The Experts below are selected from a list of 315 Experts worldwide ranked by ideXlab platform
Ronald J A Wanders - One of the best experts on this subject based on the ideXlab platform.
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fibroblast specific genome scale modelling predicts an imbalance in amino acid metabolism in Refsum Disease
FEBS Journal, 2020Co-Authors: Agnieszka B. Wegrzyn, Katharina Herzog, Albert Gerding, Marcel Kwiatkowski, Justina C. Wolters, Amalia M. Dolga, Alida E. M. Van Lint, Ronald J A WandersAbstract:Refsum Disease (RD) is an inborn error of metabolism that is characterised by a defect in peroxisomal α-oxidation of the branched-chain fatty acid phytanic acid. The disorder presents with late-onset progressive retinitis pigmentosa and polyneuropathy and can be diagnosed biochemically by elevated levels of phytanate in plasma and tissues of patients. To date, no cure exists for RD, but phytanate levels in patients can be reduced by plasmapheresis and a strict diet. In this study, we reconstructed a fibroblast-specific genome-scale model based on the recently published, FAD-curated model, based on Recon3D reconstruction. We used transcriptomics (available via GEO database with identifier GSE138379), metabolomics and proteomics (available via ProteomeXchange with identifier PXD015518) data, which we obtained from healthy controls and RD patient fibroblasts incubated with phytol, a precursor of phytanic acid. Our model correctly represents the metabolism of phytanate and displays fibroblast-specific metabolic functions. Using this model, we investigated the metabolic phenotype of RD at the genome scale, and we studied the effect of phytanate on cell metabolism. We identified 53 metabolites that were predicted to discriminate between healthy and RD patients, several of which with a link to amino acid metabolism. Ultimately, these insights in metabolic changes may provide leads for pathophysiology and therapy. Databases: Transcriptomics data are available via GEO database with identifier GSE138379, and proteomics data are available via ProteomeXchange with identifier PXD015518.
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Fibroblast-specific genome-scale modelling predicts an imbalance in amino acid metabolism in Refsum Disease
2019Co-Authors: Agnieszka B. Wegrzyn, Hans R Waterham, Ronald J A Wanders, Katharina Herzog, Albert Gerding, Marcel Kwiatkowski, Justina C. Wolters, Amalia M. Dolga, Alida E. M. Van Lint, Barbara M. BakkerAbstract:ABSTRACT Refsum Disease is an inborn error of metabolism that is characterised by a defect in peroxisomal α-oxidation of the branched-chain fatty acid phytanic acid. The disorder presents with late-onset progressive retinitis pigmentosa and polyneuropathy and can be diagnosed biochemically by elevated levels of phytanic acid in plasma and tissues of patients. To date, no cure exists for Refsum Disease, but phytanic acid levels in patients can be reduced by plasmapheresis and a strict diet. In this study, we reconstructed a fibroblast-specific genome-scale model based on the recently published, FAD-curated model, based on Recon3D reconstruction. We used transcriptomics (available via GEO database with identifier GSE138379), metabolomics, and proteomics data (available via ProteomeXchange with identifier PXD015518), which we obtained from healthy controls and Refsum Disease patient fibroblasts incubated with phytol, a precursor of phytanic acid. Our model correctly represents the metabolism of phytanic acid and displays fibroblast-specific metabolic functions. Using this model, we investigated the metabolic phenotype of Refsum Disease at the genome-scale, and we studied the effect of phytanic acid on cell metabolism. We identified 53 metabolites that were predicted to discriminate between Healthy and Refsum Disease patients, several of which with a link to amino acid metabolism. Ultimately, these insights in metabolic changes may provide leads for pathophysiology and therapy.
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Adult Refsum Disease: a form of tapetoretinal dystrophy accessible to therapy.
Survey of ophthalmology, 2010Co-Authors: Klaus Ruether, Minne Casteels, Ronald J A Wanders, Bart P. Leroy, Eleanor J Baldwin, Morten Andreas Horn, M. D. Feher, Susan Kuranoff, Anthony S WierzbickiAbstract:Adult Refsum Disease is characterized by an elevated plasma phytanic acid level and high concentrations of phytanic acid in a variety of tissues. Besides tapetoretinal degeneration, additional symptoms are anosmia, skeletal malformations, chronic polyneuropathy, cerebellar ataxia, sensorineural hearing loss, ichthyosis, and cardiac abnormalities. A diet low in phytanic acid ameliorates polyneuropathy and ataxia and slows or even stops the other manifestations. In order to be able to apply dietary therapy, as many patients as possible (even better if all of them are) have to be identified at an early stage. The ophthalmologist plays a crucial role in achieving this goal because of the early manifestation of the tapetoretinal degeneration.
