Journal article
Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?
- Repp BM Institute of Human Genetics, Technische Universität München, Trogerstrasse 32, 81675, Munich, Germany.
- Mastantuono E Institute of Human Genetics, Technische Universität München, Trogerstrasse 32, 81675, Munich, Germany.
- Alston CL Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
- Schiff M UMR1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, 75019, Paris, France.
- Haack TB Institute of Human Genetics, Technische Universität München, Trogerstrasse 32, 81675, Munich, Germany.
- Rötig A UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015, Paris, France.
- Ardissone A Unit of Molecular Neurogenetics, Fondazione Istituto Neurologico "Carlo Besta", Milan, Italy.
- Lombès A INSERM U1016, Institut Cochin, Paris, France.
- Catarino CB Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-Universität München, Munich, Germany.
- Diodato D Muscular and Neurodegenerative Disorders Unit, Bambino Gesu´ Children's Hospital, IRCCS, Rome, Italy.
- Schottmann G NeuroCure Clinical Research Center (NCRC), Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
- Poulton J Nuffield Department of Women's and Reproductive Health, University of Oxford, The Women's Centre, John Radcliffe Hospital, Oxford, UK.
- Burlina A Division of Inherited Metabolic Diseases, Department of Paediatrics, University Hospital of Padova, Padova, Italy.
- Jonckheere A Department of Pediatrics, Antwerp University Hospital, Edegem, Belgium.
- Munnich A UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015, Paris, France.
- Rolinski B ELBLAB GmbH, Riesa, Germany.
- Ghezzi D Unit of Molecular Neurogenetics, Fondazione Istituto Neurologico "Carlo Besta", Milan, Italy.
- Rokicki D Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland.
- Wellesley D Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
- Martinelli D Genetics and Rare Diseases Research Division, Unit of Metabolism, Bambino Gesù Children's Research Hospital, Rome, Italy.
- Wenhong D Department of Pediatric cardiology, Beijing Anzhe Hospital, Captital Medical University, Beijing, China.
- Lamantea E Unit of Molecular Neurogenetics, Fondazione Istituto Neurologico "Carlo Besta", Milan, Italy.
- Ostergaard E Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.
- Pronicka E Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland.
- Pierre G South West Regional Metabolic Department, Bristol Royal Hospital for Children, Bristol, BS1 3NU, UK.
- Smeets HJM Department of Genetics and Cell Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
- Wittig I Functional Proteomics, SFB 815 Core Unit, Faculty of Medicine, Goethe-University, Frankfurt am Main, Germany.
- Scurr I Department of Clinical Genetics, St Michael's Hospital, Bristol, UK.
- de Coo IFM Department of Neurology, Erasmus MC, Rotterdam, Netherlands.
- Moroni I Child Neurology, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.
- Smet J Department of Pediatric Neurology and Metabolism, Ghent University Hospital, De Pintelaan, Ghent, Belgium.
- Mayr JA Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.
- Dai L Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
- de Meirleir L Research Group Reproduction and Genetics, Vrije Universiteit Brussel, Brussels, Belgium.
- Schuelke M NeuroCure Clinical Research Center (NCRC), Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany.
- Zeviani M MRC-Mitochondrial Biology Unit, Cambridge, Cambridgeshire, UK.
- Morscher RJ Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.
- McFarland R Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
- Seneca S Center for Medical Genetics, UZ Brussel, Research Group Reproduction and Genetics (REGE), Vrije Universiteit Brussel, Brussels, Belgium.
- Klopstock T Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-Universität München, Munich, Germany.
- Meitinger T Institute of Human Genetics, Technische Universität München, Trogerstrasse 32, 81675, Munich, Germany.
- Wieland T Institute of Human Genetics, Helmholtz Zentrum München, Munich, Germany.
- Strom TM Institute of Human Genetics, Technische Universität München, Trogerstrasse 32, 81675, Munich, Germany.
- Herberg U Department of Pediatric Cardiology, University of Bonn, Bonn, Germany.
- Ahting U Institute of Human Genetics, Technische Universität München, Trogerstrasse 32, 81675, Munich, Germany.
- Sperl W Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.
- Nassogne MC Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
- Ling H Department of Pediatric cardiology, Beijing Anzhe Hospital, Captital Medical University, Beijing, China.
- Fang F Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
- Freisinger P Department of Pediatrics, Klinikum Reutlingen, Reutlingen, Germany.
- Van Coster R Department of Pediatric Neurology and Metabolism, Ghent University Hospital, De Pintelaan, Ghent, Belgium.
- Strecker V Functional Proteomics, SFB 815 Core Unit, Faculty of Medicine, Goethe-University, Frankfurt am Main, Germany.
- Taylor RW Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
- Häberle J Division of Metabolism and Children's Research Center, University Children's Hospital, Zurich, Switzerland.
- Vockley J Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, USA.
- Prokisch H Institute of Human Genetics, Technische Universität München, Trogerstrasse 32, 81675, Munich, Germany.
- Wortmann S Institute of Human Genetics, Technische Universität München, Trogerstrasse 32, 81675, Munich, Germany. wortmann-hagemann@helmholtz-muenchen.de.
- 2018-07-21
Published in:
- Orphanet journal of rare diseases. - 2018
Activities of daily living
Cardiomyopathy
Complex I
Heart transplantation
Lactic acidosis
Mitochondrial disorder
Neonatal
Prognosis
Treatment
Vitamin
Acidosis
Activities of Daily Living
Acyl-CoA Dehydrogenase
Amino Acid Metabolism, Inborn Errors
Cardiomyopathy, Hypertrophic
Electron Transport Complex I
Female
Humans
Male
Mitochondrial Diseases
Muscle Weakness
Prognosis
Riboflavin
English
BACKGROUND
Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy.
RESULTS
We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers.
CONCLUSIONS
Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.
Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy.
RESULTS
We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers.
CONCLUSIONS
Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1186/s13023-018-0784-8
- PMID 30025539
- Persistent URL
- https://sonar.ch/global/documents/30190
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