Abstract
Mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase deficiency (mHS deficiency) is a rare autosomal recessive inborn error of ketogenesis caused by a mutation in the HMGCS2 gene, which is characterized by non‐(hypo)‐ketotic hypoglycemia, lethargy, and hepatomegaly during acute infection and/or prolonged fasting. Clinical presentations are similar to fatty acid oxidation defects; however, diagnosis of mHS deficiency is difficult because of poor biochemical markers. We report the case of a 12‐month‐old Japanese boy with mHS deficiency who presented with a coma, and hepatomegaly, but no hypoglycemia after a febrile episode and poor oral intake. Metabolic acidosis and severe fatty liver were observed. Serum acylcarnitine analysis revealed a slightly decreased free carnitine (C0) level and an increased acetylcarnitine (C2) level. Urinary organic acid analysis revealed hypoketotic dicarboxylic aciduria, and increased excretions of glutarate, and, retrospectively, 4‐hydroxy‐6‐methyl‐2‐pyrone. Although the patient did not present with hypoglycemia, the severe fatty liver and elevated free fatty acids to total ketone bodies ratio strongly suggested an inborn error of ketogenesis. In the analysis of the HMGCS2 gene, compound heterozygous mutations of c.130_131ins C (L44PfsX29) and c.1156_1157insC (L386PfsX73) were identified, which led to the diagnosis of mHS deficiency. He had recovered without any complication by the therapy, including intravenous glucose infusion. Unlike the previously reported cases of mHS deficiency, our case did not present with hypoglycemia and the fatty liver lasted over several months. mHS deficiency should be taken into consideration when a patient has severe metabolic acidosis and fatty liver with no or subtle ketosis, even without hypoglycemia.
Highlights
Ketone bodies, generated from fatty acids, play an important role as an alternative energy source when glucose supply is low.[1,2] Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (EC2.3.3.10) is a key enzyme that mediates the rate-limiting step of ketone body synthesis, catalyzing the condensation reaction between the acetyl-CoA and acetoacetyl-CoA to HMG-CoA.[3]Mitochondrial HMG-CoA synthase deficiency is a rare autosomal recessive inborn error of ketogenesis caused by mutations in the HMGCS2 (3-hydroxy-3-methylglutaryl-CoA synthase-2) gene, located on chromosome 1p12-13, which consists of 10 exons.[4-6]mHS deficiency was first described in 1997.7 To date, more than 20 cases have been reported.[8-17]
4-hydroxy-6-methyl-2-pyrone (4HMP) in urine was recently reported as a possible useful specific marker,[13] diagnosis of mHS deficiency is still challenging owing to poor biochemical markers
We report a case with mHS deficiency, which was the second case diagnosed in Japan (Fukao et al, unpublished data)
Summary
Ketone bodies, generated from fatty acids, play an important role as an alternative energy source when glucose supply is low.[1,2] Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (EC2.3.3.10) is a key enzyme that mediates the rate-limiting step of ketone body synthesis, catalyzing the condensation reaction between the acetyl-CoA and acetoacetyl-CoA to HMG-CoA.[3]. Most patients presented with hypoglycemia and hepatomegaly during acute infection and prolonged fasting and showed an absence of clinical symptoms in the intermittent phase. We report the case of a Japanese boy with mHS deficiency who did not present with hypoglycemia in the acute phase. A 12-month-old Japanese boy born to nonconsanguineous parents was a second child with a healthy elder sister Around 3 months after the onset, he had enteritis He overcame it without metabolic crisis with intravenous glucose administration at the local hospital. His liver was enlarged and his AST and ALT levels spiked again (Figure 1). In 13 months after the onset, the fatty liver had mostly disappeared, but mild hepatomegaly was still detected on CT. At the age of 6 years, he had grown and developed normally
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