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Ataxia with loss of Purkinje cells in a mouse model for Refsum Disease.
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Anna W. M. Zomer, Jasper C. Komen, Ronald J A Wanders, B. T. Poll-the, Paul T. Van Der Saag, Christina E. Van Den Brink, Melissa Thanos, Frank P. T. Hamers, Pedro BritesAbstract:Refsum Disease is caused by a deficiency of phytanoyl-CoA hydroxylase (PHYH), the first enzyme of the peroxisomal alpha-oxidation system, resulting in the accumulation of the branched-chain fatty acid phytanic acid. The main clinical symptoms are polyneuropathy, cerebellar ataxia, and retinitis pigmentosa. To study the pathogenesis of Refsum Disease, we generated and characterized a Phyh knockout mouse. We studied the pathological effects of phytanic acid accumulation in Phyh(-/-) mice fed a diet supplemented with phytol, the precursor of phytanic acid. Phytanic acid accumulation caused a reduction in body weight, hepatic steatosis, and testicular atrophy with loss of spermatogonia. Phenotype assessment using the SHIRPA protocol and subsequent automated gait analysis using the CatWalk system revealed unsteady gait with strongly reduced paw print area for both fore- and hindpaws and reduced base of support for the hindpaws. Histochemical analyses in the CNS showed astrocytosis and up-regulation of calcium-binding proteins. In addition, a loss of Purkinje cells in the cerebellum was observed. No demyelination was present in the CNS. Motor nerve conduction velocity measurements revealed a peripheral neuropathy. Our results show that, in the mouse, high phytanic acid levels cause a peripheral neuropathy and ataxia with loss of Purkinje cells. These findings provide important insights in the pathophysiology of Refsum Disease.
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Phenotype of adult Refsum Disease due to a defect in peroxin 7
Neurology, 2007Co-Authors: Morten Andreas Horn, Ronald J A Wanders, B. T. Poll-the, Oddvar Stokke, D. M. Van Den Brink, Marinus Duran, Chantal M. E. Tallaksen, Hugo W. Moser, Ola H. SkjeldalAbstract:The biochemical hallmark of adult Refsum Disease (ARD) is an isolated deficiency in the breakdown of phytanic acid. This usually results from a PHYH gene defect, although some cases have been found to carry a PEX7 defect. We describe the phenotype of such a patient, indistinguishable from that of classic ARD. Hence, we propose the subdivision of ARD into type 1 and type 2, depending on which gene is defective.
Inderjit Singh - One of the best experts on this subject based on the ideXlab platform.
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Refsum Disease: a defect in the a-oxidation of phytanic acid in peroxisomes
2013Co-Authors: Inderjit Singh, Kalipada Pahan, Avtar K. Singh, Earnest BarbosatAbstract:Abstract The oxidation of phytanic acid to pristanic acid was previously demonstrated to be deficient in monolayer cultures of skin fibroblasts (Hemdon et al. 1969. J. Clin. Invest. 48 1017-1032). However, identification of subcellular organelle with deficient enzyme activity has not been established. To define the subcellular organelle with deficient enzyme activity in the catabolism of phytanic acid, we measured the oxidation of [l-14C] phytanic acid to 14C02 and pristanic acid in different subcellular organelles isolated from cultured skin fibroblasts from control and Refsum patients. The rates of oxidation of phytanic acid in peroxisomes, mitochondria, and endoplasmic reticulum were 37.1 * 2.65, 1.9 * 0.3, and 0.4 * 0.07 pmol/h per mg protein, respectively, from control fibroblasts. The phytanic acid oxidation activity in mitochondria (2.04 0.7 pmol/h per mg protein) and endoplasmic reticulum (0.43 * 0.2 pmol/h per mg protein) from Refsum fibroblasts was similar to control fibroblasts. However, phytanic acid oxidation in peroxisomes from Refsum fibroblasts was not detected at all the protein concentrations tested. On the other hand, the peroxisomes from Refsum fibroblasts had normal rates of activation and oxidation of palmitic and lignoceric acids, suggesting that the peroxisomes isolated from Refsum fibroblasts were metabolically active. The phytanoyl-CoA ligase, the first enzyme in the a-oxidation pathway, had activity similar to that in peroxisomes from control (9.86 * 0.09 nmol/h per mg protein) and Refsum (10.25 f 0.31 nmol/h per mg protein) fibroblasts. 819 The data described here clearly demonstrate that pathognomonic accumulation of phytanic acid in patients with Refsum Disease is due to the deficient activity of peroxisomal a-oxidation enzym
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Restoration of phytanic acid oxidation in Refsum Disease fibroblasts from patients with mutations in the phytanoyl‐CoA hydroxylase gene
FEBS letters, 1998Co-Authors: Amarjit Chahal, Ernest Barbosa, Mushfiquddin Khan, Shashidhar Pai, Inderjit SinghAbstract:Abstract Refsum Disease (RD) is biochemically characterized by the excessive accumulation of phytanic acid in tissues and body fluids due to deficiency of phytanoyl-CoA hydroxylase (PAHX). In this study, we screened three RD patients and identified a novel deletion (88 amino acids), and a missense mutation (Arg275Trp) in the previously reported PAHX cDNA (Jansen et al., 1997; Mihalik et al., 1997). Moreover, transfection of skin fibroblasts from two RD patients with wild-type PAHX gene restored the activity for α-oxidation of phytanic acid. Southern analysis on a somatic cell hybrid panel detected the PAHX gene on chromosome 10, corroborating radiation hybrid and homozygosity mapping data (Mihalik et al., 1997; Nadal et al., 1995).
