Abstract
We report an 8-month-old infant with decreased consciousness after a febrile episode and reduced oral intake. He was profoundly acidotic but his lactate was normal. Serum triglycerides were markedly elevated and HDL cholesterol was very low. The urine organic acid analysis during the acute episode revealed a complex pattern of relative hypoketotic dicarboxylic aciduria, suggestive of a potential fatty acid oxidation disorder. MRI showed extensive brain abnormalities concerning for a primary energy deficiency. Whole exome sequencing revealed heterozygotic HMGCS2 variants. HMGCS2 encodes mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase-2 (HMGCS2), which catalyzes the irreversible and rate-limiting reaction of ketogenesis in the mitochondrial matrix. Autosomal recessive HMG-CoA synthase deficiency (HMGCS2D) is characterized by hypoketotic hypoglycemia, vomiting, lethargy, and hepatomegaly after periods of prolonged fasting or illness. A retrospective analysis of the urine organic acid analysis identified 4-hydrox-6-methyl-2-pyrone, a recently reported putative biomarker of HMGCS2D. There was also a relative elevation of plasma acetylcarnitine as previously reported in one case. Our patient highlights a unique presentation of HMGCS2D caused by novel variants in HMGCS2. This is the first report of HMGCS2D with a significantly elevated triglyceride level and decreased HDL cholesterol level at presentation. Given this, we suggest that HMGCS2D should be considered in the differential diagnosis when hypertriglyceridemia, or low HDL cholesterol levels are seen in a child who presents with acidosis, mild ketosis, and mental status changes after illness or prolonged fasting. Although HMGCS2D is a rare disorder with nonspecific symptoms, with the advent of next-generation sequencing, and the recognition of novel biochemical biomarkers, the incidence of this condition may become better understood.
Erin Conboy and Filippo Vairo contributed equally to this work.
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Acknowledgement
The authors would like to thank the patient, his family, and the Mayo Clinic Center for Individualized Medicine team for support.
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Communicated by: JÂrn Oliver Sass
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Synopsis
3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase-2 deficiency is a rare disorder with a specific urine organic acid profile, and recently found to have presenting laboratory abnormalities of hypertriglyceridemia and low HDL.
Details of the Contributions of Individual Authors
Erin Conboy, Filippo Vairo, Matthew Schultz: Contributed significantly to the manuscript and critically reviewed manuscript.
Brendan Lanpher, David Deyle, Katherine Agre: Saw patient and critically reviewed, contributed to the manuscript, and edited manuscript.
Ross Ridsdale, Devin Oglesbee, Dimitar Gavrilov: Were essential in the analysis and interpretation of the molecular and biochemical lab results, contributed to the intellectual content of the manuscript and critically reviewed and edited manuscript.
Eric W. Klee: Was essential in the variant interpretation for the Whole-Exome Data, contributed to the intellectual content of the manuscript, and critically reviewed and edited manuscript.
Conflicts of Interest
The authors have no conflicts of interest or competing interests pertaining to the manuscript.
No funding sources were required for this work.
The study protocol was approved by the Mayo Clinic Institutional Review Board.
The patient and family consented to this report.
No laboratory animals were used for this work.
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Conboy, E. et al. (2017). Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency: Unique Presenting Laboratory Values and a Review of Biochemical and Clinical Features. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 40. JIMD Reports, vol 40. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2017_59
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DOI: https://doi.org/10.1007/8904_2017_59
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