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3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Clinical presentation and outcome in a series of 37 patients.
Mol Genet Metab 2017; 121(3):206-215MG

Abstract

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.

Authors+Show Affiliations

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.Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.Division of Clinical Chemistry & Biochemistry and Children's Research Center, University Children's Hospital, Zürich, Switzerland.Institute of Inherited Metabolic Disorders, Charles University in Prague - 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic.Division of Pediatric Nutrition and Metabolism, Department of Pediatrics, Istanbul Medical Faculty, Istanbul, Turkey.Department of Neurology, University of Tübingen, Germany.Division of Metabolism and Nutrition, Department of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey.Department of Pediatrics, Hannover Medical School, Hannover, Germany.Division of Pediatric Nutrition and Metabolism, Department of Pediatrics, Istanbul Medical Faculty, Istanbul, Turkey.Radboud University Medical Center, Nijmegen, The Netherlands.Division of Pediatric Nutrition and Metabolism, Department of Pediatrics, Istanbul Medical Faculty, Istanbul, Turkey.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.Department of Inborn Errors of Metabolism, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, Munich, Germany.Department of Neuropediatrics, University Children's Hospital, Ruhr-University Bochum, Bochum, Germany.Inborn Errors of Metabolism Unit, Institute of Pathology and Genetics, Charleroi, Gosselies, Belgium.Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany.Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University, Düsseldorf, Germany.Department of General Pediatrics, Division of Neuropediatrics and Pediatric Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany.Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.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; Division of Clinical Chemistry & Biochemistry and Children's Research Center, University Children's Hospital, Zürich, Switzerland; Bioanalytics & Biochemistry, Department of Natural Sciences, University of Applied Sciences, Rheinbach, Germany. Electronic address: joern.oliver.sass@h-brs.de.

Pub Type(s)

Journal Article
Multicenter Study

Language

eng

PubMed ID

28583327

Citation

Grünert, Sarah Catharina, et al. "3-Hydroxy-3-methylglutaryl-coenzyme a Lyase Deficiency: Clinical Presentation and Outcome in a Series of 37 Patients." Molecular Genetics and Metabolism, vol. 121, no. 3, 2017, pp. 206-215.
Grünert SC, Schlatter SM, Schmitt RN, et al. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Clinical presentation and outcome in a series of 37 patients. Mol Genet Metab. 2017;121(3):206-215.
Grünert, S. C., Schlatter, S. M., Schmitt, R. N., Gemperle-Britschgi, C., Mrázová, L., Balcı, M. C., ... Sass, J. O. (2017). 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Clinical presentation and outcome in a series of 37 patients. Molecular Genetics and Metabolism, 121(3), pp. 206-215. doi:10.1016/j.ymgme.2017.05.014.
Grünert SC, et al. 3-Hydroxy-3-methylglutaryl-coenzyme a Lyase Deficiency: Clinical Presentation and Outcome in a Series of 37 Patients. Mol Genet Metab. 2017;121(3):206-215. PubMed PMID: 28583327.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Clinical presentation and outcome in a series of 37 patients. AU - Grünert,Sarah Catharina, AU - Schlatter,Sonja Marina, AU - Schmitt,Robert Niklas, AU - Gemperle-Britschgi,Corinne, AU - Mrázová,Lenka, AU - Balcı,Mehmet Cihan, AU - Bischof,Felix, AU - Çoker,Mahmut, AU - Das,Anibh M, AU - Demirkol,Mübeccel, AU - de Vries,Maaike, AU - Gökçay,Gülden, AU - Häberle,Johannes, AU - Uçar,Sema Kalkan, AU - Lotz-Havla,Amelie Sophia, AU - Lücke,Thomas, AU - Roland,Dominique, AU - Rutsch,Frank, AU - Santer,René, AU - Schlune,Andrea, AU - Staufner,Christian, AU - Schwab,Karl Otfried, AU - Mitchell,Grant A, AU - Sass,Jörn Oliver, Y1 - 2017/05/22/ PY - 2017/04/27/received PY - 2017/05/20/accepted PY - 2017/6/7/pubmed PY - 2018/3/20/medline PY - 2017/6/7/entrez KW - Enzyme activity KW - Fatty acid metabolism KW - Ketogenesis KW - Ketone body synthesis KW - Leucine degradation KW - Organic aciduria SP - 206 EP - 215 JF - Molecular genetics and metabolism JO - Mol. Genet. Metab. VL - 121 IS - 3 N2 - 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. SN - 1096-7206 UR - https://www.unboundmedicine.com/medline/citation/28583327/3_Hydroxy_3_methylglutaryl_coenzyme_A_lyase_deficiency:_Clinical_presentation_and_outcome_in_a_series_of_37_patients_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1096-7192(17)30282-2 DB - PRIME DP - Unbound Medicine ER -