Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

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

doi:10.1038/gim.2015.22

Cited by 47 publications

(63 citation statements)

References 30 publications

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“…Because these findings are based on a Dutch patient population containing a homogenous set of mutations, it would be expedient to repeat our studies in populations with different genotypes to confirm our findings. The potential to increase residual enzyme activity in fibroblasts cultured at a low temperature has been reported previously in the context of other genetic diseases, including MPS IIIB 16, 27, 28. The increase in SGSH activity in the fibroblasts of SP patients was up to 43% of the lower limit of normal activity.…”

Section: Discussionsupporting

confidence: 64%

Prediction of phenotypic severity in mucopolysaccharidosis type IIIA

Knottnerus

Nijmeijer

IJlst

et al. 2017

Annals of Neurology

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ObjectiveMucopolysaccharidosis IIIA or Sanfilippo disease type A is a progressive neurodegenerative disorder presenting in early childhood, caused by an inherited deficiency of the lysosomal hydrolase sulfamidase. New missense mutations, for which genotype–phenotype correlations are currently unknown, are frequently reported, hampering early prediction of phenotypic severity and efficacy assessment of new disease‐modifying treatments. We aimed to design a method to determine phenotypic severity early in the disease course.MethodsFifty‐three patients were included for whom skin fibroblasts and data on disease course and mutation analysis were available. Patients were phenotypically characterized on clinical data as rapidly progressing or slowly progressing. Sulfamidase activity was measured in fibroblasts cultured at 37 °C and at 30 °C.ResultsSulfamidase activity in fibroblasts from patients homozygous or compound heterozygous for a combination of known severe mutations remained below the limit of quantification under both culture conditions. In contrast, sulfamidase activity in fibroblasts from patients homozygous or compound heterozygous for a known mild mutation increased above the limit of quantification when cultured at 30 °C. With division on the basis of the patients' phenotype, fibroblasts from slowly progressing patients could be separated from rapidly progressing patients by increase in sulfamidase activity when cultured at 30 °C (p < 0.001, sensitivity = 96%, specificity = 93%).InterpretationPhenotypic severity strongly correlates with the potential to increase sulfamidase activity in fibroblasts cultured at 30 °C, allowing reliable distinction between patients with rapidly progressing or slowly progressing phenotypes. This method may provide an essential tool for assessment of treatment effects and for health care and life planning decisions. Ann Neurol 2017;82:686–696

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Section: Discussionsupporting

confidence: 64%

Prediction of phenotypic severity in mucopolysaccharidosis type IIIA

Knottnerus

Nijmeijer

IJlst

et al. 2017

Annals of Neurology

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“…The increased levels of residual NAGLU measured in SP patients after culturing cells at 30 °C, might be due to more efficient protein folding at this lower temperature, thereby stimulating the activity of mutant enzymes (Gootjes et al 2004; Diekman et al 2015). The positive effect of culturing human fibroblasts at 30 °C on protein quantity and enzymatic activity has already been demonstrated for a distinct metabolic disorder by another group in our lab (Houten et al 2002).…”

Section: Discussionmentioning

confidence: 99%

Residual N‐acetyl‐α‐glucosaminidase activity in fibroblasts correlates with disease severity in patients with mucopolysaccharidosis type IIIB

Meijer

Welling

Valstar

et al. 2016

J of Inher Metab Disea

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BackgroundMucopolysaccharidosis type IIIB (MPS IIIB) is a rare genetic disorder in which the deficiency of the lysosomal enzyme N-acetyl-α-glucosaminidase (NAGLU) results in the accumulation of heparan sulfate (HS), leading to progressive neurocognitive deterioration. In MPS IIIB a wide spectrum of disease severity is seen. Due to a large allelic heterogeneity, establishing genotype-phenotype correlations is difficult. However, reliable prediction of the natural course of the disease is needed, in particular for the assessment of the efficacy of potential therapies.MethodsTo identify markers that correlate with disease severity, all Dutch patients diagnosed with MPS IIIB were characterised as either rapid (RP; classical, severe phenotype) or slow progressors (SP; non-classical, less severe phenotype), based on clinical data. NAGLU activity and HS levels were measured in patients’ fibroblasts after culturing at different temperatures.ResultsA small, though significant difference in NAGLU activity was measured between RP and SP patients after culturing at 37 °C (p < 0.01). Culturing at 30 °C resulted in more pronounced and significantly higher NAGLU activity levels in SP patients (p < 0.001) with a NAGLU activity of 0.58 nmol.mg-1.hr-1 calculated to be the optimal cut-off value to distinguish between the groups (sensitivity and specificity 100 %). A lower capacity of patients’ fibroblasts to increase NAGLU activity at 30 °C could significantly predict for the loss of several disease specific functions.ConclusionNAGLU activity in fibroblasts cultured at 30 °C can be used to discriminate between RP and SP MPS IIIB patients and the capacity of cells to increase NAGLU activity at lower temperatures correlates with disease symptoms.

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“…Patients should be planned as early as possible to minimize the fasting period and thereby reducing the period at risk of deterioration. Finally, measuring the fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency, and could be useful to predict severity of the disease before surgery (Diekman et al 2015).…”

Section: Principles Of Perioperative Managementmentioning

confidence: 99%

Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency and Perioperative Management in Adult Patients

et al. 2016

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Surgery and anesthesia pose a threat to patients with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), because prolonged fasting, stress, and pain are known risk factors for the induction of metabolic derangement. The optimal perioperative management in these patients is unknown and the use of volatile agents and agents dissolved in fatty acids has been related to postoperative metabolic complications. However, the occurrence of metabolic derangement is multifactorial and depends, amongst others, on the severity of the mutation and residual enzyme activity. Current guidelines suggest avoiding both volatile anesthetics as well as propofol, which seriously limits the options for providing safe anesthesia. Therefore, we reviewed the available literature on the perioperative management of patients with VLCADD. We concluded that the use of some medications, such as volatile anesthetics, in patients with VLCADD might be wrongfully avoided and could in fact prevent metabolic derangement by the adequate suppression of pain and stress during surgery. We will illustrate this with a case report of an adult VLCADD patient undergoing minor surgery. Besides the use of remifentanil, anesthesia was uneventfully maintained with the use of sevoflurane, a volatile agent, and continuous glucose infusion. The patient was monitored with a continuous glucose meter and creatinine kinase measurements.

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Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency

Cited by 47 publications

References 30 publications

Prediction of phenotypic severity in mucopolysaccharidosis type IIIA

Prediction of phenotypic severity in mucopolysaccharidosis type IIIA

Residual N‐acetyl‐α‐glucosaminidase activity in fibroblasts correlates with disease severity in patients with mucopolysaccharidosis type IIIB

Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency and Perioperative Management in Adult Patients

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