Introduction Mitochondrial HMG-CoA synthase deficiency (HMGCS2D) is an autosomal recessive disorder of ketone body synthesis characterised by hypoketotic hypoglycaemia, vomiting and hepatomegaly typically in the first year of life. Methods We report a previously well, 21-month old, unvaccinated male, of non-consanguineous Polish heritage, who presented with encephalopathy, hepatomegaly, severe anion-gap metabolic acidosis and mild hyperammonaemia following a brief intercurrent illness. While there was no documented hypoglycaemia, the sample was markedly lipaemic with Triglycerides 34 mmol/L. Unlike a similar, recently published case, he made a full neurological recovery. Results Urine organic acid analysis revealed marked ketonuria, very marked dicarboxylic aciduria and notable increase in medium chain 3-oxodicarboxylic acids. Glutarate was markedly elevated with mild increase in 3-hydroxyglutarate (3HG). 4-hydroxy-6-methyl-2-pyrone and four other putative biomarkers for HMGCSD2 were detected. DBS acetylcarnitine was raised on presentation. Acidosis and hypertriglyceridaemia gradually resolved with intravenous dextrose and bicarbonate. 3HG was slow to normalize while pyrone remained detectable. Molecular genetic analysis of the HMGCS2 gene identified compound heterozygosity for c.634G>A and c.1016+1G>A, not previously reported with this phenotype. Conclusions HMGCS2D should be considered in a child with severe unexplained metabolic acidosis even without hypoglycaemia. The condition should be added to the differential diagnosis of raised urinary glutarate and 3HG.