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restoration of phytanic acid oxidation in Refsum Disease fibroblasts from patients with mutations in the phytanoyl coa hydroxylase gene
FEBS Letters, 1998Co-Authors: Amarjit Chahal, Ernest Barbosa, Mushfiquddin Khan, Shashidhar Pai, Inderjit SinghAbstract:Abstract Refsum Disease (RD) is biochemically characterized by the excessive accumulation of phytanic acid in tissues and body fluids due to deficiency of phytanoyl-CoA hydroxylase (PAHX). In this study, we screened three RD patients and identified a novel deletion (88 amino acids), and a missense mutation (Arg275Trp) in the previously reported PAHX cDNA (Jansen et al., 1997; Mihalik et al., 1997). Moreover, transfection of skin fibroblasts from two RD patients with wild-type PAHX gene restored the activity for α-oxidation of phytanic acid. Southern analysis on a somatic cell hybrid panel detected the PAHX gene on chromosome 10, corroborating radiation hybrid and homozygosity mapping data (Mihalik et al., 1997; Nadal et al., 1995).
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phytanic acid oxidation normal activation and transport yet defective alpha hydroxylation of phytanic acid in peroxisomes from Refsum Disease and rhizomelic chondrodysplasia punctata
Journal of Lipid Research, 1996Co-Authors: Kalipada Pahan, Mushfiquddin Khan, Inderjit SinghAbstract:In humans the oxidation of phytanic acid is a peroxisomal function. To understand the possible mechanisms for the pathognomic accumulation of phytanic acid in plasma and body fluids of Refsum Disease (RD) and rhizomelic chondrodysplasia punctata (RCDP), we investigated activities of various steps (activation, transport, and oxidation) in the metabolism of phytanic acid in peroxisomes isolated from cultured skin fibroblasts from control, RD, and RCDP subjects. Activation of phytanic acid was normal in peroxisomes from both RD and RCDP. Transport of phytanic acid or phytanoyl-CoA in the absence or presence of fatty acid activating cofactors (ATP, MgCl2, and CoASH) into peroxisomes isolated from RD and RCDP skin fibroblasts was also similar to that of peroxisomes from control fibroblasts. Defective oxidation of [(2,3)-3H]- or [1-14C]phytanic acid, or [1-14C]phytanoyl-CoA (substrate for the first step of alpha-oxidation) but normal oxidation of [1-14C] alpha-hydroxyphytanic acid (substrate for the second step of the alpha-oxidation pathway) in peroxisomes from RD clearly demonstrates that excessive accumulation of phytanic acid in plasma and body fluids of RD is due to the deficiency of phytanic acid alpha-hydroxylase in peroxisomes. However, in RCDP peroxisomes, in addition to deficient oxidation of [1-14C]phytanic acid or phytanoyl-CoA or [(2,3)-3H]phytanic acid, the oxidation of [1-14C] alpha-hydroxyphytanic acid was also deficient, indicating that in RCDP the activities both of alpha-hydroxylation of phytanic acid and decarboxylation of alpha-hydroxyphytanic acid are deficient. These observations indicate that peroxisomal membrane functions (phytanic acid activation and transport) in phytanic acid metabolism are normal in both RD and RCDP. The defect in RD is in the alpha-hydroxylation of phytanic acid; whereas in RCDP both alpha-hydroxylation of phytanic acid as well as decarboxylation of alpha-hydroxyphytanic acid are deficient.
