Refining the diagnosis of mitochondrial HMG‐CoA synthase deficiency

Abstract

Mitochondrial HMG-CoA synthase deficiency is an inherited metabolic disorder caused by a defect in the enzyme that regulates the formation of ketone bodies. Patients present with hypoketotic hypoglycaemia, encephalopathy and hepatomegaly, usually precipitated by an intercurrent infection or prolonged fasting. The diagnosis may easily be missed as previously reported results of routine metabolic investigations, urinary organic acids and plasma acylcarnitines may be nonspecific or normal, and a high index of suspicion is required to proceed to further confirmatory tests. We describe a further acute case in which the combination of urinary organic acids, low free carnitine and changes in the plasma acylcarnitine profile on carnitine supplementation were very suggestive of a defect in ketone synthesis. The diagnosis of mitochondrial HMG-CoA synthase deficiency was confirmed on genotyping, revealing two novel mutations: c.614G > A (R188H) and c.971T > C (M307T). A further sibling, in whom the diagnosis had not been made acutely, was also found to be affected. The possible effects of these mutations on enzyme activity are discussed.

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

“…The levels of dicarboxylic acids, such as adipic and suberic acids, were greatly increased, dominating the profile and reflecting increased fatty acid metabolism. A large number of other metabolites related to fatty acid metabolism, such as 3-hydroxydicarboxylic acids and 5-hydroxyhexanoic acid, were also prominent, as previously reported (Aledo et al 2006;Bouchard et al 2001;Morris et al 1998;Thompson et al 1997;Zschocke et al 2002). In common with previous reports, the levels of metabolites rapidly normalized with treatment and were normal when the patients recovered.…”

“…HMCS2 deficiency belongs to the hypoketotic hypoglycemia group (Aledo et al 2006;Bouchard et al 2001;Fukao et al 2014;Morris et al 1998), so the finding of moderately increased levels of ketones in urine or blood may result in this diagnosis being discounted. Importantly, increased 3-hydroxybutyrate concentration was observed in the urine of some patients during decompensation (Fig.…”

“…Human HMCS2 deficiency (OMIM 605991) was first described in 1997 (Thompson et al 1997), and a small number of patients have subsequently been described with mutations identified in the HMGCS2 gene that encodes HMCS2 (Aledo et al 2001(Aledo et al , 2006Bouchard et al 2001;Ramos et al 2013;Shafqat et al 2010;Wolf et al 2003). HMCS2 deficiency is characterized by episodes of severe hypoglycemia and metabolic acidosis that occur during fasting and can progress rapidly to life-threatening coma.…”

Crystal Structures of Human HMG-CoA Synthase Isoforms Provide Insights into Inherited Ketogenesis Disorders and Inhibitor Design

“…Two nonsense and 15 missense mutations have been identified in the hmgcs2 gene of HMGCS2-deficient patients ( Table 2). 25,[27][28][29] The nonsense mutation is expected to result in nontranslation due to nonsense-mediated decay. On a protein level, it may lead to a premature termination at Lys387/Arg424 with an 84-residue C-terminal truncation, which encompasses the hHMGCS2 lower region and forms part of the active site.…”

HMG-CoA synthase isoenzymes 1 and 2 localize to satellite glial cells in dorsal root ganglia and are differentially regulated by peripheral nerve injury

“…HMGCS2 functions as a key enzyme for ketogenesis and is located in the mitochondrial matrix. Inherited HMGCS2 deficiency in human causes metabolic disorder presenting with hypoketotic hypoglycemia, encephalopathy, and hepatomegaly (Aledo et al, 2006). Mutation of HMGCS1 in zebrafish leads to abnormality in oligodendrocyte development and myelin gene expression (Mathews et al, 2014).…”