RÉSUMÉ
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.
Sujet(s)
Acides aminés/métabolisme , Marqueurs biologiques/analyse , Fibroblastes/anatomopathologie , Métabolome , Protéome , Maladie de Refsum/anatomopathologie , Transcriptome , Fibroblastes/métabolisme , Régulation de l'expression des gènes , Humains , Maladie de Refsum/génétique , Maladie de Refsum/métabolismeRÉSUMÉ
Hereditary motor and sensory neuropathy type Russe (HMSNR), also called CMT4G, is an autosomal recessive inherited peripheral neuropathy (IPN) caused by a founder mutation in the HK1 gene. HMSNR affects only patients with Roma origin, similar to the better known HMSN type Lom clarified earlier. By testing IPN patients with Roma origin, we realized that HMSNR affects surprisingly many patients in the Czech Republic. HMSNR is one of the most frequent types of IPN in this country and appears to be twice more frequent than HMSNL. Pronounced lower limb atrophies and severe deformities often lead to walking inability in even young patients, but hands are usually only mildly affected even after many years of disease duration. The group of 20 patients with HMSNR presented here is the first report about the prevalence of HMSNR from central Europe.
Sujet(s)
Maladie de Charcot-Marie-Tooth/génétique , Effet fondateur , Neuropathie héréditaire motrice et sensitive/génétique , Hexokinase/génétique , Mutation , Maladie de Refsum/génétique , Tsigane , Adolescent , Adulte , Maladie de Charcot-Marie-Tooth/diagnostic , Maladie de Charcot-Marie-Tooth/ethnologie , Maladie de Charcot-Marie-Tooth/anatomopathologie , Enfant , Enfant d'âge préscolaire , République tchèque , Femelle , Expression des gènes , Gènes récessifs , Haplotypes , Neuropathie héréditaire motrice et sensitive/diagnostic , Neuropathie héréditaire motrice et sensitive/ethnologie , Neuropathie héréditaire motrice et sensitive/anatomopathologie , Hétérozygote , Homozygote , Humains , Mâle , Adulte d'âge moyen , Pedigree , Maladie de Refsum/diagnostic , Maladie de Refsum/ethnologie , Maladie de Refsum/anatomopathologieRÉSUMÉ
Classic Refsum disease (RD) is a rare, autosomal recessively-inherited disorder of peroxisome metabolism due to a defect in the initial step in the alpha oxidation of phytanic acid (PA), a C16 saturated fatty acid with four methyl side groups, which accumulates in plasma and lipid enriched tissues (please see van den Brink and Wanders, Cell Mol Life Sci 63:1752-1765, 2006). It has been proposed that the disease complex in RD is in part due to the high affinity of phytanic acid for retinoid X receptors and peroxisome proliferator-activated receptors. Structurally, epidermal hyperplasia, increased numbers of cornified cell layers, presence of cells with lipid droplets in stratum basale and reduction of granular layer to a single layer have been reported by Blanchet-Bardon et al. (The ichthyoses, SP Medical & Scientific Books, New York, pp 65-69, 1978). However, lamellar body (LB) density and secretion were reportedly normal. We recently examined biopsies from four unrelated patients, using both OsO4 and RuO4 post-fixation to evaluate the barrier lipid structural organization. Although lamellar body density appeared normal, individual organelles often had distorted shape, or had non-lamellar domains interspersed with lamellar structures. Some of the organelles seemed to lack lamellar contents altogether, showing instead uniformly electron-dense contents. In addition, we also observed mitochondrial abnormalities in the nucleated epidermis. Stratum granulosum-stratum corneum junctions also showed co-existence of non-lamellar and lamellar domains, indicative of lipid phase separation. Also, partial detachment or complete absence of corneocyte lipid envelopes (CLE) was seen in the stratum corneum of all RD patients. In conclusion, abnormal LB contents, resulting in defective lamellar bilayers, as well as reduced CLEs, likely lead to impaired barrier function in RD.