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Phytanic acid oxidation: normal activation and transport yet defective alpha-hydroxylation of phytanic acid in peroxisomes from Refsum Disease and rhizomelic chondrodysplasia punctata.
Journal of lipid research, 1996Co-Authors: Kalipada Pahan, Mushfiquddin Khan, Inderjit SinghAbstract:In humans the oxidation of phytanic acid is a per- oxisomal function. To understand the possible mechanisms for the pathognomic accumulation of phytanic acid in plasma and body fluids of Refsum Disease (RD) and rhizomelic chon- drodysplasia punctata (RCDP), we investigated activities of various steps (activation, transport, and oxidation) in the metabolism of phytanic acid in peroxisomes isolated from cultured skin fibroblasts from control, RD, and RCDP sub- jects. Activation of phytanic acid was normal in peroxisomes from both RD and RCDP. Transport of phytanic acid or phytanoyl-CoA in the absence or presence of fatty acid acti- vating cofactors (ATP, MgC12, and CoASH) into peroxisomes isolated from RD and RCDP skin fibroblasts was also similar to that of peroxisomes from control fibroblasts. Defective oxidation of ((2,3)JH)- or (1-14C)phytanic acid, or (l- Wlphytanoyl-CoA (substrate for the first step of a-oxidation) but normal oxidation of ( l-14C)a-hydroxyphytanic acid (sub- strate for the second step of the a-oxidation pathway) in peroxisomes from RD clearly demonstrates that excessive accumulation of phytanic acid in plasma and body fluids of RD is due to the deficiency of phytanic acid a-hydroxylase in peroxisomes. However, in RCDP peroxisomes, in addition to deficient oxidation of ( 1-14Clphytanic acid or phytanoyl-CoA or ((2,3)sH)phytanic acid, the oxidation of ( l-W)a-hy- droxyphytanic acid was also deficient, indicating that in RCDP the activities both of a-hydroxylation of phytanic acid and decarboxylation of a-hydroxyphytanic acid are deficient. I These observations indicate that peroxisomal membrane functions (phytanic acid activation and transport) in phytanic acid metabolism are normal in both RD and RCDP. The defect in RD is in the a-hydroxylation of phytanic acid; whereas in RCDP both a-hydroxylation of phytanic acid as well as decarboxylation of a-hydroxyphytanic acid are defi- cient.-Pahan, K., M. Khan, and I. Singh. Phytanic acid oxi- dation: normal activation and transport yet defective a-hy- droxylation of phytanic acid in peroxisomes from Refsum Disease and rhizomelic chondrodysplasia punctata. J. Lipid Res. 1996.37: 1137-1143.
Georg Reiser - One of the best experts on this subject based on the ideXlab platform.
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brain lipotoxicity of phytanic acid and very long chain fatty acids harmful cellular mitochondrial activities in Refsum Disease and x linked adrenoleukodystrophy
Aging and Disease, 2016Co-Authors: Peter Schonfeld, Georg ReiserAbstract:It is increasingly understood that in the aging brain, especially in the case of patients suffering from neurodegenerative Diseases, some fatty acids at pathologically high concentrations exert detrimental activities. To study such activities, we here analyze genetic Diseases, which are due to compromised metabolism of specific fatty acids, either the branched-chain phytanic acid or very long-chain fatty acids (VLCFAs). Micromolar concentrations of phytanic acid or of VLCFAs disturb the integrity of neural cells by impairing Ca(2+) homeostasis, enhancing oxidative stress or de-energizing mitochondria. Finally, these combined harmful activities accelerate cell death. Mitochondria are more severely targeted by phytanic acid than by VLCFAs. The insertion of VLCFAs into the inner membrane distorts the arrangement of membrane constituents and their functional interactions. Phytanic acid exerts specific protonophoric activity, induces reactive oxygen species (ROS) generation, and reduces ATP generation. A clear inhibition of the Na(+), K(+)-ATPase activity by phytanic acid has also been reported. In addition to the instantaneous effects, a chronic exposure of brain cells to low micromolar concentrations of phytanic acid may produce neuronal damage in Refsum Disease by altering epigenetic transcriptional regulation. Myelin-producing oligodendrocytes respond with particular sensitivity to VLCFAs. Deleterious activity of VLCFAs on energy-dependent mitochondrial functions declines with increasing the hydrocarbon chain length (C22:0 > C24:0 > C26:0). In contrast, the reverse sequence holds true for cell death induction by VLCFAs (C22:0 < C24:0 < C26:0). In adrenoleukodystrophy, the uptake of VLCFAs by peroxisomes is impaired by defects of the ABCD1 transporter. Studying mitochondria from ABCD1-deficient and wild-type mice proves that the energy-dependent functions are not altered in the Disease model. Thus, a defective ABCD1 apparently exerts no obvious adaptive pressure on mitochondria. Further research has to elucidate the detailed mechanistic basis for the failures causing fatty acid-mediated neurodegeneration and should help to provide possible therapeutic interventions.
