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
Y1 - 2015
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
U2 - https://doi.org/10.1038/gim.2015.22
DO - https://doi.org/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 -