Sujet(s)
Gouttelettes lipidiques/ultrastructure , Maladie de Refsum/anatomopathologie , Peau/ultrastructure , Sujet âgé , Biopsie , Femelle , Humains , Métabolisme lipidique/génétique , Microscopie électronique , Adulte d'âge moyen , Mixed function oxygenases/génétique , Mutation/génétique , Récepteur de la séquence-2 d'adressage au peroxysome , Récepteurs activés par les proliférateurs de peroxysomes/métabolisme , Récepteurs cytoplasmiques et nucléaires/génétique , Maladie de Refsum/diagnostic , Maladie de Refsum/génétique , Peau/métabolismeRÉSUMÉ
Charcot-Marie-Tooth (CMT) disease is a heterogeneous condition with a large number of clinical, electrophysiological and pathological phenotypes. More than 40 genes are involved. We report a child of gypsy origin with an autosomal recessive demyelinating phenotype. Clinical data, familial history, and electrophysiological studies were in favor of a CMT4 sub-type. The characteristic N-Myc downstream-regulated gene 1 (NDRG1) mutation responsible for this CMT4D phenotype was confirmed: p.R148X. The exact molecular function of the NDRG1 protein has yet to be elucidated.
Sujet(s)
Protéines du cycle cellulaire/génétique , Maladie de Charcot-Marie-Tooth/génétique , Protéines et peptides de signalisation intracellulaire/génétique , Mutation/génétique , Maladie de Refsum/génétique , Maladie de Charcot-Marie-Tooth/anatomopathologie , Enfant , Génotype , Humains , Mâle , Microscopie électronique à transmission , Phénotype , Maladie de Refsum/anatomopathologie , Nerf sural/anatomopathologie , Nerf sural/ultrastructureRÉSUMÉ
Refsum disease is an autosomal recessive disorder of peroxisomal metabolism biochemically characterized by highly elevated concentrations of phytanic acid (Phyt) in a variety of tissues including the cerebellum. Reduction of plasma Phyt levels by dietary restriction intake ameliorates ataxia, a common clinical manifestation of this disorder, suggesting a neurotoxic role for this branched-chain fatty acid. Therefore, considering that the underlying mechanisms of cerebellum damage in Refsum disease are poorly known, in the present study we tested the effects of Phyt on important parameters of bioenergetics, such as the activities of the respiratory chain complexes I to IV, creatine kinase and Na(+), K(+)- ATPase in cerebellum preparations from young rats. The activities of complexes I, II, I-III and II-III and Na(+), K(+)- ATPase were markedly inhibited (65-85%) in a dose-dependent manner by Phyt. In contrast, creatine kinase and complex IV activities were not altered by this fatty acid. Therefore, it is presumed that impairment of the electron flow through the respiratory chain and inhibition of Na(+), K(+)- ATPase that is crucial for synaptic function may be involved in the pathophysiology of the cerebellar abnormalities manifested as ataxia in Refsum disease and in other peroxisomal disorders in which brain Phyt accumulates.
