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Cellular and Molecular Life Sciences :... Aug 2006Phytanic acid is a branched-chain fatty acid that accumulates in a variety of metabolic disorders. High levels of phytanic acid found in patients can exceed the... (Review)
Review
Phytanic acid is a branched-chain fatty acid that accumulates in a variety of metabolic disorders. High levels of phytanic acid found in patients can exceed the millimolar range and lead to severe symptoms. Degradation of phytanic acid takes place by alpha-oxidation inside the peroxisome. A deficiency of its breakdown, leading to elevated levels, can result from either a general peroxisomal dysfunction or from a defect in one of the enzymes involved in alpha-oxidation. Research on Refsum disease, belonging to the latter group of disorders and characterized by a deficiency of the first enzyme of alpha-oxidation, has extended our knowledge of phytanic acid metabolism and pathology of the disease greatly over the past few decades. This review will centre on this research on phytanic acid: its origin, the mechanism by which its alpha-oxidation takes place, its role in human disease and the way it is produced from phytol.
Topics: Aldehyde Oxidoreductases; Chondrodysplasia Punctata, Rhizomelic; Humans; Oxidation-Reduction; Peroxisomal Disorders; Peroxisomes; Phytanic Acid; Phytol; Protein Transport; Refsum Disease
PubMed: 16799769
DOI: 10.1007/s00018-005-5463-y -
Biochimica Et Biophysica Acta Dec 2006Defects in PEX genes impair peroxisome assembly and multiple metabolic pathways confined to this organelle, thus providing the biochemical and molecular bases of the... (Review)
Review
Defects in PEX genes impair peroxisome assembly and multiple metabolic pathways confined to this organelle, thus providing the biochemical and molecular bases of the peroxisome biogenesis disorders (PBD). PBD are divided into two types--Zellweger syndrome spectrum (ZSS) and rhizomelic chondrodysplasia punctata (RCDP). Biochemical studies performed in blood and urine are used to screen for the PBD. DNA testing is possible for all of the disorders, but is more challenging for the ZSS since 12 PEX genes are known to be associated with this spectrum of PBD. In contrast, PBD-RCDP is associated with defects in the PEX7 gene alone. Studies of the cellular and molecular defects in PBD patients have contributed significantly to our understanding of the role of each PEX gene in peroxisome assembly.
Topics: Amino Acid Sequence; Chondrodysplasia Punctata, Rhizomelic; Humans; Membrane Proteins; Molecular Sequence Data; Peroxisomal Disorders; Peroxisomes; Pipecolic Acids; Plasmalogens; Refsum Disease, Infantile; Zellweger Syndrome
PubMed: 17055079
DOI: 10.1016/j.bbamcr.2006.09.010 -
Journal of Neurochemistry Mar 2002Refsum's disease (hereditary motor sensory neuropathy type IV, heredopathia atactica polyneuritiformis) is an autosomal recessive disorder the clinical features of which... (Review)
Review
Refsum's disease (hereditary motor sensory neuropathy type IV, heredopathia atactica polyneuritiformis) is an autosomal recessive disorder the clinical features of which include retinitis pigmentosa, blindness, anosmia, deafness, sensory neuropathy, ataxia and accumulation of phytanic acid in plasma- and lipid-containing tissues. The transport and biochemical pathways of phytanic acid metabolism have recently been defined with the cloning of two key enzymes, phytanoyl-CoA 2-hydroxylase (PAHX) and 2-hydroxyphytanoyl-CoA lyase, together with the confirmation of their localization in peroxisomes. PAHX, an iron(II) and 2-oxoglutarate-dependent oxygenase is located on chromosome 10p13. Mutant forms of PAHX have been shown to be responsible for some, but not all, cases of Refsum's disease. Certain cases have been shown to be atypical mild variants of rhizomelic chondrodysplasia punctata type 1a. Other atypical cases with low-plasma phytanic acid may be caused by alpha-methylacyl-CoA racemase deficiency. A sterol-carrier protein-2 (SCP-2) knockout mouse model shares a similar clinical phenotype to Refsum's disease, but no mutations in SCP-2 have been described to-date in man. This review describes the clinical, biochemical and metabolic features of Refsum's disease and shows how the biochemistry of the alpha-oxidation pathway may be linked to the regulation of metabolic pathways controlled by isoprenoid lipids, involving calcineurin or the peroxisomal proliferator activating alpha-receptor.
Topics: Animals; Carrier Proteins; Humans; Mice; Mice, Knockout; Mixed Function Oxygenases; Mutation; Oxidation-Reduction; Peroxisomes; Phenotype; Phytanic Acid; Plant Proteins; Refsum Disease
PubMed: 11948235
DOI: 10.1046/j.0022-3042.2002.00766.x -
Aging and Disease Mar 2016It is increasingly understood that in the aging brain, especially in the case of patients suffering from neurodegenerative diseases, some fatty acids at pathologically... (Review)
Review
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.
