1480C>T (p.Arg494*) and a previously reported c.1502G>C (p.Arg501Pro), while the female was compound heterozygous for the c.1502G>C (p.Arg501Pro) and a previously reported mutation, c.520T>C (p.Phe174Leu). Interestingly, c.1502G>C (p.Arg501Pro) was not only found in both of our patients but also detected heterozygously in 9 out of 1081 unrelated individuals (allele frequency of 9/2162; 0.42%) in our in-house Thai exome database. Discovery of this common mutation suggests there could be about 14 babies with HMGCS2D within 800,000 newborns in Thailand annually. Therefore, awareness of HMGCS2D among medical personnel in Thailand should be raised. SN - 1878-0849 UR - https://www.unboundmedicine.com/medline/citation/33045405/Expanding_phenotypic_and_mutational_spectra_of_mitochondrial_HMG_CoA_synthase_deficiency_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1769-7212(20)30796-5 DB - PRIME DP - Unbound Medicine ER -