Sujet(s)
Cervelet/enzymologie , Complexe enzymatique de la chaine respiratoire mitochondriale/antagonistes et inhibiteurs , Protéines de tissu nerveux/antagonistes et inhibiteurs , Acide phytanique/pharmacologie , Maladie de Refsum/enzymologie , Sodium-Potassium-Exchanging ATPase/antagonistes et inhibiteurs , Synapses/enzymologie , Animaux , Cervelet/anatomopathologie , Cervelet/physiopathologie , Transport d'électrons/effets des médicaments et des substances chimiques , Complexe enzymatique de la chaine respiratoire mitochondriale/métabolisme , Humains , Protéines de tissu nerveux/métabolisme , Rats , Rat Wistar , Maladie de Refsum/anatomopathologie , Maladie de Refsum/physiopathologie , Sodium-Potassium-Exchanging ATPase/métabolisme , Synapses/anatomopathologieRÉSUMÉ
CMT4D disease is a severe autosomal recessive demyelinating neuropathy with extensive axonal loss leading to early disability, caused by mutations in the N-myc downstream regulated gene 1 (NDRG1). NDRG1 is expressed at particularly high levels in the Schwann cell (SC), but its physiological function(s) are unknown. To help with their understanding, we characterise the phenotype of a new mouse model, stretcher (str), with total Ndrg1 deficiency, in comparison with the hypomorphic Ndrg1 knock-out (KO) mouse. While both models display normal initial myelination and a transition to overt pathology between weeks 3 and 5, the markedly more severe str phenotype suggests that even low Ndrg1 expression results in significant phenotype rescue. Neither model replicates fully the features of CMT4D: although axon damage is present, regenerative capacity is unimpaired and the mice do not display the early severe axonal loss typical of the human disease. The widespread large fibre demyelination coincides precisely with the period of rapid growth of the animals and the dramatic (160-500-fold) increase in myelin volume and length in large fibres. This is followed by stabilisation after week 10, while small fibres remain unaffected. Gene expression profiling of str peripheral nerve reveals non-specific secondary changes at weeks 5 and 10 and preliminary data point to normal proteasomal function. Our findings do not support the proposed roles of NDRG1 in growth arrest, terminal differentiation, gene expression regulation and proteasomal degradation. Impaired SC trafficking failing to meet the considerable demands of nerve growth, emerges as the likely pathogenetic mechanism in NDRG1 deficiency.
Sujet(s)
Protéines du cycle cellulaire/métabolisme , Maladies démyélinisantes/métabolisme , Protéines et peptides de signalisation intracellulaire/métabolisme , Gaine de myéline/métabolisme , Cellules de Schwann/métabolisme , Animaux , Technique de Western , Protéines du cycle cellulaire/génétique , Maladie de Charcot-Marie-Tooth/génétique , Maladie de Charcot-Marie-Tooth/métabolisme , Maladie de Charcot-Marie-Tooth/anatomopathologie , Maladies démyélinisantes/génétique , Maladies démyélinisantes/anatomopathologie , Modèles animaux de maladie humaine , Électrophysiologie , Expression des gènes , Protéines et peptides de signalisation intracellulaire/génétique , Souris , Souris knockout , Gaine de myéline/génétique , Gaine de myéline/anatomopathologie , Maladie de Refsum/génétique , Maladie de Refsum/métabolisme , Maladie de Refsum/anatomopathologie , Cellules de Schwann/anatomopathologie , Nerf ischiatique/métabolisme , Nerf ischiatique/anatomopathologieRÉSUMÉ
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 alpha-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.
Sujet(s)
Calcium/physiologie , Acides gras/pharmacologie , Hippocampe/physiologie , Mitochondries/physiologie , Acide phytanique/pharmacologie , Maladie de Refsum/métabolisme , Maladie de Refsum/anatomopathologie , Animaux , Animaux nouveau-nés , Astrocytes/physiologie , Cellules cultivées , Neurones/physiologie , Oligodendroglie/physiologie , Rats , Rat WistarRÉSUMÉ
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.