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phytanic acid and pristanic acid branched chain fatty acids associated with Refsum Disease and other inherited peroxisomal disorders mediate intracellular ca2 signaling through activation of free fatty acid receptor gpr40
Neurobiology of Disease, 2011Co-Authors: Nicol Kruska, Georg ReiserAbstract:The accumulation of the two branched-chain fatty acids phytanic acid and pristanic acid is known to play an important role in several Diseases with peroxisomal impairment, like Refsum Disease, Zellweger syndrome and α-methylacyl-CoA racemase deficiency. Recent studies elucidated that the toxic activity of phytanic acid and pristanic acid is mediated by multiple mitochondrial dysfunctions, generation of reactive oxygen species and Ca2+ deregulation via the InsP3-Ca2+ signaling pathway in glial cells. However, the exact signaling mechanism through which both fatty acids mediate toxicity is still under debate. Here, we studied the ability of phytanic acid and pristanic acid to activate the free fatty acid receptor GPR40, a G-protein-coupled receptor, which was described to be involved in the Ca2+ signaling of fatty acids. We treated HEK 293 cells expressing the GPR40 receptor with phytanic acid or pristanic acid. This resulted in a significant increase in the intracellular Ca2+ level, similar to the effect seen after treatment with the synthetic GPR40 agonist GW9508. Furthermore, we demonstrate that the GPR40 activation might be due to an interaction of the carboxylate moiety of fatty acids with the receptor. Our findings indicate that the phytanic acid- and pristanic acid-mediated Ca2+ deregulation can involve the activation of GPR40. Therefore, we suppose that activation of GPR40 might be part of the signaling cascade of the toxicity of phytanic and pristanic acids.
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the influence of the branched chain fatty acids pristanic acid and Refsum Disease associated phytanic acid on mitochondrial functions and calcium regulation of hippocampal neurons astrocytes and oligodendrocytes
Neurobiology of Disease, 2009Co-Authors: Sabine Ronicke, Stefan Kahlert, Nicol Kruska, Georg ReiserAbstract:Abstract Pristanic acid and phytanic acid are branched-chain fatty acids, which play an important role in Diseases with peroxisomal impairment, like Refsum Disease (MIM 266500), Zellwegers syndrome and α-methylacyl-CoA racemase deficiency (MIM 604489). Several studies revealed that the toxic activity of phytanic acid is mediated by multiple mitochondrial dysfunctions. However, the action of pristanic acid on brain cells is still completely unknown. Here, we exposed astrocytes, oligodendrocytes and neurons in mixed culture to pristanic acid and phytanic acid to analyse cellular consequences. Pristanic acid exerts a strong cytotoxic activity on brain cells, displayed by dramatic Ca2+ deregulation, in situ mitochondrial depolarization and cell death. Interestingly, pristanic acid strongly induced generation of reactive oxygen species (ROS), whereas phytanic acid exerts weaker effects on ROS production. In conclusion, pristanic acid as well as phytanic acid induced a complex array of toxic activities with mitochondrial dysfunction and Ca2+ deregulation.
