Abstract
Very-long chain acyl-CoA dehydrogenase deficiency (VLCADD) is a clinically heterogeneous disorder with three major phenotypes: severe neonatal/infantile, milder childhood and late onset myopathic. VLCADD is genetically heterogeneous with numerous pathogenic mutations and variants of uncertain significance. VLCADD is included in many newborn screening programs but these suffer from high false positive rates, primarily due to positive screens in heterozygotes. Separating these and newborns with two low-risk “mild” variants from clinically at risk patients can be problematic, as clinical and biochemical markers are often unreliable, particularly in stable neonates. We have measured fibroblast fatty acid oxidation flux using [9,10-H3]myristic acid and [9,10-H3]oleic acid from 69 clinically presenting VLCADD patients including myopathic and infantile phenotypes and 13 positive newborn screened patients. We also measured fibroblast VLCADD enzyme activity by UV-HPLC detection of product in a sub-set of patients and compared these results to oleate FAO-flux. Fibroblast enzyme assay by UV-HPLC detection failed to clearly discriminate between some clinically presenting VLCADD patient cell lines and cell lines from some simple heterozygotes. FAO-flux clearly discriminated between clinically presenting VLCADD patients and the false positive screened patients. FAO-flux at 37 °C provides information as to the likely clinical phenotype but FAO-flux at 41 °C is the best discriminator for identifying clinically at risk patients.
Highlights
Newborn (NB) screening programs in much of Europe and in other countries around the world including the USA, Canada, New Zealand and Australia include very long-chain acyl-CoA dehydrogenase deficiency (VLCADD OMIM 201475) [1,2,3,4,5]
Very-long chain acyl-CoA dehydrogenase deficiency (VLCADD) can present with three major phenotypes: a severe neonatal/infantile form, with early onset non-ketotic hypoglycemia, a high incidence of cardiomyopathy and high mortality; a milder childhood form, usually with hypoketotic hypoglycemia as the main presenting feature, often with exercise intolerance; and rhabdomyolysis, in older children, and a late onset myopathic form in adults [7,8]
Newborn screening for VLCADD suffers from a high false positive rate due to false positive results in many heterozygotes and to elevated acylcarnitines including C14:1 in some catabolic neonates even in the absence of ACADVL mutations
Summary
Newborn (NB) screening programs in much of Europe and in other countries around the world including the USA, Canada, New Zealand and Australia include very long-chain acyl-CoA dehydrogenase deficiency (VLCADD OMIM 201475) [1,2,3,4,5]. This, in conjunction with unreliable biochemical markers, not infrequently poses real difficulties in separating infants at risk of disease from those who do not require continued intervention or follow up [11,12,13]. Functional assays such as very long-chain acyl-CoA dehydrogenase (VLCAD) activity in lymphocytes or acylcarnitine profiles following palmitate loading in fibroblasts are useful tools in these difficult cases, though they are by no means always definitive [11,14,15,16,17]. We report fatty acid oxidation flux (FAO-flux) by measuring [9,10-H3]myristic acid and [9,10-H3]oleic acid oxidation in fibroblast cell lines from several patient groups and compare results of FAO-flux with fibroblast VLCADD enzyme activity
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