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Novel HMGCS2 pathogenic variants in a Chinese family with mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency.
Pediatr Investig. 2019 Jun; 3(2):86-90.PI

Abstract

Importance

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase deficiency is a rare and underdiagnosed disorder with fewer than 30 patients reported worldwide. The application of whole-exome sequencing in patients could improve our understanding of this disorder.

Objective

To identify the genetic causes and evaluate the phenotype of mitochondrial HMG-CoA synthase deficiency in a pediatric patient with uncommon features that included ketosis and elevated lactate and ammonia.

Methods

The proband was referred to the pediatric intensive care unit of Beijing Children's Hospital and selected for molecular testing with whole-exome sequencing. Her parents and sibling also underwent sequencing for segregation information.

Results

We identified two novel mutations (c.1347_1351delAGCCT/p.Ala450Profs*7 and c.1201G>T/ p.Glu401*) in the HMG-CoA synthase-2 gene (HMGCS2, NM_005518.3) in the proband and her brother. Both variants were classified as pathogenic variants according to the American College of Medical Genetics and Genomics/ Association for Molecular Pathology guidelines. Metabolic acidosis in the proband was corrected with continuous renal replacement therapy and she left hospital after 21 days of treatment.

Interpretation

Our results extend the genotypic and phenotypic spectrum of HMGCS2 mutation in mitochondrial HMG-CoA synthase deficiency patients and serve as a reminder for physicians to consider mitochondrial HMG-CoA synthase deficiency in newborns and children with coma and hypoketotic hypoglycemia after fasting.

Authors+Show Affiliations

Department of Pediatric Intensive Care Unit Beijing Children's Hospital Capital Medical University; National Center for Children's Health Beijing 100045 China.Beijing Key Laboratory for Genetics of Birth Defects Beijing Pediatric Research Institute; MOE Key Laboratory of Major Diseases in Children; Genetics and Birth Defects Control Center Beijing Children's Hospital Capital Medical University National Center for Children's Health Beijing China. Henan Key Laboratory of Pediatric Inherited & Metabolic Diseases Henan Children's Hospital Zhengzhou Hospital of Beijing Children's Hospital Zhengzhou China.Beijing Key Laboratory for Genetics of Birth Defects Beijing Pediatric Research Institute; MOE Key Laboratory of Major Diseases in Children; Genetics and Birth Defects Control Center Beijing Children's Hospital Capital Medical University National Center for Children's Health Beijing China. Henan Key Laboratory of Pediatric Inherited & Metabolic Diseases Henan Children's Hospital Zhengzhou Hospital of Beijing Children's Hospital Zhengzhou China.Beijing Key Laboratory for Genetics of Birth Defects Beijing Pediatric Research Institute; MOE Key Laboratory of Major Diseases in Children; Genetics and Birth Defects Control Center Beijing Children's Hospital Capital Medical University National Center for Children's Health Beijing China. Henan Key Laboratory of Pediatric Inherited & Metabolic Diseases Henan Children's Hospital Zhengzhou Hospital of Beijing Children's Hospital Zhengzhou China.Beijing Key Laboratory for Genetics of Birth Defects Beijing Pediatric Research Institute; MOE Key Laboratory of Major Diseases in Children; Genetics and Birth Defects Control Center Beijing Children's Hospital Capital Medical University National Center for Children's Health Beijing China. Henan Key Laboratory of Pediatric Inherited & Metabolic Diseases Henan Children's Hospital Zhengzhou Hospital of Beijing Children's Hospital Zhengzhou China.Department of Pediatric Intensive Care Unit Beijing Children's Hospital Capital Medical University; National Center for Children's Health Beijing 100045 China.Beijing Key Laboratory for Genetics of Birth Defects Beijing Pediatric Research Institute; MOE Key Laboratory of Major Diseases in Children; Genetics and Birth Defects Control Center Beijing Children's Hospital Capital Medical University National Center for Children's Health Beijing China. Henan Key Laboratory of Pediatric Inherited & Metabolic Diseases Henan Children's Hospital Zhengzhou Hospital of Beijing Children's Hospital Zhengzhou China.Department of Pediatric Intensive Care Unit Beijing Children's Hospital Capital Medical University; National Center for Children's Health Beijing 100045 China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32851297