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brain pyruvate and 2 oxoglutarate dehydrogenase complexes are mitochondrial targets of the coa ester of the Refsum Disease marker phytanic acid
FEBS Letters, 2006Co-Authors: Victoria I. Bunik, Gunter Raddatz, Georg ReiserAbstract:Pyruvate and 2-oxoglutarate dehydrogenase com- plexes are strongly inhibited by phytanoyl-CoA (IC50 � 10 � 6 - 10 � 7 M). Palmitoyl-CoA is 10-fold less potent. Phytanic or palmitic acids have no inhibitory effect up to 0.3 mM. At the sub- strate saturation, the acyl-CoA's affect the first and second enzy- matic components of the 2-oxoglutarate dehydrogenase complex, while the third component is inhibited only at a low saturation with its substrate dihydrolipoamide. Thus, key regulatory branch points of mitochondrial metabolism are targets of a cellular derivative of phytanic acid. Decreased activity of the complexes might therefore contribute to neurological symptoms upon accu- mulation of phytanic acid in Refsum Disease. � 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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mechanism of toxicity of the branched chain fatty acid phytanic acid a marker of Refsum Disease in astrocytes involves mitochondrial impairment
International Journal of Developmental Neuroscience, 2006Co-Authors: Georg Reiser, Peter Schonfeld, Stefan KahlertAbstract:Phytanic acid is a saturated branched-chain fatty acid, which is formed by bacterial degradation of chlorophyll in the intestinal tract of ruminants. The methyl group in beta-position prevents degradation of phytanic acid by the beta-oxidation pathway. Therefore, degradation of phytanic acid is initiated by alpha-oxidation in peroxisomes. The inherited peroxisomal disorder Refsum Disease is characterised by accumulation of phytanic acid. Unusually high concentrations of phytanic acid can be found in the plasma of Refsum Disease patients, who suffer from neurodegeneration and muscle dystrophy. Phytanic acid has been suggested to be causally involved in the clinical symptoms. To elucidate the pathogenic mechanism, we investigated the influence of phytanic acid in rat hippocampal astrocytes by monitoring the cytosolic Ca(2+) concentration, the mitochondrial membrane potential (Deltapsi(m)), the generation of reactive oxygen species as well as the cellular ATP level. In response to phytanic acid (100 microM) cytosolic Ca(2+) was quickly increased. The phytanic acid-evoked Ca(2+) response was transient and involved activation of intracellular Ca(2+) stores. In isolated rat brain mitochondria, phytanic acid dissipated Deltapsi(m) in a reversible and dose-dependent manner. Moreover, phytanic acid released cytochrome c from mitochondria. Depending on the mitochondrial activity state, phytanic acid either stimulated or inhibited the electron flux within the respiratory chain. In addition, phytanic acid induced substantial generation of reactive oxygen species in isolated mitochondria as well as in intact cells. Phytanic acid caused cell death of astrocytes within a few hours of exposure. In conclusion, we suggest that phytanic acid initiates astrocyte cell death by activating the mitochondrial route of apoptosis.
Anthony S Wierzbicki - One of the best experts on this subject based on the ideXlab platform.
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Adult Refsum Disease: a form of tapetoretinal dystrophy accessible to therapy.
Survey of ophthalmology, 2010Co-Authors: Klaus Ruether, Minne Casteels, Ronald J A Wanders, Bart P. Leroy, Eleanor J Baldwin, Morten Andreas Horn, M. D. Feher, Susan Kuranoff, Anthony S WierzbickiAbstract:Adult Refsum Disease is characterized by an elevated plasma phytanic acid level and high concentrations of phytanic acid in a variety of tissues. Besides tapetoretinal degeneration, additional symptoms are anosmia, skeletal malformations, chronic polyneuropathy, cerebellar ataxia, sensorineural hearing loss, ichthyosis, and cardiac abnormalities. A diet low in phytanic acid ameliorates polyneuropathy and ataxia and slows or even stops the other manifestations. In order to be able to apply dietary therapy, as many patients as possible (even better if all of them are) have to be identified at an early stage. The ophthalmologist plays a crucial role in achieving this goal because of the early manifestation of the tapetoretinal degeneration.
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The effectiveness of dietary therapy over 10 years in the treatment of Adult Refsum Disease
Journal of Neurology Neurosurgery and Psychiatry, 2010Co-Authors: Eleanor J Baldwin, F. Brian Gibberd, Claire Harley, M. D. Feher, Margaret C Sidey, Anthony S WierzbickiAbstract:Objective: to evaluate the long-term effectiveness of dietary therapy with regular dietetic reinforcement for Adult Refsum Disease Methods: Retrospective case note analysis of records of plasma phytanic acid and hospital admission of 13 patients with Adult Refsum Disease who attended the specialist centre and repeatedly received dietary instruction for a minimum of ten years. Results: Patients undergoing review had attended for 11-28 years totaling 237 years. Median baseline phytanic acid concentrations at presentation were 1631 (370- 2911) µmol/l and declined by 89±11% to 85 (10-1325) µmol/l. Levels of phytanic acid were completely normalised ( 300pmol/L in 15%. The time required for phytanic acid levels to halve was 44.2±15.9 months in patients compliant with diet. No patient required admission or plasmapheresis/apheresis during this period for acute neuro-ophthalmological complications despite occasional spikes in phytanic acid levels attributable to intercurrent illness, surgery, sudden weight loss or psychological illness. Interpretation: Dietary modification with regular reinforcement in Adult Refsum Disease can significantly reduce phytanic acid levels with time.
