The Use of [9,10-3H]Myristate, [9,10-3H]Palmitate and [9,10-3H]Oleate for the Detection and Diagnosis of Medium and Long-Chain Fatty Acid Oxidation Disorders in Intact Cultured Fibroblasts

Olpin, S. E.; Manning, N. J.; Pollitt, R. J.; Bonham, James R.; Downing, M; Clark, S.

doi:10.1007/0-306-46818-2_37

Cited by 23 publications

(22 citation statements)

References 5 publications

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“…18,21,24 Measurements were made at 37 °C in quadruplicate, and oxidation rates were expressed as nanomoles of fatty acid oxidized per hour per milligram of cellular protein. Original research article…”

Section: Lc-fao Flux Analysismentioning

confidence: 99%

Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

Diekman

Ferdinandusse

Pol

et al. 2015

Genetics in Medicine

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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.

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Section: Lc-fao Flux Analysismentioning

confidence: 99%

Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

Diekman

Ferdinandusse

Pol

et al. 2015

Genetics in Medicine

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“…In fibroblasts, FAO flux activities provide an estimate of the rate of mitochondrial FAO, whereas acylcarnitine profiling improves insight on both the site and the severity of the enzymatic block . In very long‐chain acyl‐CoA dehydrogenase deficiency, long‐chain FAO flux analysis in fibroblasts has been shown to correlate with the phenotype in patients using a clinical severity score . Comparable studies in fibroblasts of neonatal onset MADD‐patients demonstrated a markedly reduced FAO activity, in contrast to a less diminished or even normal flux in fibroblasts of later‐onset patients .…”

Section: Introductionmentioning

confidence: 99%

Prediction of disease severity in multiple acyl‐CoA dehydrogenase deficiency: A retrospective and laboratory cohort study

Rijt

Ferdinandusse

Giannopoulos

et al. 2019

J of Inher Metab Disea

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Summary Multiple acyl‐CoA dehydrogenase deficiency (MADD) is an ultra‐rare inborn error of mitochondrial fatty acid oxidation (FAO) and amino acid metabolism. Individual phenotypes and treatment response can vary markedly. We aimed to identify markers that predict MADD phenotypes. We performed a retrospective nationwide cohort study; then developed an MADD‐disease severity scoring system (MADD‐DS3) based on signs and symptoms with weighed expert opinions; and finally correlated phenotypes and MADD‐DS3 scores to FAO flux (oleate and myristate oxidation rates) and acylcarnitine profiles after palmitate loading in fibroblasts. Eighteen patients, diagnosed between 1989 and 2014, were identified. The MADD‐DS3 entails enumeration of eight domain scores, which are calculated by averaging the relevant symptom scores. Lifetime MADD‐DS3 scores of patients in our cohort ranged from 0 to 29. FAO flux and [U‐13C]C2‐, C5‐, and [U‐13C]C16‐acylcarnitines were identified as key variables that discriminated neonatal from later onset patients (all P < .05) and strongly correlated to MADD‐DS3 scores (oleate: r = −.86; myristate: r = −.91; [U‐13C]C2‐acylcarnitine: r = −.96; C5‐acylcarnitine: r = .97; [U‐13C]C16‐acylcarnitine: r = .98, all P < .01). Functional studies in fibroblasts were found to differentiate between neonatal and later onset MADD‐patients and were correlated to MADD‐DS3 scores. Our data may improve early prediction of disease severity in order to start (preventive) and follow‐up treatment appropriately. This is especially relevant in view of the inclusion of MADD in population newborn screening programs.

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“…Fatty acid oxidation flux was measured in fibroblasts by the tritium release assay as previously reported (Olpin et al 1999) 13 C] palmitate and Lcarnitine for 96 h, followed by quantitative acylcarnitine profiling of the incubation medium by tandem mass spectrometry essentially as previously reported (Ventura et al 1999). MCAD activity was measured in fibroblasts using phenylpropionyl-CoA as substrate, essentially as described previously (Wanders et al 2010).…”

Section: Methodsmentioning

confidence: 99%

Recurrent Ventricular Tachycardia in Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

et al. 2015

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We report a baby with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency who presented on day 2 with poor feeding and lethargy. She was floppy with hypoglycaemia (1.8 mmol/l) and hyperammonaemia (182 mmol/l). Despite correction of these and a continuous intravenous infusion of glucose at 4.5-6.2 mg/kg/min, she developed generalised tonic clonic seizures on day 3. She also suffered two episodes of pulseless ventricular tachycardia, from which she was resuscitated successfully. Unfortunately, she died on day 5, following a third episode of pulseless ventricular tachycardia.Arrhythmias are generally thought to be rarer in MCAD deficiency than in disorders of long-chain fatty acid oxidation. This is, however, the sixth report of ventricular tachyarrhythmias in MCAD deficiency. Five of these involved neonates and it may be that patients with MCAD deficiency are particularly prone to ventricular arrhythmias in the newborn period. Three of the patients (including ours) had normal blood glucose concentrations at the time of the arrhythmias and had been receiving intravenous glucose for many hours. These cases suggest that arrhythmias can be induced by medium-chain acylcarnitines or other metabolites accumulating in MCAD deficiency. Summary Sentence Ventricular tachyarrhythmias can occur in MCAD deficiency, especially in neonates.

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The Use of [9,10-3H]Myristate, [9,10-3H]Palmitate and [9,10-3H]Oleate for the Detection and Diagnosis of Medium and Long-Chain Fatty Acid Oxidation Disorders in Intact Cultured Fibroblasts

Cited by 23 publications

References 5 publications

Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

Prediction of disease severity in multiple acyl‐CoA dehydrogenase deficiency: A retrospective and laboratory cohort study

Recurrent Ventricular Tachycardia in Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

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