Abstract
Background: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is included in many newborn screening programmes worldwide. In addition to the prevalent mutation c.985A>G in the ACADM gene, potentially mild mutations like c.199T>C are frequently found in screening cohorts. There is ongoing discussion whether this mutation is associated with a clinical phenotype.
Methods: In 37 MCADD patients detected by newborn screening, biochemical phenotype (octanoylcarnitine (C8), ratios of C8 to acetylcarnitine (C2), decanoylcarnitine (C10) and dodecanoylcarnitine (C12) at screening and confirmation) and clinical phenotype (inpatient emergency treatment, metabolic decompensations, clinical assessments, psychometric tests) were assessed in relation to genotype.
Results: 16 patients were homozygous for c.985A>G (group 1), 11 compound heterozygous for c.199T>C and c.985A>G/another mutation (group 2) and 7 compound heterozygous for c.985A>G and mutations other than c.199T>C (group 3) and 3 carried neither c.985A>G nor c.199T>C but other known homozygous mutations (group 4). At screening C8/C2 and C8/C10, at confirmation C8/C2, C8/C10 and C8/C12 differed significantly between patients compound heterozygous for c.199T>C (group 2) and other genotypes. C8, C10 and C8/C2 at screening were strongly associated with time of sampling in groups 1 + 3 + 4, but not in group 2. Clinical phenotype did not differ between genotypes. Two patients compound heterozygous for c.199T>C and a severe mutation showed neonatal decompensation with hypoglycaemia.
Conclusion: Biochemical phenotype differs between MCADD patients compound heterozygous for c.199T>C with a severe mutation and other genotypes. In patients detected by newborn screening, clinical phenotype does not differ between genotypes following uniform treatment recommendations. Neonatal decompensation can also occur in patients with the presumably mild mutation c.199T>C prior to diagnosis.
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Acknowledgements
This study was made possible by the continuous and generous support of the Dietmar Hopp Foundation, St. Leon-Rot.
The authors thank all patients and their families for their participation and trust.
Many thanks to all the colleagues who provided information on their patients: U. Wendel, E. Thimm (Düsseldorf), E. Mengel (Mainz), F.K. Trefz (Reutlingen) and M. Baumgartner (Zürich).
Enzyme activity in patients 18 and 29 was analysed by Prof. Wanders, AMC, Amsterdam, the Netherlands, and in patients 17 and 28 by Prof. Spiekerkötter at the University Children’s Hospital, Düsseldorf, Germany.
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Communicated by: Rodney Pollitt, PhD
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Take-Home Message
Biochemical but not clinical phenotype differs between MCADD patients with different genotypes detected by newborn screening following uniform treatment recommendations. Neonatal decompensation can also occur in patients carrying the presumably mild mutation c.199T>C compound heterozygous with a severe mutation prior to diagnosis.
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G. Gramer received support for travel expenses to a scientific meeting from Merck Serono.
G. Haege reports no disclosures.
J. Fang-Hoffmann reports no disclosures.
G.F. Hoffmann received lecture fees from Nutricia, Friedrichsdorf i.T.
C. R. Bartram reports no disclosures.
K. Hinderhofer reports no disclosures.
P. Burgard is member of an advisory board for Merck Serono, Darmstadt, and received lecture fees from Merck Serono, Darmstadt; Vitaflo, Bad Homburg; and Nutricia, Friedrichsdorf i.T.
M. Lindner received lecture fees from Orphan Europe, Milupa and Nutricia.
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Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients/their parents for being included in the study. The study was approved by the University Hospital Heidelberg ethical committee (IRB code 104/2005).
Authors’ Contributions
G. Gramer: Study design; recruitment of patients; collection, evaluation and interpretation of data; drafting and writing the manuscript
G. Haege: Statistical analysis; evaluation and interpretation of data; writing and revision of the manuscript
J. Fang-Hoffmann: Data collection; revision of the manuscript
G. F. Hoffmann: Study design; evaluation and interpretation of data; revision of the manuscript
C. R. Bartram: Molecular genetic analyses; revision of the manuscript
K. Hinderhofer: Molecular genetic analyses; revision of the manuscript
P. Burgard: Study design; recruitment of patients; collection, evaluation and interpretation of data; statistical analysis; revision of the manuscript
M. Lindner: Study design; recruitment of patients; collection, evaluation and interpretation of data; revision of the manuscript
All authors approved the final version of the manuscript.
G. Gramer serves as guarantor for the article.
Funding
This study was supported by the Dietmar Hopp Foundation, St. Leon-Rot, Germany. The authors confirm independence from the sponsor; the content of the article has not been influenced by the sponsor.
G. Gramer was supported by a research scholarship (Olympia Morata Programme) of the Medical Faculty of the University of Heidelberg.
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Gramer, G. et al. (2015). Medium-Chain Acyl-CoA Dehydrogenase Deficiency: Evaluation of Genotype-Phenotype Correlation in Patients Detected by Newborn Screening. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 23. JIMD Reports, vol 23. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_439
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