3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Clinical presentation and outcome in a series of 37 patients

Abstract

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare inborn error of ketone body synthesis
and leucine degradation, caused bymutations in theHMGCL gene. In order to obtain a comprehensive view
on this disease,we have collected clinical and biochemical data aswell as information onHMGCL mutations of 37
patients (35 families) from metabolic centers in Belgium, Germany, The Netherlands, Switzerland, and Turkey.
All patients were symptomatic at some stage with 94% presenting with an acute metabolic decompensation. In
50% of the patients, the disorder manifested neonatally, mostly within the first days of life. Only 8% of patients
presented after one year of age. Six patients died prior to data collection. Long-term neurological complications
were common. Half of the patients had a normal cognitive developmentwhile the remainder showed psychomotor
deficits.We identified seven novel HMGCLmutations. In agreementwith previous reports, no clear genotypephenotype
correlation could be found. This is the largest cohort ofHMGCLD patients reported so far, demonstrating
that HMGCLD is a potentially life-threatening disease with variable clinical outcome. Our findings suggest
that the clinical course of HMGCLD cannot be predicted accurately from HMGCL genotype. The overall outcome
in HMGCLD appears limited, thus rendering early diagnosis and strict avoidance of metabolic crises important.