PubMed: 27114847
DOI: 10.14336/AD.2015.0823 -
Indian Journal of Dermatology,... 2010Diet has an important role to play in many skin disorders, and dermatologists are frequently faced with the difficulty of separating myth from fact when it comes to... (Review)
Review
Diet has an important role to play in many skin disorders, and dermatologists are frequently faced with the difficulty of separating myth from fact when it comes to dietary advice for their patients. Patients in India are often anxious about what foods to consume, and what to avoid, in the hope that, no matter how impractical or difficult this may be, following this dictum will cure their disease. There are certain disorders where one or more components in food are central to the pathogenesis, e.g. dermatitis herpetiformis, wherein dietary restrictions constitute the cornerstone of treatment. A brief list, although not comprehensive, of other disorders where diet may have a role to play includes atopic dermatitis, acne vulgaris, psoriasis vulgaris, pemphigus, urticaria, pruritus, allergic contact dermatitis, fish odor syndrome, toxic oil syndrome, fixed drug eruption, genetic and metabolic disorders (phenylketonuria, tyrosinemia, homocystinuria, galactosemia, Refsum's disease, G6PD deficiency, xanthomas, gout and porphyria), nutritional deficiency disorders (kwashiorkar, marasmus, phrynoderma, pellagra, scurvy, acrodermatitis enteropathica, carotenemia and lycopenemia) and miscellaneous disorders such as vitiligo, aphthous ulcers, cutaneous vasculitis and telogen effluvium. From a practical point of view, it will be useful for the dermatologist to keep some dietary information handy to deal with the occasional patient who does not seem to respond in spite of the best, scientific and evidence-based therapy.
Topics: Animals; Dermatitis, Atopic; Dermatology; Diet; Diet, Gluten-Free; Food Hypersensitivity; Humans; Skin Diseases
PubMed: 20228538
DOI: 10.4103/0378-6323.60540 -
Biochimica Et Biophysica Acta.... Apr 2023Refsum disease is an inherited peroxisomal disorder caused by severe deficiency of phytanoyl-CoA hydroxylase activity. Affected patients develop severe cardiomyopathy of...
Refsum disease is an inherited peroxisomal disorder caused by severe deficiency of phytanoyl-CoA hydroxylase activity. Affected patients develop severe cardiomyopathy of poorly known pathogenesis that may lead to a fatal outcome. Since phytanic acid (Phyt) concentrations are highly increased in tissues of individuals with this disease, it is conceivable that this branched-chain fatty acid is cardiotoxic. The present study investigated whether Phyt (10-30 μM) could disturb important mitochondrial functions in rat heart mitochondria. We also determined the influence of Phyt (50-100 μM) on cell viability (MTT reduction) in cardiac cells (H9C2). Phyt markedly increased mitochondrial state 4 (resting) and decreased state 3 (ADP-stimulated) and uncoupled (CCCP-stimulated) respirations, besides reducing the respiratory control ratio, ATP synthesis and the activities of the respiratory chain complexes I-III, II, and II-III. This fatty acid also reduced mitochondrial membrane potential and induced swelling in mitochondria supplemented by exogenous Ca, which were prevented by cyclosporin A alone or combined with ADP, suggesting the involvement of the mitochondrial permeability transition (MPT) pore opening. Mitochondrial NAD(P)H content and Ca retention capacity were also decreased by Phyt in the presence of Ca. Finally, Phyt significantly reduced cellular viability (MTT reduction) in cultured cardiomyocytes. The present data indicate that Phyt, at concentrations found in the plasma of patients with Refsum disease, disrupts by multiple mechanisms mitochondrial bioenergetics and Ca homeostasis, which could presumably be involved in the cardiomyopathy of this disease.
Topics: Rats; Animals; Refsum Disease; Phytanic Acid; Calcium; Rats, Wistar; Cardiomyopathies; Energy Metabolism; Mitochondria, Heart; Fatty Acids; Mitochondrial Permeability Transition Pore; Homeostasis
PubMed: 36812958
DOI: 10.1016/j.bbabio.2023.148961 -
Orphanet Journal of Rare Diseases Nov 2006Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some... (Review)
Review
Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years. This group encompasses a large number of rare diseases, the most frequent in Caucasian population being Friedreich ataxia (estimated prevalence 2-4/100,000), ataxia-telangiectasia (1-2.5/100,000) and early onset cerebellar ataxia with retained tendon reflexes (1/100,000). Other forms ARCA are much less common. Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorder), ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features. These diseases are due to mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, alpha-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED), aprataxin in ataxia with oculomotor apraxia (AOA1), and senataxin in ataxia with oculomotor apraxia (AOA2). Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, scanning), electrophysiological examination, and mutation analysis when the causative gene is identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to autosomal recessive inheritance, previous familial history of affected individuals is unlikely. For most ARCA there is no specific drug treatment except for coenzyme Q10 deficiency and abetalipoproteinemia.
