Phytanic acid disturbs mitochondrial homeostasis in heart of young rats: a possible pathomechanism of cardiomyopathy in Refsum disease

Adult Refsum disease is an inherited disorder in which phytanic acid accumulates in tissues and serum. Two hypotheses have been proposed to explain the pathogenesis of this condition. The molecular distortion hypothesis suggests that phytanic acid may alter membrane composition and structure, thereby affecting membrane function(s). The anti-metabolite hypothesis suggests that an accumulation of phytanic acid in membranes may interfere with vitamin E function. These two hypotheses were investigated by studying the effects of modulating phytanic acid and α-tocopherol concentrations on the fatty acid composition and certain physical parameters of cultured retinal cells. Results showed that (a) the phospholipid fraction of retinal cells readily incorporated phytanic acid, (b) the incorporation of phytanic acid increased membrane fluidity, (c) there was no competition for uptake between phytanic acid and α-tocopherol, and (d) the incorporation of phytanic acid did not increase the susceptibility of membranes to lipid peroxidation in vitro. These results obtained with cultured retinal cells suggest that the molecular distortion hypothesis, but not the anti-metabolite hypothesis, could explain the pathogenesis of adult Refsum disease. In vitro tissue culture models can, however, only approximate to the much more complex situation that occurs in vivo.

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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 ◽

10.1016/j.ijdevneu.2005.11.002 ◽

2006 ◽

Vol 24 (2-3) ◽

pp. 113-122 ◽

Cited By ~ 43

Author(s):

Georg Reiser ◽

Peter Schönfeld ◽

Stefan Kahlert

Keyword(s):

Fatty Acid ◽

Phytanic Acid ◽

Chain Fatty Acid ◽

Refsum Disease ◽

Mitochondrial Impairment ◽

Mechanism Of Toxicity ◽

Branched Chain

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Effects of phytanic acid on the vitamin E status, lipid composition and physical properties of retinal cell membranes: implications for adult Refsum disease

Clinical Science ◽

10.1042/cs20010075 ◽

2001 ◽

Vol 101 (6) ◽

pp. 697 ◽

Cited By ~ 4

Author(s):

S. P. YOUNG ◽

A. W. JOHNSON ◽

D. P. R. MULLER

Keyword(s):

Vitamin E ◽

Physical Properties ◽

Lipid Composition ◽

Phytanic Acid ◽

Cell Membranes ◽

Retinal Cell ◽

Refsum Disease ◽

Vitamin E Status

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The Refsum disease marker phytanic acid, a branched chain fatty acid, affects Ca2+ homeostasis and mitochondria, and reduces cell viability in rat hippocampal astrocytes

Neurobiology of Disease ◽

10.1016/j.nbd.2004.08.010 ◽

2005 ◽

Vol 18 (1) ◽

pp. 110-118 ◽

Cited By ~ 45

Author(s):

Stefan Kahlert ◽

Peter Schönfeld ◽

Georg Reiser

Keyword(s):

Fatty Acid ◽

Cell Viability ◽

Phytanic Acid ◽

Chain Fatty Acid ◽

Refsum Disease ◽

Disease Marker ◽

Branched Chain ◽

Hippocampal Astrocytes

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Ophthalmic Diagnosis and Novel Management of Infantile Refsum Disease with Combination Docosahexaenoic Acid and Cholic Acid

Case Reports in Ophthalmological Medicine ◽

10.1155/2021/1345937 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

Omar Elghawy ◽

Alice Y. Zhang ◽

Ryan Duong ◽

William G. Wilson ◽

Eugene Y. Shildkrot

Keyword(s):

Hearing Loss ◽

Docosahexaenoic Acid ◽

Retinitis Pigmentosa ◽

Sensorineural Hearing Loss ◽

Cholic Acid ◽

Phytanic Acid ◽

Sensorineural Hearing ◽

Refsum Disease ◽

Restricted Diet ◽

Infantile Refsum Disease

Infantile Refsum disease is a rare peroxisomal biogenesis disorder characterized by impaired alpha-oxidation and accumulation of phytanic acid in the tissues. Patients often present with fundus changes resembling retinitis pigmentosa, developmental delay, sensorineural hearing loss, ataxia, and hepatomegaly. Traditionally, mainstay treatment for this condition has been a phytanic acid-restricted diet, although supplementation with either docosahexaenoic acid or cholic acid has rarely been described in the literature. We present a case of infantile Refsum disease in a child with retinitis pigmentosa-like ocular findings, sensorineural hearing loss, and self-resolving hepatic disease, who developed novel findings of macular edema refractory to carbonic anhydrase inhibitors. We describe management with a phytanic acid-restricted diet and combination docosahexaenoic acid, and cholic acid therapy, which helped to limit progression of her disease.

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Fibroblast-specific genome-scale modelling predicts an imbalance in amino acid metabolism in Refsum disease

10.1101/776575 ◽

2019 ◽

Author(s):

Agnieszka B. Wegrzyn ◽

Katharina Herzog ◽

Albert Gerding ◽

Marcel Kwiatkowski ◽

Justina C. Wolters ◽

...

Keyword(s):

Amino Acid ◽

Phytanic Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Disease Patient ◽

Metabolic Phenotype ◽

Scale Model ◽

Refsum Disease ◽

Model Based ◽

Genome Scale

ABSTRACTRefsum 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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