Novel <i><scp>HMGCS</scp>2</i> pathogenic variants in a Chinese family with mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase deficiency

Zhang, Pengfei; Hu, Xuyun; Guo, Ruolan; Guo, Jun; Li, Wei; Qian, Suyun; Hao, Chanjuan; Li, Jun

doi:10.1002/ped4.12130

Cited by 4 publications

(2 citation statements)

References 15 publications

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“…Both HMGCS and HMGCL deficiency are underrecognized ketogenic disorders. Less than 40 cases of HMGCS deficiency 5 and less than 150 cases of HMGCL deficiency are reported worldwide till date. 6 Both these disorders are clinically heterogeneous ranging from the most severe neonatal form having a potentially fatal outcome to a milder presentation in adulthood.…”

Section: Discussionmentioning

confidence: 99%

Inborn Errors of Ketogenesis: Novel Variants, Clinical Presentation, and Follow-Up in a Series of Four Patients

et al. 2022

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Inborn errors of ketogenesis are rare disorders that result in acute and fulminant decompensation during lipolytic stress, particularly in infants and children. These include mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS) deficiency and HMG-CoA lyase (HMGCL) deficiency. In this series, we describe the clinical, biochemical, and molecular profiles of four patients along with dietary interventions and their outcomes on a long-term follow-up. Two patients each of HMGCS and HMGCL deficiency were evaluated with clinical history, biochemical investigations, including tandem mass spectrometry (TMS) and urine gas chromatography-mass spectrometry (GCMS). Molecular analysis was performed by whole-exome sequencing, as well as exon array validated by long-range polymerase chain reaction. All individuals were diagnosed with acute metabolic decompensation in the early infancy period except one with HMGCL deficiency who had the first presentation at 5 years of age. Central nervous system manifestations, severe metabolic acidosis, hyperammonemia, hypoglycemia with a normal lactate, and absence of urinary ketones were observed in all the affected individuals. The disorder was life-threatening in three individuals and one succumbed to the illness. TMS was nonspecific and urine GCMS revealed dicarboxylic aciduria in HMGCS deficiency. Both the patients with HMGCL deficiency demonstrated elevated 3 hydroxyisovaleryl carnitine levels in TMS and metabolites of leucine degradation in urine GCMS. We identified five novel variants that included a large deletion involving exon 2 in HMGCL gene. There was no evidence of long-term neurological sequelae in the living individuals. Diet with moderation of fat intake was followed in two individuals with HMGCS deficiency. Low leucine and protein diet with moderation of fat intake was followed in the individual with HMGCL deficiency. All affected individuals are thriving well with no further major metabolic decompensation.

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Section: Discussionmentioning

confidence: 99%

Inborn Errors of Ketogenesis: Novel Variants, Clinical Presentation, and Follow-Up in a Series of Four Patients

et al. 2022

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“…He was referred to Clinic of Development & Behavioral Pediatrics for Short Stature and DD. A de novo SMARCA2 mutation was identified and was therefore diagnosed as Nicolaides-Baraitser syndrome (Zhang P. et al, 2019). This syndrome was less recognizable and always misdiagnosed as Coffin-Siris syndrome, Williams syndrome, etc.…”

Section: Clinical Impact Of Genetic Diagnosesmentioning

confidence: 99%

Parallel Tests of Whole Exome Sequencing and Copy Number Variant Sequencing Increase the Diagnosis Yields of Rare Pediatric Disorders

Guo

et al. 2020

Front. Genet.

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Background: Both whole exome sequencing and copy number variants sequencing were applied to identify the genetic cause of rare pediatric disorders. In our study, we aimed to investigate the diagnostic yield of parallel tests of trio whole exome sequencing and copy number variants sequencing and its clinical utility. Methods: After collecting detailed clinical information, a total of 60 patients were referred to parallel tests of whole exome sequencing and copy number variants sequencing, which used shared initial libraries. Results: 26 pathogenic or likely pathogenic single nucleotide variants and 11 copy number variants were identified in 32 patients. 65.4% (17/26) of the SNVs were novel. The overall diagnosis rate was 53.3%. For the patients with positive results, 22 (36.7%) patients were diagnosed by whole exome sequencing and 10 (16.7%) patients were diagnosed by copy number variants sequencing. We also reviewed clinical impact on selected cases. Conclusion: We adopted an approach by performing parallel tests of trio whole exome sequencing and copy number variants sequencing with shared initial libraries. This strategy is relatively efficient and cost-effective for the diagnosis of rare pediatric disorders with high heterogeneity.

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Expanding phenotypic and mutational spectra of mitochondrial HMG-CoA synthase deficiency

Rojnueangnit

Maneechai

Thaweekul

et al. 2020

European Journal of Medical Genetics

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

Cited by 4 publications

References 15 publications

Inborn Errors of Ketogenesis: Novel Variants, Clinical Presentation, and Follow-Up in a Series of Four Patients

Inborn Errors of Ketogenesis: Novel Variants, Clinical Presentation, and Follow-Up in a Series of Four Patients

Parallel Tests of Whole Exome Sequencing and Copy Number Variant Sequencing Increase the Diagnosis Yields of Rare Pediatric Disorders

Expanding phenotypic and mutational spectra of mitochondrial HMG-CoA synthase deficiency

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