Abstract
The aim of our study was to evaluate the prevalence of long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) in the general Estonian population and among patients with symptoms suggestive of fatty acid oxidation (FAO) defects. We collected DNA from a cohort of 1,040 anonymous newborn blood spot samples. We screened these samples for the presence of the common c.1528G>C mutation in the HADHA gene. Based on the clinical suspicion of FAO defects, we screened suspected individuals since 2004 for the common c.1528G>C mutation in the HADHA gene and since 2008 in addition by tandem mass spectrometric analysis of plasma acylcarnitines. Our results showed that the carrier frequency of the c.1528G>C mutation in the Estonian population is high – 1:173. During the screening of symptomatic patients, we identified five LCHADD patients in four families. Three patients were retrospectively identified by molecular screening of the HADHA gene. One patient was homozygous for the c.1528G>C mutation in the HADHA gene, and two siblings were compound heterozygotes with HADHA genotype c.[1528G>C]+[1690-2A>G]. Among patients tested using acylcarnitine profiling, we identified two cases with an abnormal acylcarnitine profile typical to LCHADD. Molecular analysis showed homozygosity for c.1528G>C mutation. Based on a carrier frequency of 1:173 (95% Confidence Interval 1:76–1:454) and taking into account that the c.1528G>C mutation makes up 87.5% of disease alleles in Estonian LCHADD patients, the estimated prevalence of LCHADD in Estonia would be 1: 91,700.
Competing interest: None declared.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- LCHADD:
-
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
- FAO:
-
Fatty acid oxidation
References
Carpenter K, Middleton B, Pollitt R (1992a) Purification of long-chain 3-hydroxyacyl-CoA dehydrogenase from human infant liver. Prog Clin Biol Res 375:75–84
Carpenter K, Pollitt RJ, Middleton B (1992b) Human liver long-chain 3-hydroxyacyl-coenzyme A dehydrogenase is a multifunctional membrane-bound beta-oxidation enzyme of mitochondria. Biochem Biophys Res Commun 183(2):443–448
den Boer ME, Ijlst L, Wijburg FA, Oostheim W, van Werkhoven MA, van Pampus MG et al (2000) Heterozygosity for the common LCHAD mutation (1528g>C) is not a major cause of HELLP syndrome and the prevalence of the mutation in the Dutch population is low. Pediatr Res 48(2):151–154
den Boer ME, Wanders RJ, Morris AA, Ijlst L, Heymans HS, Wijburg FA (2002) Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients. Pediatrics 109(1):99–104
Duran M (2003) Disorders of mitochondrial fatty acid oxidation and ketone handling. In: Blau N, Duran M, Blaskovich ME, Gibson KM (eds) Physician’s guide to the laboratory diagnosis of metabolic diseases, 2nd edn. Springer, Berlin, pp 309–334
Gregersen N, Olsen RK (2010) Disease mechanisms and protein structures in fatty acid oxidation defects. J Inherit Metab Dis 33(5):547–553
Hagenfeldt L, Venizelos N, von Dobeln U (1995) Clinical and biochemical presentation of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. J Inherit Metab Dis 18(2):245–248
Ijlst L, Ruiter JP, Vreijling J, Wanders RJ (1996) Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a new method to identify the G1528C mutation in genomic DNA showing its high frequency (approximately 90%) and identification of a new mutation (T2198C). J Inherit Metab Dis 19(2):165–168
Ijlst L, Wanders RJ, Ushikubo S, Kamijo T, Hashimoto T (1994) Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of the major disease-causing mutation in the alpha-subunit of the mitochondrial trifunctional protein. Biochim Biophys Acta 1215(3):347–350
Kamijo T, Wanders RJ, Saudubray JM, Aoyama T, Komiyama A, Hashimoto T (1994) Mitochondrial trifunctional protein deficiency. Catalytic heterogeneity of the mutant enzyme in two patients. J Clin Invest 93(4):1740–1747. doi:10.1172/JCI117158
Laugesaar R, Kahre T, Kolk A, Uustalu U, Kool P, Talvik T (2010) Factor V Leiden and prothrombin 20210G>A [corrected] mutation and paediatric ischaemic stroke: a case-control study and two meta-analyses. Acta Paediatr 99(8):1168–1174
Lindner M, Hoffmann GF, Matern D (2010) Newborn screening for disorders of fatty-acid oxidation: experience and recommendations from an expert meeting. J Inherit Metab Dis 33(5):521–526
Matern D (2008) Acylcarnitines, including in vitro loading tests. In: Blau N, Duran M, Gibson KM (eds) Laboratory guide to the methods in biochemical genetics. Springer, Berlin, pp 171–206
Olpin SE, Clark S, Andresen BS, Bischoff C, Olsen RK, Gregersen N et al (2005) Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency. J Inherit Metab Dis 28(4):533–544. doi:10.1007/s10545-005-0533-8