Citation

Zhang, Pengfei, et al. "Novel HMGCS2 Pathogenic Variants in a Chinese Family With Mitochondrial 3-hydroxy-3-methylglutaryl-CoA Synthase Deficiency." Pediatric Investigation, vol. 3, no. 2, 2019, pp. 86-90.
Zhang P, Hu X, Guo R, et al. Novel HMGCS2 pathogenic variants in a Chinese family with mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency. Pediatr Investig. 2019;3(2):86-90.
Zhang, P., Hu, X., Guo, R., Guo, J., Li, W., Qian, S., Hao, C., & Liu, J. (2019). Novel HMGCS2 pathogenic variants in a Chinese family with mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency. Pediatric Investigation, 3(2), 86-90. https://doi.org/10.1002/ped4.12130
Zhang P, et al. Novel HMGCS2 Pathogenic Variants in a Chinese Family With Mitochondrial 3-hydroxy-3-methylglutaryl-CoA Synthase Deficiency. Pediatr Investig. 2019;3(2):86-90. PubMed PMID: 32851297.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel HMGCS2 pathogenic variants in a Chinese family with mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency. AU - Zhang,Pengfei, AU - Hu,Xuyun, AU - Guo,Ruolan, AU - Guo,Jun, AU - Li,Wei, AU - Qian,Suyun, AU - Hao,Chanjuan, AU - Liu,Jun, Y1 - 2019/06/25/ PY - 2019/03/20/received PY - 2019/04/22/accepted PY - 2020/8/28/entrez PY - 2019/6/25/pubmed PY - 2019/6/25/medline KW - HMGCS2 mutation KW - Hypoketotic hypoglycemia KW - Mitochondrial HMG‐CoA synthase deficiency KW - Pediatric intensive care unit KW - Whole‐exome sequencing SP - 86 EP - 90 JF - Pediatric investigation JO - Pediatr Investig VL - 3 IS - 2 N2 - Importance: Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase deficiency is a rare and underdiagnosed disorder with fewer than 30 patients reported worldwide. The application of whole-exome sequencing in patients could improve our understanding of this disorder. Objective: To identify the genetic causes and evaluate the phenotype of mitochondrial HMG-CoA synthase deficiency in a pediatric patient with uncommon features that included ketosis and elevated lactate and ammonia. Methods: The proband was referred to the pediatric intensive care unit of Beijing Children's Hospital and selected for molecular testing with whole-exome sequencing. Her parents and sibling also underwent sequencing for segregation information. Results: We identified two novel mutations (c.1347_1351delAGCCT/p.Ala450Profs*7 and c.1201G>T/ p.Glu401*) in the HMG-CoA synthase-2 gene (HMGCS2, NM_005518.3) in the proband and her brother. Both variants were classified as pathogenic variants according to the American College of Medical Genetics and Genomics/ Association for Molecular Pathology guidelines. Metabolic acidosis in the proband was corrected with continuous renal replacement therapy and she left hospital after 21 days of treatment. Interpretation: Our results extend the genotypic and phenotypic spectrum of HMGCS2 mutation in mitochondrial HMG-CoA synthase deficiency patients and serve as a reminder for physicians to consider mitochondrial HMG-CoA synthase deficiency in newborns and children with coma and hypoketotic hypoglycemia after fasting. SN - 2574-2272 UR - https://www.unboundmedicine.com/medline/citation/32851297/Novel_HMGCS2_pathogenic_variants_in_a_Chinese_family_with_mitochondrial_3_hydroxy_3_methylglutaryl_CoA_synthase_deficiency_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32851297/ DB - PRIME DP - Unbound Medicine ER -
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