Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

Eugene F. Diekman; Sacha Ferdinandusse; Ludo van der Pol; Hans R. Waterham; Jos P. N. Ruiter; Lodewijk Ijlst; Ronald J. Wanders; Sander M. Houten; Frits A. Wijburg; A. Christiaan Blank; Folkert W. Asselbergs; Riekelt H. Houtkooper; Gepke Visser

doi:10.1038/gim.2015.22

Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

Eugene F. Diekman, Sacha Ferdinandusse, Ludo van der Pol, Hans R. Waterham, Jos P. N. Ruiter, Lodewijk Ijlst, Ronald J. Wanders, Sander M. Houten, Frits A. Wijburg, A. Christiaan Blank, Folkert W. Asselbergs, Riekelt H. Houtkooper, Gepke Visser^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Purpose: Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an inherited disorder of mitochondrial long-chain fatty acid beta-oxidation (LC-FAO) and is included in many newborn screening (NBS) programs worldwide. Patients may-present with hypoketotic hypoglycemia, cardiomyopathy, and/or myopathy, but clinical severity varies widely and the clinical outcome is -unpredictable. We investigated predictive markers that may determine clinical severity.

Methods: We developed a clinical severity score (CSS), which was determined for 13 Dutch patients with VLCADD, all of whom were diagnosed before the introduction of VLCADD in NBS to prevent bias from early diagnosis. In cultured skin fibroblasts from these patients, we measured LC-FAO flux (the rate of oleate oxidation), VLCAD activity, and acylcarnitine profiles following palmitate loading.

Results: The strongest correlation (r = 0.93; P <0.0001) was observed between LC-FAO flux and the CSS. VLCAD activity -measurement and the C14/C16-to-acylcarnitine ratio correlated much less. A median LC-FAO flux of 6% of control values (range 5.6-6.8%) was associated with cardiomyopathy (P <0.01), and 32.4% (range 5.6-50.5%) was associated with myopathy (P <0.05).

Conclusion: Our results demonstrate a very strong correlation between LC-FAO flux in fibroblasts and the clinical severity of VLCADD. LC-FAO flux measurements may thus predict whether patients are likely to develop symptoms.

Original language	English
Pages (from-to)	989-994
Number of pages	6
Journal	Genetics in Medicine
Volume	17
Issue number	12
DOIs	https://doi.org/10.1038/gim.2015.22
Publication status	Published - Dec 2015

Keywords

clinical severity score
newborn screening
oleate oxidation
predictive marker
VLCAD deficiency
COA DEHYDROGENASE-DEFICIENCY
INTACT CULTURED FIBROBLASTS
BETA-OXIDATION
DEFECTS
DISORDERS
NEWBORN
DIAGNOSIS
PHENOTYPE
GENOTYPE
CELLS

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10.1038/gim.2015.22

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Diekman, E. F., Ferdinandusse, S., van der Pol, L., Waterham, H. R., Ruiter, J. P. N., Ijlst, L., Wanders, R. J., Houten, S. M., Wijburg, F. A., Blank, A. C., Asselbergs, F. W., Houtkooper, R. H., & Visser, G. (2015). Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency. Genetics in Medicine, 17(12), 989-994. https://doi.org/10.1038/gim.2015.22

@article{0651aac4cf0e43e4936c32ee2a48c7af,

title = "Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency",

abstract = "Purpose: Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an inherited disorder of mitochondrial long-chain fatty acid beta-oxidation (LC-FAO) and is included in many newborn screening (NBS) programs worldwide. Patients may-present with hypoketotic hypoglycemia, cardiomyopathy, and/or myopathy, but clinical severity varies widely and the clinical outcome is -unpredictable. We investigated predictive markers that may determine clinical severity.Methods: We developed a clinical severity score (CSS), which was determined for 13 Dutch patients with VLCADD, all of whom were diagnosed before the introduction of VLCADD in NBS to prevent bias from early diagnosis. In cultured skin fibroblasts from these patients, we measured LC-FAO flux (the rate of oleate oxidation), VLCAD activity, and acylcarnitine profiles following palmitate loading.Results: The strongest correlation (r = 0.93; P <0.0001) was observed between LC-FAO flux and the CSS. VLCAD activity -measurement and the C14/C16-to-acylcarnitine ratio correlated much less. A median LC-FAO flux of 6% of control values (range 5.6-6.8%) was associated with cardiomyopathy (P <0.01), and 32.4% (range 5.6-50.5%) was associated with myopathy (P <0.05).Conclusion: Our results demonstrate a very strong correlation between LC-FAO flux in fibroblasts and the clinical severity of VLCADD. LC-FAO flux measurements may thus predict whether patients are likely to develop symptoms.",