Piekutowska-Abramczuk D, Olsen RK, Wierzba J, Popowska E, Jurkiewicz D, Ciara E et al (2010) A comprehensive HADHA c.1528G>C frequency study reveals high prevalence of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency in Poland. J Inherit Metab Dis doi:10.1007/s10545-010-9190-7
Sander J, Sander S, Steuerwald U, Janzen N, Peter M, Wanders RJ et al (2005) Neonatal screening for defects of the mitochondrial trifunctional protein. Mol Genet Metab 85(2):108–114
Saudubray JM, Martin D, de Lonlay P, Touati G, Poggi-Travert F, Bonnet D et al (1999) Recognition and management of fatty acid oxidation defects: a series of 107 patients. J Inherit Metab Dis 22(4):488–502
Sims HF, Brackett JC, Powell CK, Treem WR, Hale DE, Bennett MJ et al (1995) The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy. Proc Natl Acad Sci USA 92(3):841–845
Teek R, Kruustuk K, Zordania R, Joost K, Reimand T, Mols T et al (2010) Prevalence of c.35delG and p.M34T mutations in the GJB2 gene in Estonia. Int J Pediatr Otorhinolaryngol 74(9):1007–1012
Tyni T, Pihko H (1999) Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Acta Paediatr 88(3):237–245
Wanders RJ, Duran M, Ijlst L, de Jager JP, van Gennip AH, Jakobs C et al (1989) Sudden infant death and long-chain 3-hydroxyacyl-CoA dehydrogenase. Lancet 2(8653):52–53
Zhu JM, Yang Z, Yu M, Wang R, Ye RH, Yang HX et al (2005) Screening for the G1528C mutation in long chain fatty acid oxidation enzyme in Han nationality in Beijing population. Beijing Da Xue Xue Bao 37(1):72–74
Acknowledgements
This research was supported by the Estonian Science Foundation SF0180044s09, SF0182695s05 GARBK 7494 and GARLA 8175 grants. The study by K. Joost in Amsterdam MC in The Netherlands was partly supported by the Archimedes Foundation. We thank Prof. E. Mönch from the Charité-Virchow Klinikum in Berlin, Germany for performing the acylcarnitine analysis. We are grateful to E. Roomets for her technical assistance. We thank David Hougaard of the Department of Clinical Biochemistry and Immunology, Statens Serum Institute in Copenhagen, Denmark for providing dried bloodspots collected from the general Danish population.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Jerry Vockley.
Appendices
Concise One-Sentence Take-Home Message
The carrier frequency of the c.1528G>C mutation in the HADHA gene in the Estonian population is 1:173.
Abbreviated Title
LCHADD in Estonia
References to Electronic Databases
OMIM #609016
Details of the Contributions Made by Individual Authors
K. Joost – development of method and performance of tandem MS analysis of acylcarnitines of all investigated individuals, diagnosis of suspected and confirmed cases, compilation of manuscript, treatment of a patient with LCHAD deficiency.
K. Õunap – planning of study, selection of suspected cases, moderation of cooperation between different centers, diagnosis of suspected patients, compilation of manuscript
R. Žordania – selection of suspected cases, diagnosis and evaluation of a family with LCHAD deficiency
M.-L. Uudelepp – evaluation and treatment of a patient with LCHAD deficiency
R.K. Olsen – sequencing of HADHA gene
K. Kall – performance of organic acid GC/MS analyses during the confirmation/exclusion of suspected LCHADD cases
K. Kilk – development of tandem MS analysis of acylcarnitines
U. Soomets – planning of strategy for biochemical diagnosis using tandem MS
T. Kahre – performance of molecular analysis for main mutation in HADHA gene in all investigated individuals, compilation of manuscript
Guarantor of Article
Kairit Joost
Statement of Competing Interest
All of the authors confirm that they have no competing interests to declare. There is no financial or nonfinancial interest in publishing this article.
Details of Funding
This work was supported by the SF0180044s09, SF0182695s05 GARBK 7494 and GARLA 8175 grants from the Estonian Science Foundation.
Details of the Ethics Approval
The Ethics Review Committee on Human Research of the University of Tartu approved the study.
Patient Consent Statement
Informed consent was obtained from the parents of the children involved in the research.
Rights and permissions
Copyright information
© 2011 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Joost, K. et al. (2011). Prevalence of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency in Estonia. In: JIMD Reports - Case and Research Reports, 2011/2. JIMD Reports, vol 2. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2011_51
Download citation
DOI: https://doi.org/10.1007/8904_2011_51
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-24757-6
Online ISBN: 978-3-642-24758-3
eBook Packages: MedicineMedicine (R0)