Topics: Abetalipoproteinemia; Abnormalities, Multiple; Adolescent; Adult; Brain; Cerebellar Ataxia; Child; Child, Preschool; Chromosome Aberrations; DNA Repair-Deficiency Disorders; Diagnosis, Differential; Friedreich Ataxia; Genes, Recessive; Humans; Infant; Infant, Newborn; Middle Aged; Refsum Disease; Spinocerebellar Degenerations; Syndrome; Vitamin E Deficiency; Xanthomatosis, Cerebrotendinous; Young Adult
PubMed: 17112370
DOI: 10.1186/1750-1172-1-47 -
Nutrients May 2023Adult Refsum disease (ARD) is a rare peroxisomal biogenesis disorder inherited in an autosomal recessive fashion and is often characterized by retinitis pigmentosa,...
Adult Refsum disease (ARD) is a rare peroxisomal biogenesis disorder inherited in an autosomal recessive fashion and is often characterized by retinitis pigmentosa, cerebellar ataxia, and polyneuropathy. Many patients with ARD require diet modification, psychosocial support, and various specialist visits to manage their symptoms. In this study, we explored the quality of life in individuals with ARD by analyzing retrospective survey data collected by the Coordination of Rare Diseases at Sanford (CoRDS) Registry and Global Defeat Adult Refsum Everywhere (DARE) Foundation. Statistical tests used were frequencies, mean, and median. There were 32 respondents, ranging between 11 and 32 responses for each question. The mean age at diagnosis was 35.5 ± 14.5 years (range 6-64) with 36.4% male and 63.6% female respondents. The average age for retinitis pigmentosa diagnosis was 22.8 ± 15.7 years (range 2-61). Dieticians were the most frequently seen (41.7%) for management of low-phytanic-acid diets. Most participants exercise at least once per week (92.5%). Depression symptoms were reported in 86.2% of the participants. Early diagnosis of ARD is important for managing symptoms and preventing progression of visual impairment due to phytanic acid buildup. Interdisciplinary approach should be used for patients to address physical and psychosocial impairments of ARD.
Topics: Adult; Humans; Male; Female; Child, Preschool; Child; Adolescent; Young Adult; Middle Aged; Refsum Disease; Phytanic Acid; Retrospective Studies; Quality of Life; Retinitis Pigmentosa; Life Style
PubMed: 37299514
DOI: 10.3390/nu15112551 -
Case Reports in Ophthalmological... 2021Infantile Refsum disease is a rare peroxisomal biogenesis disorder characterized by impaired alpha-oxidation and accumulation of phytanic acid in the tissues. Patients...
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.
PubMed: 34664020
DOI: 10.1155/2021/1345937 -
Medicina 2013Chronic ataxias are an heterogeneous group of disorders that affect the child at different ages. Thus, the congenital forms, generally non progressive are observed from... (Review)
Review
Chronic ataxias are an heterogeneous group of disorders that affect the child at different ages. Thus, the congenital forms, generally non progressive are observed from first months of life and are expressed by hypotonia and motor delay long before the ataxia became evident. The cerebral magnetic resonance images (MRI) may be diagnostic in some pictures like Joubert syndrome. The group of progressive hereditary ataxias, usually begin after the infant period. The clinical signs are gait instability and ocular apraxia that can be associated with oculocutaneous telangiectasias (ataxia-telangiesctasia) or with sensory neuropathy (Friedreich ataxia). In this review are briefly described congenital ataxias and in more detailed form the progressive hereditary ataxias autosomal recessive, autosomal dominants and mitochondrials. The importance of genetic study is emphasized, because it is the key to obtain the diagnosis in the majority of these diseases. Although now there are no treatments for the majority of progressive hereditary ataxias, some they have like Refsum disease, vitamine E deficiency, Coenzyme Q10 deficiency and others, thus the diagnosis in these cases is even more important. At present the diagnosis of childhood hereditary ataxia not yet treatable is fundamental to obtain suitable handling, determine a precise outcome and to give to the family an opportune genetic counseling.
Topics: Ataxia; Cerebellar Ataxia; Child; Chronic Disease; Female; Humans; Male; Mitochondrial Diseases; Muscle Weakness; Spinocerebellar Degenerations; Ubiquinone
PubMed: 24072050
DOI: No ID Found