Sujet(s)
Ataxie/anatomopathologie , Cellules de Purkinje/anatomopathologie , Maladie de Refsum/anatomopathologie , Animaux , Ataxie/enzymologie , Ataxie/physiopathologie , Automatisation , Comportement animal/effets des médicaments et des substances chimiques , Système nerveux central/malformations , Système nerveux central/effets des médicaments et des substances chimiques , Système nerveux central/enzymologie , Système nerveux central/anatomopathologie , Compléments alimentaires , Modèles animaux de maladie humaine , Démarche/effets des médicaments et des substances chimiques , Ciblage de gène , Vecteurs génétiques , Lipidoses/enzymologie , Lipidoses/anatomopathologie , Mâle , Souris , Mixed function oxygenases/déficit , Mixed function oxygenases/génétique , Neuropathies périphériques/enzymologie , Neuropathies périphériques/anatomopathologie , Phénotype , Acide phytanique/sang , Phytol/administration et posologie , Phytol/pharmacologie , Cellules de Purkinje/effets des médicaments et des substances chimiques , Cellules de Purkinje/enzymologie , Maladie de Refsum/enzymologie , Maladie de Refsum/physiopathologie , Spermatogonies/effets des médicaments et des substances chimiques , Spermatogonies/enzymologie , Spermatogonies/anatomopathologieSujet(s)
Maladie de Refsum/anatomopathologie , Biopsie , Enfant , Diagnostic différentiel , Femelle , Études de suivi , Humains , Nourrisson , Mâle , Nerf sural/anatomopathologieRÉSUMÉ
OBJECTIVES: If Refsum disease (RD) is not considered as a differential at onset of the initial manifestations the diagnosis of RD remains unrecognized for a long time as in the following case. CASE REPORT: A 55-y old Caucasian female with hyperextensible joints developed progressive visual impairment due to retinitis pigmentosa and sensorimotor polyneuropathy of the lower limbs since age 32 y. Screening for causes of polyneuropathy at age 40 y revealed markedly elevated serum phytanic acid (PA) with a maximum value of 293.6 microg/ml (n:<6 microg/ml) why RD was diagnosed. Since age 48 y slowly progressive hypacusis was noted. RD was caused by the known transition A135G in exon 3 of the PHYH gene. Additionally, the polymorphism T153C in exon 3 of the PHYH gene was detected. Upon strict adherence to the Chelsea diet PA levels slightly decreased since onset of this therapy. CONCLUSION: This case confirms that RD remains unrecognized for a long time if RD is not considered as a differential of retinitis pigmentosa as the initial manifestation of the disease. Early recognition of RD is important since there is the therapeutic option of starting a diet.
Sujet(s)
Exons/génétique , Mixed function oxygenases/génétique , Sites d'épissage d'ARN/génétique , Maladie de Refsum/génétique , Rétinite pigmentaire/génétique , ADN/génétique , Régime alimentaire , Femelle , Chromatographie gazeuse-spectrométrie de masse , Humains , Adulte d'âge moyen , Mutation/génétique , Mutation/physiologie , Examen neurologique , Acide phytanique/sang , Maladie de Refsum/complications , Maladie de Refsum/anatomopathologie , Rétinite pigmentaire/complications , Rétinite pigmentaire/anatomopathologie , Triglycéride/génétique , Triglycéride/métabolismeRÉSUMÉ
Refsum's disease is a rare autosomal recessive disorder with clinical features including retinitis pigmentosa, anosmia, deafness, chronic sensory-motor neuropathy, ataxia and the accumulation of phytanic acid in blood plasma and body tissues. We report the occurrence of Refsum's disease in two sisters, both presenting with acute demyelinating polyneuropathy mimicking the familial Guillain Barre syndrome. Thus, when GBS is suspected, particularly in cases of familial recurrence as well as in atypical cases of acute polyneuropathy, the diagnosis of Refsum's disease should be considered, looking for other features of the disease and, if appropriate, testing plasma phytanic acid levels.
Sujet(s)
Syndrome de Guillain-Barré/diagnostic , Maladie de Refsum/diagnostic , Adulte , Diagnostic différentiel , Femelle , Syndrome de Guillain-Barré/anatomopathologie , Humains , Pedigree , Acide phytanique/sang , Maladie de Refsum/génétique , Maladie de Refsum/anatomopathologieRÉSUMÉ
The saturated branched chain fatty acid, phytanic acid, a degradation product of chlorophyll, accumulates in Refsum disease, an inherited peroxisomal disorder with neurological clinical features. To elucidate the pathogenic mechanism, we investigated the influence of phytanic acid on cellular physiology of rat hippocampal astrocytes. Phytanic acid (100 microM) induced an immediate transient increase in cytosolic Ca2+ concentration, followed by a plateau. The peak of this biphasic Ca2+ response was largely independent of extracellular Ca2+, indicating activation of cellular Ca2+ stores by phytanic acid. Phytanic acid depolarized mitochondria without causing in situ swelling of mitochondria. The slow decrease of mitochondrial potential is not consistent with fast and simultaneous opening of the mitochondrial permeability transition pore. However, phytanic acid induced substantial generation of reactive oxygen species. Phytanic acid caused astroglia cell death after a few hours of exposure. We suggest that the cytotoxic effect of phytanic acid seems to be due to a combined action on Ca2+ regulation, mitochondrial depolarization, and increased ROS generation in brain cells.
