Treatment of HMG-CoA Lyase Deficiency-Longitudinal Data on Clinical and Nutritional Management of 10 Australian Cases

Abstract

3-Hydroxy-3-Methylglutaryl-CoA Lyase (HMGCL) deficiency can be a very severe disorder that typically presents with acute metabolic decompensation with features of hypoketotic hypoglycemia, hyperammonemia, and metabolic acidosis. A retrospective chart and literature review of Australian patients over their lifespan, incorporating acute and long-term dietary management, was performed. Data from 10 patients contributed to this study. The index case of this disorder was lost to follow-up, but there is 100% survival in the remainder of the cases despite several having experienced life-threatening episodes. In the acute setting, five of nine patients have used 900 mg/kg/day of sodium D,L 3-hydroxybutyrate in combination with intravenous dextrose-containing fluids (delivering glucose above estimated basal utilization requirements). All patients have been on long-term protein restriction, and those diagnosed more recently have had additional fat restriction. Most patients take L-carnitine. Three children and none of the adults take nocturnal uncooked cornstarch. Of the cohort, there were two patients that presented atypically-one with fulminant liver failure and the other with isolated developmental delay. Dietary management in patients with HMGCL deficiency is well tolerated, and rapid institution of acute supportive metabolic treatment is imperative to optimizing survival and improve outcomes in this disorder.

Keywords: 3 Hydroxybutyrate; HMG Co A Lyase; fat oxidation; hyperammonemia; ketones; leucine oxidation; liver failure; low-fat diet; low-protein diet; metabolic decompensation.

Figure 1

Graphical illustration of the various enzymes and metabolites involved in leucine catabolism and ketone body synthesis. HMG-CoA Lyase is the enzyme involved in the final step of mitochondrial ketone body production from both fatty acid oxidation and leucine catabolism. Reduced or absent function of this enzyme causes accumulation of HMG (3-hydroxy-3-methylglutyrate), MGC (3-methylglutaconate), MGL (3-methylglutarate), and 3HIV (3-hydroxyisovalerate) in bodily fluids.