Dataset Information

Novel HMGCS2 pathogenic variants in a Chinese family with mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency.

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.

SUBMITTER: Zhang P

PROVIDER: S-EPMC7331301 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Novel <i>HMGCS2</i> pathogenic variants in a Chinese family with mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency.

Zhang Pengfei P Hu Xuyun X Guo Ruolan R Guo Jun J Li Wei W Qian Suyun S Hao Chanjuan C Liu Jun J

Pediatric investigation 20190625 2

<h4>Importance</h4>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.<h4>Objective</h4>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 amm ...[more]

PMID: 32851297

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Project description:Background: Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMGCS2D) is a rare autosomal recessive metabolic disorder caused by mutations of the HMGCS2 gene. To date, no more than 60 patients have been reported throughout the world. Purpose: To analyze the clinical, biochemical, molecular, and outcome features of HMGCS2D in a case series of 10 new Chinese patients. Methods: This retrospective study includes 10 Chinese patients diagnosed with HMGCS2D. We collected and analyzed clinical data for all patients. We also reviewed clinical data for 39 cases that had been reported previously. Results: All of our patients had experienced their first metabolic crisis before 12 months old. The most common clinical manifestations were anorexia, dyspnea, and disturbance of consciousness (10/10), followed by vomiting (8/10), fever (7/10), cough (4/10), diarrhea, and seizures (3/10). Each patient (10/10) had a different degree of hepatomegaly and increased aminotransferase, severe metabolic acidosis, and hypofibrinogenemia. 9 patients presented with severe hypoglycemia and weak positives on qualitative tests of urinary ketone body. Patient 3 was the only one without hypoglycemia. Five patients had hypocalcemia, five patients had hyperammonemia, four patients had hyperuricemia, and three had hypertriglyceridemia. During the metabolic acidosis episode, we observed high dicarboxylic acid values in urine, and the elevated ratio of blood acetylcarnitine to free carnitine may have been an additional biochemical signature. However, all returned to normal during the interictal interval. Molecular analysis identified 15 variants in the HMGCS2 gene, of which 10 were novel (c.220G>A/p.E74K, c.407A>G/p.D136G, c.422T>A/p.V141D, c.719A>C/p.D240A, c.821G>A/p.R274H, c.39dupA/p.L14Tfs*59, c.1394delA/p.N465Tfs*10, c.788delT/p.L263Cfs*36, c.717T>G/p.Y239*, and c.1017-2A>G). Combining these with previous cases, the known mutation c.1201G>T/p.E401* has been found in 6/40 (15.0%) of mutated alleles in 21 Chinese patients from 20 families, while none have been found in other populations. We found that patients with biallelic truncation mutation appeared to show a more severe clinical condition through a literature review. Conclusion: This study analyzed the phenotypic and genetic features of HMGCS2D in a Chinese case series. We also expanded the HMGCS2 mutational spectrum with 10 novel variants. The c.1201G>T/p.E401* mutation was the most frequent, representing 15.0% of the mutated alleles in reported unrelated Chinese patients, and thus, it may be a hot spot mutation.