3-Hydroxy-3-methylglutaric aciduria: A possible pitfall in diagnosis

Abstract

The mitochondrial enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (EC 4.1.3.4) is a component of the pathway for leucine catabolism and, in the liver, has a key role in the synthesis of the ketone body, acetoacetate [l]. Babies with an inherited deficiency of this enzyme (McKusick 24645) generally present during the first year of life with episodic severe hypoglycaemia and metabolic acidosis, but no ketosis, which may progress to coma and death [l-4]. Fatty infiltration of the liver has been reported in the acute illness [4,5]. With prompt diagnosis and dietary management, and avoidance of prolonged fasting, the prognosis may be good. There is a characteristic organic aciduria, with excretion of large amounts of 3-hydroxy-3-methylglutaric (HMG), 3-methylglutaconic, 3-methylglutaric and 3-hydroxyisovaleric acids and sometimes, during acute epidoses, increases in hexanedioic and glutaric acids and excretion of 3-methylcrotonylglycine [1,3,6]. Seriously ill babies with an acquired deficiency of the enzyme have also been reported [7-91. We recently investigated a 5-month-old baby, who had a cot death, for a possible inherited metabolic disorder. His liver was grossly enlarged and fatty. Initial examination of a urinary extract for organic acids by gas chromatography suggested the possibility of HMG-CoA lyase deficiency, but the HMG peak was small in relation to 3-methylglutaconic acid. Fourteen days later, analysis of the same urine extract