Mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase deficiency: urinary organic acid profiles and expanded spectrum of mutations

Abstract

Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase (HMCS2) deficiency results in episodes of hypoglycemia and increases in fatty acid metabolites. Metabolite abnormalities described to date in HMCS2 deficiency are nonspecific and overlap with other inborn errors of metabolism, making the biochemical diagnosis of HMCS2 deficiency difficult. Urinary organic acid profiles from periods of metabolic decompensation were studied in detail in HMCS2-deficient patients from four families. An additional six unrelated patients were identified from clinical presentation and/or qualitative identification of abnormal organic acids. The diagnosis was confirmed by sequencing and deletion/duplication analysis of the HMGCS2 gene. Seven related novel organic acids were identified in urine profiles. Five of them (3,5-dihydroxyhexanoic 1,5 lactone; trans-5-hydroxyhex-2-enoate; 4-hydroxy-6-methyl-2-pyrone; 5-hydroxy-3-ketohexanoate; 3,5-dihydroxyhexanoate) were identified by comparison with synthesized or commercial authentic compounds. We provisionally identified trans-3-hydroxyhex-4-enoate and 3-hydroxy-5-ketohexanoate by their mass spectral characteristics. These metabolites were found in samples taken during periods of decompensation and normalized when patients recovered. When cutoffs of adipic >200 and 4-hydroxy-6-methyl-2-pyrone >20 μmol/mmol creatinine were applied, all eight samples taken from five HMCS2-deficient patients during episodes of decompensation were flagged with a positive predictive value of 80% (95% confidence interval 35-100%). Some ketotic patients had increased 4-hydroxy-6-methyl-2-pyrone. Molecular studies identified a total of 12 novel mutations, including a large deletion of HMGCS2 exon 1 in two families, highlighting the need to perform quantitative gene analyses. There are now 26 known HMGCS2 mutations, which are reviewed in the text. 4-Hydroxy-6-methyl-2-pyrone and related metabolites are markers for HMCS2 deficiency. Detection of these metabolites will streamline the biochemical diagnosis of this disorder.

A Japanese case of mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase deficiency who presented with severe metabolic acidosis and fatty liver without hypoglycemia

“…Our patient had two frame‐shift mutations. To date, this is the only patient with two apparent null mutations beside homozygous deletion of exon 1 . His phenotype was not more severe than those of other cases with missense mutations.…”

“…No other significant disease-specific findings were detected at that time. 4HMP, which was retrospectively detected after the report of Pitt et al, 13 was not detected at the time of diagnosis.…”

“…7 To date, more than 20 cases have been reported. [8][9][10][11][12][13][14][15][16][17] Most patients presented with hypoglycemia and hepatomegaly during acute infection and prolonged fasting and showed an absence of clinical symptoms in the intermittent phase. Non-(hypo)-ketotic hypoglycemia with high free fatty acids (FFA) is the predominant laboratory finding.…”

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

“…Naturally occurring loss-of-function HMGCS2 mutations in humans cause bouts of hypoketotic hypoglycemia (Pitt et al, 2015; Thompson et al, 1997). Robust HMGCS2 expression is restricted to hepatocytes and colonic epithelium, and its expression and enzymatic activity are coordinated through diverse mechanisms (Mascaro et al, 1995; McGarry and Foster, 1980; Robinson and Williamson, 1980).…”

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

“…The diagnosis of mitochondrial HMG‐CoA synthase deficiency outside of a fasting situation is challenging because biochemical tests results are typically normal and enzymatic activity testing requires an invasive liver biopsy. Increased levels of seven specific components of the urine metabolic profile during the onset period have been identified, which has improved the diagnostic value of mass spectrometry . Moreover, genetic testing has made the diagnosis more effective.…”