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Orphanet J Rare Dis. 2018 Jul 19;13(1):120. doi: 10.1186/s13023-018-0784-8.

Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?

Author information

1
Institute of Human Genetics, Technische Universität München, Trogerstrasse 32, 81675, Munich, Germany.
2
Institute of Human Genetics, Helmholtz Zentrum München, Munich, Germany.
3
Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.
4
UMR1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, 75019, Paris, France.
5
Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, APHP, 75019, Paris, France.
6
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
7
UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015, Paris, France.
8
Unit of Molecular Neurogenetics, Fondazione Istituto Neurologico "Carlo Besta", Milan, Italy.
9
Child Neurology, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.
10
Department of Molecular and Translational Medicine DIMET, University of Milan-Bicocca, Milan, Italy.
11
INSERM U1016, Institut Cochin, Paris, France.
12
Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-Universität München, Munich, Germany.
13
Muscular and Neurodegenerative Disorders Unit, Bambino Gesu´ Children's Hospital, IRCCS, Rome, Italy.
14
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.
15
Nuffield Department of Women's and Reproductive Health, University of Oxford, The Women's Centre, John Radcliffe Hospital, Oxford, UK.
16
Division of Inherited Metabolic Diseases, Department of Paediatrics, University Hospital of Padova, Padova, Italy.
17
Department of Pediatrics, Antwerp University Hospital, Edegem, Belgium.
18
ELBLAB GmbH, Riesa, Germany.
19
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
20
Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland.
21
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
22
Genetics and Rare Diseases Research Division, Unit of Metabolism, Bambino Gesù Children's Research Hospital, Rome, Italy.
23
Department of Pediatric cardiology, Beijing Anzhe Hospital, Captital Medical University, Beijing, China.
24
Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.
25
South West Regional Metabolic Department, Bristol Royal Hospital for Children, Bristol, BS1 3NU, UK.
26
Department of Genetics and Cell Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
27
Functional Proteomics, SFB 815 Core Unit, Faculty of Medicine, Goethe-University, Frankfurt am Main, Germany.
28
Department of Clinical Genetics, St Michael's Hospital, Bristol, UK.
29
Department of Neurology, Erasmus MC, Rotterdam, Netherlands.
30
Department of Clinical Genetics, Research School GROW, Maastricht University Medical Centre, Maastricht, The Netherlands.
31
Department of Pediatric Neurology and Metabolism, Ghent University Hospital, De Pintelaan, Ghent, Belgium.
32
Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.
33
Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
34
Research Group Reproduction and Genetics, Vrije Universiteit Brussel, Brussels, Belgium.
35
Department of Pediatric Neurology, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
36
MRC-Mitochondrial Biology Unit, Cambridge, Cambridgeshire, UK.
37
Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
38
Center for Medical Genetics, UZ Brussel, Research Group Reproduction and Genetics (REGE), Vrije Universiteit Brussel, Brussels, Belgium.
39
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
40
Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
41
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
42
Department of Pediatric Cardiology, University of Bonn, Bonn, Germany.
43
Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
44
Department of Pediatrics, Klinikum Reutlingen, Reutlingen, Germany.
45
Division of Metabolism and Children's Research Center, University Children's Hospital, Zurich, Switzerland.
46
Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, USA.
47
Institute of Human Genetics, Technische Universität München, Trogerstrasse 32, 81675, Munich, Germany. wortmann-hagemann@helmholtz-muenchen.de.
48
Institute of Human Genetics, Helmholtz Zentrum München, Munich, Germany. wortmann-hagemann@helmholtz-muenchen.de.
49
Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria. wortmann-hagemann@helmholtz-muenchen.de.

Abstract

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.

KEYWORDS:

Activities of daily living; Cardiomyopathy; Complex I; Heart transplantation; Lactic acidosis; Mitochondrial disorder; Neonatal; Prognosis; Treatment; Vitamin

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