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2.
JIMD Rep ; 34: 71-75, 2017.
Article in English | MEDLINE | ID: mdl-27557811

ABSTRACT

BACKGROUND: Peroxisome biogenesis disorders (PBDs) may have a variable clinical expression, ranging from severe, lethal to mild phenotypes with progressive evolution. PBDs are autosomal recessive disorders caused by mutations in PEX genes, which encode proteins called peroxins, involved in the assembly of the peroxisome. Patient Description: We herein report a patient who is currently 9 years old and who is compound heterozygous for two novel mutations in the PEX3 gene. RESULTS: Mild biochemical abnormalities of the peroxisomal parameters suggested a Zellweger spectrum defect in the patient. Sequence analysis of the PEX3 gene identified two novel heterozygous, pathogenic mutations. CONCLUSION: Mutations in PEX3 usually result in a severe, early lethal phenotype. We report a patient compound heterozygous for two novel mutations in the PEX3 gene, who is less affected than previously reported patients with a defect in the PEX3 gene. Our findings indicate that PEX3 defects may cause a disease spectrum similar as previously observed for other PEX gene defects.

3.
JIMD Rep ; 27: 11-5, 2016.
Article in English | MEDLINE | ID: mdl-26404458

ABSTRACT

We report a baby with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency who presented on day 2 with poor feeding and lethargy. She was floppy with hypoglycaemia (1.8 mmol/l) and hyperammonaemia (182 µmol/l). Despite correction of these and a continuous intravenous infusion of glucose at 4.5-6.2 mg/kg/min, she developed generalised tonic clonic seizures on day 3. She also suffered two episodes of pulseless ventricular tachycardia, from which she was resuscitated successfully. Unfortunately, she died on day 5, following a third episode of pulseless ventricular tachycardia. Arrhythmias are generally thought to be rarer in MCAD deficiency than in disorders of long-chain fatty acid oxidation. This is, however, the sixth report of ventricular tachyarrhythmias in MCAD deficiency. Five of these involved neonates and it may be that patients with MCAD deficiency are particularly prone to ventricular arrhythmias in the newborn period. Three of the patients (including ours) had normal blood glucose concentrations at the time of the arrhythmias and had been receiving intravenous glucose for many hours. These cases suggest that arrhythmias can be induced by medium-chain acylcarnitines or other metabolites accumulating in MCAD deficiency. Ventricular tachyarrhythmias can occur in MCAD deficiency, especially in neonates.

4.
Clin Genet ; 89(2): 193-7, 2016 Feb.
Article in English | MEDLINE | ID: mdl-25827434

ABSTRACT

Carnitine palmitoyltransferase II (CPT2) deficiency is a rare inborn error of mitochondrial fatty acid metabolism associated with various phenotypes. Whereas most patients present with postnatal signs of energetic failure affecting muscle and liver, a small subset of patients presents antenatal malformations including brain dysgenesis and neuronal migration defects. Here, we report recurrence of severe cerebral dysgenesis with Dandy-Walker malformation in three successive pregnancies and review previously reported antenatal cases. Interestingly, we also report that acylcarnitines profile, tested retrospectively on the amniotic fluid of last pregnancy, was not sensitive enough to allow reliable prenatal diagnosis of CPT2 deficiency. Finally, because fetuses affected by severe cerebral malformations are frequently aborted, CPT2 deficiency may be underestimated and fatty acid oxidation disorders should be considered when faced with a fetus with Dandy-Walker anomaly or another brain dysgenesis.


