Expanding the clinical spectrum of mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase deficiency with Turkish cases harboring novel HMGCS2 gene mutations and literature review

Abstract

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS) deficiency is a very rare autosomal recessive inborn error of ketone body synthesis and presents with hypoketotic hypoglycemia, metabolic acidosis, lethargy, encephalopathy, and hepatomegaly with fatty liver precipitated by catabolic stress. We report acute presentation of two patients from unrelated two families with novel homozygous c.862C>T and c.725-2A>C mutations, respectively, in HMGCS2 gene. Affected patients had severe hypoketotic hypoglycemia, lethargy, encephalopathy, severe metabolic and lactic acidosis and hepatomegaly after infections. Surprisingly, molecular screening of the second family showed more affected patients without clinical findings. These cases expand the clinic spectrum of this extremely rare disease.

Colonic ketogenesis, a microbiota-regulated process, contributes to blood ketones and protects against colitis in mice

“…We found a significant decrease in survival even with the heterozygous deletion of the enzyme whereas the previous study did not find any difference between WT mice and heterozygous mice. Loss-of-function mutations in HMGCS2 occur in humans with severe biochemical and clinical consequences, but a decrease in postnatal survival is not among the reported findings in affected individuals [ 18 , 19 ]. It is possible that this phenomenon is specific for mice.…”

“…Even though several patients have been reported in the published literature with loss-of-function mutations in HMGCS2 [ 18 , 19 ], most of the clinical descriptions focus on biochemical features and gross clinical findings such as fatty liver and hepatomegaly. Furthermore, all of the published reports are on children.…”

“…Hepatic ketogenesis plays an obligatory role in the biology of neonates [ 20 ]. The importance of ketogenesis in neonatal period is supported by the metabolic and clinical consequences of genetic deficiency of HMGCS2 [ 18 , 19 ]. HMGCS2 deficiency is an inborn error of metabolism with symptoms which include hypoketotic hypoglycemia, hepatomegaly with fatty liver, encephalopathy, lethargy, and metabolic acidosis, evident in neonates and young children.…”