Sujet(s)
Astrocytes/métabolisme , Calcium/métabolisme , Mitochondries/métabolisme , Acide phytanique/métabolisme , Maladie de Refsum/métabolisme , Animaux , Animaux nouveau-nés , Astrocytes/effets des médicaments et des substances chimiques , Astrocytes/anatomopathologie , Signalisation calcique/effets des médicaments et des substances chimiques , Signalisation calcique/physiologie , Survie cellulaire/effets des médicaments et des substances chimiques , Survie cellulaire/physiologie , Cellules cultivées , Cytosol/effets des médicaments et des substances chimiques , Cytosol/métabolisme , Hippocampe/effets des médicaments et des substances chimiques , Hippocampe/métabolisme , Hippocampe/physiopathologie , Homéostasie/effets des médicaments et des substances chimiques , Homéostasie/physiologie , Membranes intracellulaires/effets des médicaments et des substances chimiques , Membranes intracellulaires/anatomopathologie , Potentiels de membrane/effets des médicaments et des substances chimiques , Potentiels de membrane/physiologie , Mitochondries/effets des médicaments et des substances chimiques , Acide phytanique/toxicité , Rats , Rat Wistar , Maladie de Refsum/étiologie , Maladie de Refsum/anatomopathologie , Régulation positive/effets des médicaments et des substances chimiques , Régulation positive/physiologieRÉSUMÉ
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 alpha-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.
Sujet(s)
Récepteurs cytoplasmiques et nucléaires/génétique , Maladie de Refsum/génétique , Acetyl-coA C-acetyltransferase/génétique , Acetyl-coA C-acetyltransferase/métabolisme , Adulte , Allèles , Cellules cultivées , Chromosomes humains de la paire 6 , Femelle , Fibroblastes/cytologie , Fibroblastes/enzymologie , Liaison génétique , Humains , Mâle , Mixed function oxygenases/génétique , Mixed function oxygenases/métabolisme , Mutation , Récepteur de la séquence-2 d'adressage au peroxysome , Acide phytanique/sang , Acétalphosphatides/biosynthèse , Acétalphosphatides/génétique , Maladie de Refsum/anatomopathologie , Maladie de Refsum/physiopathologie , Fratrie , Peau/cytologieRÉSUMÉ
Patients with the Zellweger syndrome and its variants have very low levels of docosahexaenoic acid (DHA) in the brain, retina, and other tissues. Such a marked DHA deficiency could be related to the pathogenesis of peroxisomal disorders. Therefore, restoring the DHA levels in these patients can probably improve the clinical course of the disease. With this rationale, 20 patients with generalized peroxisomal disorders have been treated to date with DHA ethyl ester, at daily doses of 100-500 mg, for variable periods of time. Treatment has been always accompanied by a nutritious diet, normal for the age, in order to provide all the necessary nutrients and avoid a polyunsaturated fatty acid (PUFA) imbalance. The most constant improvement has been normalization of the DHA levels and liver function. Vision has improved in about half the patients and muscle tone has generally increased. Magnetic resonance imaging (MRI) examination revealed improvement of myelination in 9 patients. Significantly, the clinical improvement has been most marked in those patients who started the treatment before 6 mo of age. Biochemically, the plasma very long-chain fatty acids (VLCFA) 26:0 and 26:1n-9 decreased markedly despite the complete diet provided. In erythrocytes, the plasmalogen ratio 18: ODMA/18:0 increased in most cases, and sometimes even normalized. All these beneficial effects suggest that DHA deficiency plays a fundamental role in the pathogenesis of peroxisomal disease. Because DHA accretion is maximal during early brain development, it is essential to initiate the treatment as soon as possible. Otherwise, restoration of brain DHA levels and prevention of further damage will not be possible.
