Abstract
Deficiency of the mitochondrial trifunctional protein (TFP) and long-chain 3-Hydroxy Acyl-CoA dehydrogenase (LCHAD) impairs long-chain fatty acid oxidation and presents with hypoglycemia, cardiac, liver, eye, and muscle involvement. Without treatment, both conditions can be life-threatening. These diseases are identified by newborn screening (NBS), but the impact of early treatment on long-term clinical outcome is unknown. Moreover, there is lack of consensus on treatment, particularly on the use of carnitine supplementation. Here, we report clinical and biochemical data in five patients with TFP/LCHAD deficiency, three of whom were diagnosed by newborn screening. All patients had signs and symptoms related to their metabolic disorder, including hypoglycemia, elevated creatine kinase (CK), and rhabdomyolysis, and experienced episodes of metabolic decompensation triggered by illness. Treatment was started shortly after diagnosis in all patients and consisted of a diet low in long-chain fats supplemented with medium chain triglycerides (MCT), essential fatty acids, and low-dose carnitine (25 mg/kg/day). Patients had growth restriction early in life that resolved after 2 years of age. All patients but the youngest (2 years old) developed pigmentary retinopathy. Long-chain hydroxylated acylcarnitines did not change significantly with age, but increased during acute illnesses. Free carnitine levels were maintained within the normal range and did not correlate with long-chain hydroxylated acylcarnitines. These results show that patients with LCHAD deficiency can have normal growth and development with appropriate treatment. Low-dose carnitine supplements prevented carnitine deficiency and did not result in increased long-chain hydroxylated acylcarnitines or any specific toxicity.
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References
American College of Medical Genetics Newborn Screening Expert Group (2006) Newborn screening: toward a uniform screening panel and system--executive summary. Pediatrics 117:S296–S307
Bakermans AJ, van Weeghel M, Denis S, Nicolay K, Prompers JJ, Houten SM (2013) Carnitine supplementation attenuates myocardial lipid accumulation in long-chain acyl-CoA dehydrogenase knockout mice. J Inherit Metab Dis 36:973–981
Borghi E, de Onis M, Garza C et al (2006) Construction of the World Health Organization child growth standards: selection of methods for attained growth curves. Stat Med 25:247–265
den Boer ME, Wanders RJ, IJlst L, Morris AA, Heymans HS, Wijburg FA (2002) Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients. Pediatrics 109:99–104
Fahnehjelm KT, Holmstrom G, Ying L et al (2008) Ocular characteristics in 10 children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a cross-sectional study with long-term follow-up. Acta Ophthalmol 86:329–337
Gillingham MB, Connor WE, Matern D et al (2003) Optimal dietary therapy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Mol Genet Metab 79:114–123
Gillingham MB, Weleber RG, Neuringer M et al (2005) Effect of optimal dietary therapy upon visual function in children with long-chain 3-hydroxyacyl CoA dehydrogenase and trifunctional protein deficiency. Mol Genet Metab 86:124–133
Haglind CB, Stenlid MH, Ask S et al (2013) Growth in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. JIMD Rep 8:81–90
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 1215:347–350
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 19:165–168
IJlst L, Oostheim W, Ruiter JP, Wanders RJ (1997) Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of two new mutations. J Inherit Metab Dis 20:420–422
Karall D, Brunner-Krainz M, Kogelnig K et al (2015) Clinical outcome, biochemical and therapeutic follow-up in 14 Austrian patients with Long-Chain 3-Hydroxy Acyl CoA Dehydrogenase Deficiency (LCHADD). Orphanet J Rare Dis 10:21
Kuczmarski RJ, Ogden CL, Grummer-Strawn LM et al (2000) CDC growth charts: United States. Adv Data 314:1–27
Potter BK, Little J, Chakraborty P et al (2012) Variability in the clinical management of fatty acid oxidation disorders: results of a survey of Canadian metabolic physicians. J Inherit Metab Dis 35:115–123
Primassin S, Ter Veld F, Mayatepek E, Spiekerkoetter U (2008) Carnitine supplementation induces acylcarnitine production in tissues of very long-chain acyl-CoA dehydrogenase deficient mice, without replenishing low free carnitine. Pediatr Res 63:632–637
Rocchiccioli F, Wanders RJ, Aubourg P et al (1990) Deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase: a cause of lethal myopathy and cardiomyopathy in early childhood. Pediatr Res 28(6):657–662
Spiekerkoetter U, Lindner M, Santer R et al (2009) Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from a workshop. J Inherit Metab Dis 32:488–497
Tucci S, Flögel U, Hermann S, Sturm M, Schäfers M, Spiekerkoetter U (2014) Development and pathomechanisms of cardiomyopathy in very long-chain acyl-CoA dehydrogenase deficient (VLCAD−/−) mice. Biochim Biophys Acta 1842:677–685
Wanders RJ, IJ L, van Gennip AH et al (1990) Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of a new inborn error of mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis 13:311–314
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This work was supported by the ARUP Institute for Clinical and Experimental Pathology®.
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Communicated by: Jerry Vockley, M.D., Ph.D.
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Synopsis
Patients with mitochondrial trifunctional protein or long-chain 3-Hydroxy Acyl-CoA dehydrogenase deficiency can achieve normal growth and development with proper treatment, which includes diet and low-dose carnitine supplements.
Individual Authors’ Contributions
IDB, MP, and NL designed the study; NL, KSV, and LB collected the data; IDB, AL, TY, and MP contributed with data collection and interpretation; IDB, KSV, and NL wrote the manuscript. All authors were involved in revising the manuscript critically for content.
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This work was supported by the ARUP Institute for Clinical and Experimental Pathology®. The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.
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Irene De Biase declares that she has no conflict of interest.
Krista S. Viau declares that she has no conflict of interest.
Aiping Liu declares that she has no conflict of interest.
Tatiana Yuzyuk declares that she has no conflict of interest.
Lorenzo D. Botto declares that he has no conflict of interest.
Marzia Pasquali declares that she has no conflict of interest.
Nicola Longo declares that he has no conflict of interest.
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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 waived by our Institutional Review Board in view of the retrospective nature of the study and the minimal risks to patients.
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This article does not contain any studies with animal subjects performed by any of the authors.
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De Biase, I. et al. (2016). Diagnosis, Treatment, and Clinical Outcome of Patients with Mitochondrial Trifunctional Protein/Long-Chain 3-Hydroxy Acyl-CoA Dehydrogenase Deficiency. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 31. JIMD Reports, vol 31. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2016_558
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DOI: https://doi.org/10.1007/8904_2016_558
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