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The effectiveness of long-term dietary therapy in the treatment of adult Refsum Disease
Journal of neurology neurosurgery and psychiatry, 2010Co-Authors: Eleanor J Baldwin, M C Sidey, F. Brian Gibberd, Claire Harley, M. D. Feher, Anthony S WierzbickiAbstract:Objective To evaluate the long-term effectiveness of dietary therapy with regular dietetic reinforcement for adult Refsum Disease. Methods Retrospective case note analysis of records of plasma phytanic acid and hospital admission of 13 patients with adult Refsum Disease who attended the specialist centre and repeatedly received dietary instruction for a minimum of 10 years. Results Patients undergoing review had attended for 11–28 years totalling 237 years. Median baseline phytanic acid concentrations at presentation were 1631 (370–2911) μmol/l and declined by 89±11% to 85 (10–1325) μmol/l. Levels of phytanic acid were completely normalised ( 300 pmol/l in 15%. The time required for phytanic acid levels to halve was 44.2±15.9 months in patients compliant with diet. No patient required admission or plasmapheresis/apheresis during this period for acute neuro-ophthalmological complications despite occasional spikes in phytanic acid levels attributable to intercurrent illness, surgery, sudden weight loss or psychological illness. Interpretation Dietary modification with regular reinforcement in Adult Refsum Disease can significantly reduce phytanic acid levels with time.
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metabolism of phytanic acid and 3 methyl adipic acid excretion in patients with adult Refsum Disease
Journal of Lipid Research, 2003Co-Authors: Anthony S Wierzbicki, M C Sidey, M. D. Feher, Phillip D Mayne, Matthew D Lloyd, David Burston, Guam Mei, Brian F GibberdAbstract:Adult Refsum Disease (ARD) is associated with defective alpha-oxidation of phytanic acid (PA). omega-Oxidation of PA to 3-methyl-adipic acid (3-MAA) occurs although its clinical significance is unclear. In a 40 day study of a new ARD patient, where the plasma half-life of PA was 22.4 days, omega-oxidation accounted for 30% initially and later all PA excretion. Plasma and adipose tissue PA and 3-MAA excretion were measured in a cross-sectional study of 11 patients. The capacity of the omega-oxidation pathway was 6.9 (2.8-19.4) mg [20.4 (8.3-57.4) micromol] PA/day. 3-MAA excretion correlated with plasma PA levels (r = 0.61; P = 0.03) but not adipose tissue PA content. omega-Oxidation during a 56 h fast was studied in five patients. 3-MAA excretion increased by 208 +/- 58% in parallel with the 158 (125-603)% rise in plasma PA. Plasma PA doubled every 29 h, while 3-MAA excretion followed second-order kinetics. Acute sequelae of ARD were noted in three patients (60%) after fasting. The omega-oxidation pathway can metabolise PA ingested by patients with ARD, but this activity is dependent on plasma PA concentration. omega-Oxidation forms a functional reserve capacity that enables patients with ARD undergoing acute stress to cope with limited increases in plasma PA levels.
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Identification of PEX7 as the Second Gene Involved in Refsum Disease
American journal of human genetics, 2003Co-Authors: Daan M. Van Den Brink, G A Jansen, Anthony S Wierzbicki, John Mitchell, Jacqueline De Belleroche, Pedro Brites, Janet Haasjes, Michelle Lambert-hamill, Hans R WaterhamAbstract:Patients affected with Refsum Disease (RD) have elevated levels of phytanic acid due to a deficiency of the peroxisomal enzyme phytanoyl-CoA hydroxylase (PhyH). In most patients with RD, Disease-causing mutations in the PHYH gene have been identified, but, in a subset, no mutations could be found, indicating that the condition is genetically heterogeneous. Linkage analysis of a few patients diagnosed with RD, but without mutations in PHYH, suggested a second locus on chromosome 6q22-24. This region includes the PEX7 gene, which codes for the peroxin 7 receptor protein required for peroxisomal import of proteins containing a peroxisomal targeting signal type 2. Mutations in PEX7 normally cause rhizomelic chondrodysplasia punctata type 1, a severe peroxisomal disorder. Biochemical analyses of the patients with RD revealed defects not only in phytanic acid α-oxidation but also in plasmalogen synthesis and peroxisomal thiolase. Furthermore, we identified mutations in the PEX7 gene. Our data show that mutations in the PEX7 gene may result in a broad clinical spectrum ranging from severe rhizomelic chondrodysplasia punctata to relatively mild RD and that clinical diagnosis of conditions involving retinitis pigmentosa, ataxia, and polyneuropathy may require a full screen of peroxisomal functions.
G A Jansen - One of the best experts on this subject based on the ideXlab platform.
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Molecular basis of Refsum Disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7).