Subject(s)
Carnitine O-Palmitoyltransferase/deficiency , Metabolism, Inborn Errors/diagnosis , Adult , Fatal Outcome , Female , Humans , Infant, Newborn , Male , Pregnancy
5.
Neurology ; 78(17): 1304-8, 2012 Apr 24.
Article in English | MEDLINE | ID: mdl-22459681

ABSTRACT

OBJECTIVE: Peroxisomal blood tests are generally considered to be conclusive. We observed several patients with a clinical and MRI phenotype suggestive of an infantile onset peroxisomal defect, but no convincing abnormalities in initial peroxisomal blood tests. Brain MRI showed typical abnormalities as observed in the neonatal adrenoleukodystrophy variant of infantile peroxisomal disorders. Our aim was to evaluate the accuracy of this MRI diagnosis with further peroxisomal testing. METHODS: We searched our database of unclassified leukoencephalopathies and found 6 such patients. We collected clinical data and scored available MRIs of these patients. We performed further peroxisomal studies in fibroblasts, including immunofluorescence microscopy analysis with antibodies against catalase, a peroxisomal matrix enzyme. We performed complementation analysis and analyzed the suspected genes. RESULTS: We confirmed the diagnosis of Zellweger spectrum disorder in 3 patients and D-bifunctional protein deficiency in the others. The clinical findings were within the spectrum known for these diagnoses. Sequential MRIs showed that the abnormalities started in the hilus of the dentate nucleus and superior cerebellar peduncles. Subsequently, the cerebellar white matter and brainstem tracts were affected, followed by the parieto-occipital white matter, splenium of the corpus callosum, and posterior limb of the internal capsule. Eventually, all cerebral white matter became abnormal. The thalamus was typically affected as well. CONCLUSIONS: If MRI reveals abnormalities suggestive of infantile onset peroxisomal defects, negative peroxisomal blood tests do not exclude the diagnosis. Further tests in fibroblasts should be performed, most importantly immunofluorescence microscopy analysis with antibodies against catalase to stain peroxisomes.


Subject(s)
Brain/pathology , Magnetic Resonance Imaging , Peroxisomal Disorders/diagnosis , Brain Stem/pathology , Cerebellar Nuclei/pathology , Cerebellum/pathology , Child, Preschool , Corpus Callosum/pathology , Diagnosis, Differential , Fibroblasts/pathology , Humans , Infant, Newborn , Internal Capsule/pathology , Male , Refsum Disease/diagnosis , Retrospective Studies , Zellweger Syndrome/diagnosis
6.
Biochim Biophys Acta ; 1801(3): 272-80, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20064629

ABSTRACT

Peroxisomes play an essential role in cellular lipid metabolism as exemplified by the existence of a number of genetic diseases in humans caused by the impaired function of one of the peroxisomal enzymes involved in lipid metabolism. Key pathways in which peroxisomes are involved include: (1.) fatty acid beta-oxidation; (2.) etherphospholipid biosynthesis, and (3.) fatty acid alpha-oxidation. In this paper we will describe these different pathways in some detail and will provide an overview of peroxisomal disorders of metabolism and in addition discuss the toxicity of the intermediates of peroxisomal metabolism as they accumulate in the different peroxisomal deficiencies.


Subject(s)
Fatty Acids/metabolism , Lipid Metabolism Disorders/metabolism , Lipid Peroxidation , Peroxisomes/metabolism , Animals , Disease Models, Animal , Humans , Metabolic Networks and Pathways
7.
J Neurol Neurosurg Psychiatry ; 79(4): 448-50, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18032455

ABSTRACT

Alpha-methylacyl-CoA racemase (AMACR) deficiency is a rare disorder of fatty acid metabolism which has recently been described in three adult cases. We have identified a further patient with clinical features of a relapsing encephalopathy, seizures and cognitive decline over a 40 year period. Biochemical studies revealed grossly elevated plasma pristanic acid levels, and a deficiency of AMACR in skin fibroblasts. Sequence analysis of AMACR cDNA identified a homozygous point mutation (c154T>C). This case adds to the phenotypic variation seen in this peroxisomal disorder and highlights the importance of screening for plasma pristanic acid levels in patients with unexplained relapsing encephalopathies.


