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@ARTICLE{Repp:140094,
author = {Repp, Birgit M and Mastantuono, Elisa and Alston, Charlotte
L and Schiff, Manuel and Haack, Tobias B and Rötig, Agnes
and Ardissone, Anna and Lombès, Anne and Catarino, Claudia
B and Diodato, Daria and Schottmann, Gudrun and Poulton,
Joanna and Burlina, Alberto and Jonckheere, An and Munnich,
Arnold and Rolinski, Boris and Ghezzi, Daniele and Rokicki,
Dariusz and Wellesley, Diana and Martinelli, Diego and
Wenhong, Ding and Lamantea, Eleonora and Ostergaard, Elsebet
and Pronicka, Ewa and Pierre, Germaine and Smeets, Hubert J
M and Wittig, Ilka and Scurr, Ingrid and de Coo, Irenaeus F
M and Moroni, Isabella and Smet, Joél and Mayr, Johannes A
and Dai, Lifang and de Meirleir, Linda and Schuelke, Markus
and Zeviani, Massimo and Morscher, Raphael J and McFarland,
Robert and Seneca, Sara and Klopstock, Thomas and Meitinger,
Thomas and Wieland, Thomas and Strom, Tim M and Herberg,
Ulrike and Ahting, Uwe and Sperl, Wolfgang and Nassogne,
Marie-Cecile and Ling, Han and Fang, Fang and Freisinger,
Peter and Van Coster, Rudy and Strecker, Valentina and
Taylor, Robert W and Häberle, Johannes and Vockley, Jerry
and Prokisch, Holger and Wortmann, Saskia},
title = {{C}linical, biochemical and genetic spectrum of 70 patients
with {ACAD}9 deficiency: is riboflavin supplementation
effective?},
journal = {Orphanet journal of rare diseases},
volume = {13},
number = {1},
issn = {1750-1172},
address = {London},
publisher = {BioMed Central},
reportid = {DZNE-2020-06416},
pages = {120},
year = {2018},
abstract = {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.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cohort of 70 patients, of whom 29 previously unpublished.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.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 = {Acidosis: genetics / Acidosis: metabolism / Acidosis:
pathology / Activities of Daily Living / Acyl-CoA
Dehydrogenase: deficiency / Acyl-CoA Dehydrogenase: genetics
/ Acyl-CoA Dehydrogenase: metabolism / Amino Acid
Metabolism, Inborn Errors: genetics / Amino Acid Metabolism,
Inborn Errors: metabolism / Amino Acid Metabolism, Inborn
Errors: pathology / Cardiomyopathy, Hypertrophic: genetics /
Cardiomyopathy, Hypertrophic: metabolism / Cardiomyopathy,
Hypertrophic: pathology / Electron Transport Complex I:
metabolism / Female / Humans / Male / Mitochondrial
Diseases: genetics / Mitochondrial Diseases: metabolism /
Mitochondrial Diseases: pathology / Muscle Weakness: drug
therapy / Muscle Weakness: genetics / Muscle Weakness:
metabolism / Muscle Weakness: pathology / Prognosis /
Riboflavin: therapeutic use / Acyl-CoA Dehydrogenase (NLM
Chemicals) / Electron Transport Complex I (NLM Chemicals) /
Riboflavin (NLM Chemicals)},
cin = {AG Levin},
ddc = {610},
cid = {I:(DE-2719)1111016},
pnm = {899H - Addenda (POF3-899H)},
pid = {G:(DE-HGF)POF3-899H},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:30025539},
pmc = {pmc:PMC6053715},
doi = {10.1186/s13023-018-0784-8},
url = {https://pub.dzne.de/record/140094},
}