Human mutation, 2004Co-Authors: G A Jansen, Hans R Waterham, Ronald J A WandersAbstract:Refsum Disease has long been known to be an inherited disorder of lipid metabolism characterized by the accumulation of phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) caused by an alpha-oxidation deficiency of this branched chain fatty acid in peroxisomes. The mechanism of phytanic acid alpha-oxidation and the enzymes involved had long remained mysterious, but they have been resolved in recent years. This has led to the resolution of the molecular basis of Refsum Disease. Interestingly, Refsum Disease is genetically heterogeneous; two genes, PHYH (also named PAHX) and PEX7, have been identified to cause Refsum Disease, as reviewed in this work.
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Identification of PEX7 as the Second Gene Involved in Refsum Disease
American journal of human genetics, 2003Co-Authors: Daan M. Van Den Brink, G A Jansen, Anthony S Wierzbicki, John Mitchell, Jacqueline De Belleroche, Pedro Brites, Janet Haasjes, Michelle Lambert-hamill, Hans R WaterhamAbstract:Patients affected with Refsum Disease (RD) have elevated levels of phytanic acid due to a deficiency of the peroxisomal enzyme phytanoyl-CoA hydroxylase (PhyH). In most patients with RD, Disease-causing mutations in the PHYH gene have been identified, but, in a subset, no mutations could be found, indicating that the condition is genetically heterogeneous. Linkage analysis of a few patients diagnosed with RD, but without mutations in PHYH, suggested a second locus on chromosome 6q22-24. This region includes the PEX7 gene, which codes for the peroxin 7 receptor protein required for peroxisomal import of proteins containing a peroxisomal targeting signal type 2. Mutations in PEX7 normally cause rhizomelic chondrodysplasia punctata type 1, a severe peroxisomal disorder. Biochemical analyses of the patients with RD revealed defects not only in phytanic acid α-oxidation but also in plasmalogen synthesis and peroxisomal thiolase. Furthermore, we identified mutations in the PEX7 gene. Our data show that mutations in the PEX7 gene may result in a broad clinical spectrum ranging from severe rhizomelic chondrodysplasia punctata to relatively mild RD and that clinical diagnosis of conditions involving retinitis pigmentosa, ataxia, and polyneuropathy may require a full screen of peroxisomal functions.
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Atypical Refsum Disease with pipecolic acidemia and abnormal catalase distribution.
Annals of neurology, 2000Co-Authors: Matthias R. Baumgartner, G A Jansen, Frank Roels, Marc Espeel, Nanda M. Verhoeven, P.a. Mooyer, C.a.j.m. Jakobs, A. Fourmaintraux, H. Bellet, R. J. A. WandersAbstract:We describe an 18-year-old patient with psychomotor retardation and abnormally short metatarsi and metacarpals but no other signs of classic Refsum Disease. Molecular analysis of the phytanoyl-coenzyme A hydroxylase gene revealed a homozygous deletion causing a frameshift. Surprisingly, L-pipecolic acid was elevated in plasma, and microscopy of the liver showed a reduced number of peroxisomes per cell and a larger average peroxisome size. These abnormal peroxisomes lacked catalase as did peroxisomes in fibroblasts of this patient. Such generalized peroxisomal abnormalities are not present in classic Refsum Disease.
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Refsum Disease is caused by mutations in the phytanoyl-CoA hydroxylase gene.
Nature genetics, 1997Co-Authors: G A Jansen, Ola H. Skjeldal, Rob Ofman, Lodewijk Ijlst, Anton O. Muijsers, Oddvar Stokke, G. T. N. Besley, James E. WraithAbstract:Refsum Disease is an autosomal-recessively inherited disorder characterized clinically by a tetrad of abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia and elevated protein levels in the cerebrospinal fluid (CSF) without an increase in the number of cells in the CSF. All patients exhibit accumulation of an unusual branched-chain fatty acid, phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), in blood and tissues. Biochemically, the Disease is caused by the deficiency of phytanoyl-CoA hydroxylase (PhyH), a peroxisomal protein catalyzing the first step in the α-oxidation of phytanic acid. We have purified PhyH from rat-liver peroxisomes and determined the N-terminal amino-acid sequence, as well as an additional internal amino-acid sequence obtained after Lys-C digestion of the purified protein. A search of the EST database with these partial amino-acid sequences led to the identification of the full-length human cDNA sequence encoding PhyH: the open reading frame encodes a 41.2-kD protein of 338 amino acids, which contains a cleavable peroxisomal targeting signal type 2 (PTS2). Sequence analysis of PHYH fibroblast cDNA from five patients with Refsum Disease revealed distinct mutations, including a one-nucleotide deletion, a 111-nucleotide deletion and a point mutation. This analysis confirms our finding that Refsum Disease is caused by a deficiency of PhyH.