Abstract
Background3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is an autosomal recessive disorder of ketogenesis and leucine degradation due to mutations in HMGCL.MethodWe performed a systematic literature search to identify all published cases. Two hundred eleven patients of whom relevant clinical data were available were included in this analysis. Clinical course, biochemical findings and mutation data are highlighted and discussed. An overview on all published HMGCL variants is provided.ResultsMore than 95% of patients presented with acute metabolic decompensation. Most patients manifested within the first year of life, 42.4% already neonatally. Very few individuals remained asymptomatic. The neurologic long-term outcome was favorable with 62.6% of patients showing normal development.ConclusionThis comprehensive data analysis provides a systematic overview on all published cases with HMGCLD including a list of all known HMGCL mutations.
Highlights
The mitochondrial enzyme 3-hydroxy-3-methylglutarylcoenzyme A lyase (HMGCL; EC 4.1.3.4) is required for the catabolism of the essential branched-chain amino acid leucine, and for the synthesis of the ketone bodies acetoacetate and 3-hydroxy-n-butyrate [1]
With this approach we identified a total of 211 hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) patients, mainly published in case reports as well as few case series
Results of HMGCL mutation analysis were reported for 118 patients
Summary
The mitochondrial enzyme 3-hydroxy-3-methylglutarylcoenzyme A lyase (HMGCL; EC 4.1.3.4) is required for the catabolism of the essential branched-chain amino acid leucine, and for the synthesis of the ketone bodies acetoacetate and 3-hydroxy-n-butyrate [1]. Ketone bodies are an important source of energy for extrahepatic organs, in particular of the brain, in times of insufficient energy supply. Due to the accumulation of characteristic leucine metabolites HMGCLD can be diagnosed via urinary organic acid analysis and usually is associated with an abnormal blood acylcarnitine profile as well. Confirmatory testing is available by enzyme activity assays in patient cells and by mutation analysis of the HMGCL gene. A comprehensive meta-analysis that covers all HMGCLD patients described in the literature so far is missing
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