Sujet(s)
Adrénoleucodystrophie/traitement médicamenteux , Encéphale/métabolisme , Acide docosahexaénoïque/usage thérapeutique , Maladie de Refsum/traitement médicamenteux , Syndrome de Zellweger/traitement médicamenteux , Adrénoleucodystrophie/métabolisme , Adrénoleucodystrophie/anatomopathologie , Facteurs âges , Encéphale/embryologie , Encéphale/anatomopathologie , Enfant , Enfant d'âge préscolaire , Maladies démyélinisantes/prévention et contrôle , Acide docosahexaénoïque/administration et posologie , Acide docosahexaénoïque/sang , Acide docosahexaénoïque/pharmacocinétique , Membrane érythrocytaire/composition chimique , Femelle , Âge gestationnel , Humains , Nourrisson , Nouveau-né , Métabolisme lipidique , Foie/métabolisme , Imagerie par résonance magnétique , Mâle , Lipides membranaires/métabolisme , Gaine de myéline/métabolisme , Gaine de myéline/anatomopathologie , Péroxysomes/métabolisme , Acétalphosphatides/métabolisme , Qualité de vie , Maladie de Refsum/métabolisme , Maladie de Refsum/anatomopathologie , Résultat thérapeutique , Syndrome de Zellweger/métabolisme , Syndrome de Zellweger/anatomopathologieRÉSUMÉ
Infantile Refsum disease (IRD) appears with varying degrees of impaired vision, hearing loss, developmental delays, and neuromotor deficiencies. We report on four Amish sibs with IRD from a consanguineous marriage; biochemical testing supported the diagnosis of IRD. Of particular interest in this sibship are characteristic poorly formed yellow-orange teeth in at least three of the four affected sibs and behavior problems in the affected females.
Sujet(s)
Maladie de Refsum/génétique , Adolescent , Antidépresseurs/usage thérapeutique , Enfant , Consanguinité , Femelle , Fluoxétine/usage thérapeutique , Humains , Lorazépam/usage thérapeutique , Mâle , Maladie de Refsum/traitement médicamenteux , Maladie de Refsum/anatomopathologie , Maladie de Refsum/physiopathologie , Rispéridone/usage thérapeutiqueRÉSUMÉ
Refsum's disease, or heredopathia atactica polyneuritiformis, is a peroxisomal disorder leading to the accumulation of phytanic acid throughout the body. It affects sensory and motor neurons and the skeletal system. Peripheral neuropathy, ataxia, blindness, deafness, and skeletal hyperostosis are significant findings used in the diagnosis of the disease.
Sujet(s)
Pied/anatomopathologie , Maladie de Refsum/anatomopathologie , Sujet âgé , Issue fatale , Humains , Mâle , Maladie de Refsum/diagnostic , Maladie de Refsum/étiologieRÉSUMÉ
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.
Sujet(s)
Chondrodysplasie ponctuée rhizomélique/métabolisme , Microcorps/métabolisme , Acide phytanique/métabolisme , Maladie de Refsum/métabolisme , Transport biologique/physiologie , Cellules cultivées , Chondrodysplasie ponctuée rhizomélique/anatomopathologie , Coenzyme A/métabolisme , Fibroblastes/métabolisme , Humains , Hydroxylation , Oxydoréduction , Acide phytanique/analogues et dérivés , Valeurs de référence , Maladie de Refsum/anatomopathologieRÉSUMÉ
Author reports a case of neural muscular atrophy of a 59-year-old female patient, verified by autopsy and histologic examination. The histologic picture corresponded to the both I. and III. type of sensory-motor polyneuropathyes.