Journal
EUROPEAN JOURNAL OF MEDICAL GENETICS
Volume 56, Issue 8, Pages 411-415Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejmg.2013.05.008
Keywords
Mitochondrial HMG-CoA synthase deficiency; Mutations; Ketone bodies
Categories
Funding
- Diputacion General de Aragon (DGA) (Grupo Consolidado) [B20]
- European Social Fund
- Spanish Ministry of Education and Science [SAF2004-06843-C03]
- Spanish Ministerio de Ciencia and Ministerio de Economia y Competitividad [SAF2007-61926, IPT2011-0964-900000, SAF2011-13156-E]
- Spanish Instituto de Salud Carlos III (CIBER Fisiopatologia de la Obesidad y Nutricion)
- European Commission through EU [HEALTH-F3-2009-223431, HEALTH-2011-278603]
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Mitochondrial HMG-CoA synthase deficiency is a rare inherited metabolic disorder that affects ketone-body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycaemia, dicarboxylic aciduria, and in severe cases, coma. This deficiency may have been under-diagnosed owing to the absence of specific clinical and biochemical markers, limitations in liver biopsy and the lack of an effective method of expression and enzyme assay for verifying the mutations found. To date, eight patients have been reported with nine allelic variants of the HMGCS2 gene. We present a new method of enzyme expression and a modification of the activity assay that allows, for first time, the functional study of missense mutations found in patients with this deficiency. Four of the missense mutations (p.V54M, p.R188H, p.G212R and p.G388R) did not produce proteins that could have been detected in soluble form by western blot; three produced a total loss of activity (p.Y167C, p.M307T and p.R500H) and one, variant p.F174L, gave an enzyme with a catalytic efficiency of 11.5%. This indicates that the deficiency may occur with partial loss of activity of enzyme. In addition, we describe a new patient with this deficiency, in which we detected the missense allelic variant, c.1162G>A (p.G388R) and the nonsense variant c.1270C>T (p.R424X). (C) 2013 Elsevier Masson SAS. All rights reserved.
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