Genetics in medicine : official journal of the American College of Medical Genetics · 2015
Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency.
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Diekman Eugene F, Ferdinandusse Sacha, van der Pol Ludo, Waterham Hans R, Ruiter Jos P N, Ijlst Lodewijk, Wanders Ronald J, Houten Sander M, Wijburg Frits A, Blank A Christiaan, Asselbergs Folkert W, Houtkooper Riekelt H, Visser Gepke
Аннотация
PURPOSE: Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an inherited disorder of mitochondrial long-chain fatty acid β-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.
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.
Предметные рубрики MeSH
3-Hydroxyacyl CoA DehydrogenasesAcetyl-CoA C-AcyltransferaseAcyl-CoA Dehydrogenase, Long-ChainBiomarkersCarbon-Carbon Double Bond IsomerasesCongenital Bone Marrow Failure SyndromesDenmarkEnoyl-CoA HydrataseHumansInfant, NewbornLipid Metabolism, Inborn ErrorsMitochondrial DiseasesMuscular DiseasesNeonatal ScreeningOxidation-ReductionRacemases and EpimerasesSeverity of Illness Index