3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare inborn error of ketone body synthesis and leucine degradation, caused by mutations in the HMGCL gene. In order to obtain a comprehensive view on this disease, we have collected clinical and biochemical data as well as information on HMGCL 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 development while the remainder showed psychomotor deficits. We identified seven novel HMGCL mutations. In agreement with previous reports, no clear genotype-phenotype correlation could be found. This is the largest cohort of HMGCLD 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.

Centre de Recherche and Département de Pédiatrie CHU Sainte Justine Université de Montréal Montréal Québec Canada; Département de Biochimie Université de Montréal Montréal Québec Canada

Department of General Pediatrics Adolescent Medicine and Neonatology Medical Center University of Freiburg Faculty of Medicine Freiburg Germany

Department of General Pediatrics Adolescent Medicine and Neonatology Medical Center University of Freiburg Faculty of Medicine Freiburg Germany; Division of Clinical Chemistry and Biochemistry and Children's Research Center University Children's Hospital Zürich Switzerland; Bioanalytics and Biochemistry Department of Natural Sciences University of Applied Sciences Rheinbach Germany

Department of General Pediatrics Division of Neuropediatrics and Pediatric Metabolic Medicine University Hospital Heidelberg Heidelberg Germany

Department of General Pediatrics Münster University Children's Hospital Münster Germany

Department of General Pediatrics Neonatology and Pediatric Cardiology University Children's Hospital Heinrich Heine University Düsseldorf Germany

Department of Inborn Errors of Metabolism Dr von Hauner Children's Hospital Ludwig Maximilians University Munich Germany

Department of Neurology University of Tübingen Germany

Department of Neuropediatrics University Children's Hospital Ruhr University Bochum Bochum Germany

Department of Pediatrics Hannover Medical School Hannover Germany

Department of Pediatrics University Medical Center Hamburg Eppendorf Hamburg Germany

Division of Clinical Chemistry and Biochemistry and Children's Research Center University Children's Hospital Zürich Switzerland

Division of Metabolism and Children's Research Center University Children's Hospital Zürich Switzerland

Division of Metabolism and Nutrition Department of Pediatrics Faculty of Medicine Ege University Izmir Turkey

Division of Pediatric Nutrition and Metabolism Department of Pediatrics Istanbul Medical Faculty Istanbul Turkey

Inborn Errors of Metabolism Unit Institute of Pathology and Genetics Charleroi Gosselies Belgium

Institute of Inherited Metabolic Disorders Charles University Prague 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic

Radboud University Medical Center Nijmegen The Netherlands

References provided by Crossref.org

A newborn screening approach to diagnose 3-hydroxy-3-methylglutaryl-CoA lyase deficiency