Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?
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Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency : is riboflavin supplementation effective? / Repp, Birgit M; Mastantuono, Elisa; Alston, Charlotte L; Schiff, Manuel; Haack, Tobias B; Rötig, Agnes; Ardissone, Anna; Lombès, Anne; Catarino, Claudia B; Diodato, Daria; Schottmann, Gudrun; Poulton, Joanna; Burlina, Alberto; Jonckheere, An; Munnich, Arnold; Rolinski, Boris; Ghezzi, Daniele; Rokicki, Dariusz; Wellesley, Diana; Martinelli, Diego; Wenhong, Ding; Lamantea, Eleonora; Ostergaard, Elsebet; Pronicka, Ewa; Pierre, Germaine; Smeets, Hubert J M; Wittig, Ilka; Scurr, Ingrid; de Coo, Irenaeus F M; Moroni, Isabella; Smet, Joél; Mayr, Johannes A; Dai, Lifang; de Meirleir, Linda; Schuelke, Markus; Zeviani, Massimo; Morscher, Raphael J; McFarland, Robert; Seneca, Sara; Klopstock, Thomas; Meitinger, Thomas; Wieland, Thomas; Strom, Tim M; Herberg, Ulrike; Ahting, Uwe; Sperl, Wolfgang; Nassogne, Marie-Cecile; Ling, Han; Fang, Fang; Freisinger, Peter; Van Coster, Rudy; Strecker, Valentina; Taylor, Robert W; Häberle, Johannes; Vockley, Jerry; Prokisch, Holger; Wortmann, Saskia.
In: Orphanet Journal of Rare Diseases, Vol. 13, 120, 2018.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency
T2 - is riboflavin supplementation effective?
AU - Repp, Birgit M
AU - Mastantuono, Elisa
AU - Alston, Charlotte L
AU - Schiff, Manuel
AU - Haack, Tobias B
AU - Rötig, Agnes
AU - Ardissone, Anna
AU - Lombès, Anne
AU - Catarino, Claudia B
AU - Diodato, Daria
AU - Schottmann, Gudrun
AU - Poulton, Joanna
AU - Burlina, Alberto
AU - Jonckheere, An
AU - Munnich, Arnold
AU - Rolinski, Boris
AU - Ghezzi, Daniele
AU - Rokicki, Dariusz
AU - Wellesley, Diana
AU - Martinelli, Diego
AU - Wenhong, Ding
AU - Lamantea, Eleonora
AU - Ostergaard, Elsebet
AU - Pronicka, Ewa
AU - Pierre, Germaine
AU - Smeets, Hubert J M
AU - Wittig, Ilka
AU - Scurr, Ingrid
AU - de Coo, Irenaeus F M
AU - Moroni, Isabella
AU - Smet, Joél
AU - Mayr, Johannes A
AU - Dai, Lifang
AU - de Meirleir, Linda
AU - Schuelke, Markus
AU - Zeviani, Massimo
AU - Morscher, Raphael J
AU - McFarland, Robert
AU - Seneca, Sara
AU - Klopstock, Thomas
AU - Meitinger, Thomas
AU - Wieland, Thomas
AU - Strom, Tim M
AU - Herberg, Ulrike
AU - Ahting, Uwe
AU - Sperl, Wolfgang
AU - Nassogne, Marie-Cecile
AU - Ling, Han
AU - Fang, Fang
AU - Freisinger, Peter
AU - Van Coster, Rudy
AU - Strecker, Valentina
AU - Taylor, Robert W
AU - Häberle, Johannes
AU - Vockley, Jerry
AU - Prokisch, Holger
AU - Wortmann, Saskia
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Acidosis/genetics
KW - Activities of Daily Living
KW - Acyl-CoA Dehydrogenase/deficiency
KW - Amino Acid Metabolism, Inborn Errors/genetics
KW - Cardiomyopathy, Hypertrophic/genetics
KW - Electron Transport Complex I/metabolism
KW - Female
KW - Humans
KW - Male
KW - Mitochondrial Diseases/genetics
KW - Muscle Weakness/drug therapy
KW - Prognosis
KW - Riboflavin/therapeutic use
U2 - 10.1186/s13023-018-0784-8
DO - 10.1186/s13023-018-0784-8
M3 - Journal article
C2 - 30025539
VL - 13
JO - Orphanet Journal of Rare Diseases
JF - Orphanet Journal of Rare Diseases
SN - 1750-1172
M1 - 120
ER -
ID: 216562268