keywords = "clinical severity score, newborn screening, oleate oxidation, predictive marker, VLCAD deficiency, COA DEHYDROGENASE-DEFICIENCY, INTACT CULTURED FIBROBLASTS, BETA-OXIDATION, DEFECTS, DISORDERS, NEWBORN, DIAGNOSIS, PHENOTYPE, GENOTYPE, CELLS",

author = "Diekman, {Eugene F.} and Sacha Ferdinandusse and {van der Pol}, Ludo and Waterham, {Hans R.} and Ruiter, {Jos P. N.} and Lodewijk Ijlst and Wanders, {Ronald J.} and Houten, {Sander M.} and Wijburg, {Frits A.} and Blank, {A. Christiaan} and Asselbergs, {Folkert W.} and Houtkooper, {Riekelt H.} and Gepke Visser",

year = "2015",

month = dec,

doi = "10.1038/gim.2015.22",

language = "English",

volume = "17",

pages = "989--994",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Lippincott Williams & Wilkins",

number = "12",

}

TY - JOUR

T1 - Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

AU - Diekman, Eugene F.

AU - Ferdinandusse, Sacha

AU - van der Pol, Ludo

AU - Waterham, Hans R.

AU - Ruiter, Jos P. N.

AU - Ijlst, Lodewijk

AU - Wanders, Ronald J.

AU - Houten, Sander M.

AU - Wijburg, Frits A.

AU - Blank, A. Christiaan

AU - Asselbergs, Folkert W.

AU - Houtkooper, Riekelt H.

AU - Visser, Gepke

PY - 2015/12

Y1 - 2015/12

N2 - Purpose: Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an inherited disorder of mitochondrial long-chain fatty acid beta-oxidation (LC-FAO) and is included in many newborn screening (NBS) programs worldwide. Patients may-present with hypoketotic hypoglycemia, cardiomyopathy, and/or myopathy, but clinical severity varies widely and the clinical outcome is -unpredictable. We investigated predictive markers that may determine clinical severity.Methods: We developed a clinical severity score (CSS), which was determined for 13 Dutch patients with VLCADD, all of whom were diagnosed before the introduction of VLCADD in NBS to prevent bias from early diagnosis. In cultured skin fibroblasts from these patients, we measured LC-FAO flux (the rate of oleate oxidation), VLCAD activity, and acylcarnitine profiles following palmitate loading.Results: The strongest correlation (r = 0.93; P <0.0001) was observed between LC-FAO flux and the CSS. VLCAD activity -measurement and the C14/C16-to-acylcarnitine ratio correlated much less. A median LC-FAO flux of 6% of control values (range 5.6-6.8%) was associated with cardiomyopathy (P <0.01), and 32.4% (range 5.6-50.5%) was associated with myopathy (P <0.05).Conclusion: Our results demonstrate a very strong correlation between LC-FAO flux in fibroblasts and the clinical severity of VLCADD. LC-FAO flux measurements may thus predict whether patients are likely to develop symptoms.

AB - Purpose: Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an inherited disorder of mitochondrial long-chain fatty acid beta-oxidation (LC-FAO) and is included in many newborn screening (NBS) programs worldwide. Patients may-present with hypoketotic hypoglycemia, cardiomyopathy, and/or myopathy, but clinical severity varies widely and the clinical outcome is -unpredictable. We investigated predictive markers that may determine clinical severity.Methods: We developed a clinical severity score (CSS), which was determined for 13 Dutch patients with VLCADD, all of whom were diagnosed before the introduction of VLCADD in NBS to prevent bias from early diagnosis. In cultured skin fibroblasts from these patients, we measured LC-FAO flux (the rate of oleate oxidation), VLCAD activity, and acylcarnitine profiles following palmitate loading.Results: The strongest correlation (r = 0.93; P <0.0001) was observed between LC-FAO flux and the CSS. VLCAD activity -measurement and the C14/C16-to-acylcarnitine ratio correlated much less. A median LC-FAO flux of 6% of control values (range 5.6-6.8%) was associated with cardiomyopathy (P <0.01), and 32.4% (range 5.6-50.5%) was associated with myopathy (P <0.05).Conclusion: Our results demonstrate a very strong correlation between LC-FAO flux in fibroblasts and the clinical severity of VLCADD. LC-FAO flux measurements may thus predict whether patients are likely to develop symptoms.

KW - clinical severity score

KW - newborn screening

KW - oleate oxidation

KW - predictive marker

KW - VLCAD deficiency

KW - COA DEHYDROGENASE-DEFICIENCY

KW - INTACT CULTURED FIBROBLASTS

KW - BETA-OXIDATION

KW - DEFECTS

KW - DISORDERS

KW - NEWBORN

KW - DIAGNOSIS

KW - PHENOTYPE

KW - GENOTYPE

KW - CELLS

U2 - 10.1038/gim.2015.22

DO - 10.1038/gim.2015.22

M3 - Article

C2 - 25834949

SN - 1098-3600

VL - 17

SP - 989

EP - 994

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 12

ER -

Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

Abstract

Keywords

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