Subject(s)
Brain Diseases, Metabolic, Inborn/diagnosis , Brain Diseases, Metabolic, Inborn/genetics , Dementia/diagnosis , Dementia/genetics , Fatty Acids/blood , Heredodegenerative Disorders, Nervous System/diagnosis , Heredodegenerative Disorders, Nervous System/genetics , Peroxisomal Disorders/diagnosis , Peroxisomal Disorders/genetics , Racemases and Epimerases/deficiency , Refsum Disease/diagnosis , Refsum Disease/genetics , Amino Acid Substitution/genetics , Brain/pathology , Cerebral Cortex/pathology , Female , Gene Expression Regulation, Enzymologic/physiology , Homozygote , Humans , Magnetic Resonance Imaging , Middle Aged , Neurologic Examination , Neuropsychological Tests , Phenotype , Point Mutation/genetics , Recurrence , Sequence Analysis, DNA
8.
J Lipid Res ; 48(1): 77-85, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17015885

ABSTRACT

Phytol, a branched-chain fatty alcohol, is the naturally occurring precursor of phytanic and pristanic acid, branched-chain fatty acids that are both ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARalpha). To investigate the metabolism of phytol and the role of PPARalpha in its regulation, wild-type and PPARalpha knockout (PPARalpha-/-) mice were fed a phytol-enriched diet or, for comparison, a diet enriched with Wy-14,643, a synthetic PPARalpha agonist. After the phytol-enriched diet, phytol could only be detected in small intestine, the site of uptake, and liver. Upon longer duration of the diet, the level of the (E)-isomer of phytol increased significantly in the liver of PPARalpha-/- mice compared with wild-type mice. Activity measurements of the enzymes involved in phytol metabolism showed that treatment with a PPARalpha agonist resulted in a PPARalpha-dependent induction of at least two steps of the phytol degradation pathway in liver. Furthermore, the enzymes involved showed a higher activity toward the (E)-isomer than the (Z)-isomer of their respective substrates, indicating a stereospecificity toward the metabolism of (E)-phytol. In conclusion, the results described here show that the conversion of phytol to phytanic acid is regulated via PPARalpha and is specific for the breakdown of (E)-phytol.


Subject(s)
PPAR alpha/deficiency , PPAR alpha/physiology , Phytic Acid/metabolism , Phytol/metabolism , Animals , Homeostasis , Immunoblotting , Mice , Mice, Knockout , PPAR alpha/genetics , Peroxisome Proliferators/pharmacology , Pyrimidines/pharmacology , Reverse Transcriptase Polymerase Chain Reaction
9.
Mol Genet Metab ; 89(1-2): 111-5, 2006.
Article in English | MEDLINE | ID: mdl-16837225

ABSTRACT

Sjögren-Larsson syndrome (SLS) is caused by a deficiency of fatty aldehyde dehydrogenase (FALDH), encoded by the ALDH3A2 gene. In animal studies, the expression of the murine ortholog of FALDH, has been shown to be under the control of peroxisome proliferator-activated receptor alpha (PPARalpha). In the present study, we investigated whether the hypolipidemic drug bezafibrate, which is a pan-agonist of all PPAR-isoforms, might induce FALDH activity in human fibroblasts of control subjects and SLS patients that still have some residual FALDH activity. Our results show that FALDH activity was induced 1.4-fold after a 3-day treatment with 800 microM bezafibrate in fibroblasts of control subjects. Interestingly, in fibroblasts of two SLS patients homozygous for the p.R228C substitution, FALDH activity could be induced to 37% of control values by bezafibrate treatment. mRNA analysis in fibroblasts of these patients also revealed a mean 1.8-fold induction of FALDH mRNA after bezafibrate treatment. No induction was observed in fibroblasts of patients with mutations that cause instability of FALDH mRNA or that result in a protein without any residual activity. These data suggest that bezafibrate treatment could be effective in patients with expression of FALDH protein and some residual enzyme activity. Further research is needed to resolve whether patients could benefit from treatment with bezafibrate.


Subject(s)
Aldehyde Oxidoreductases/metabolism , Bezafibrate/therapeutic use , Hypolipidemic Agents/therapeutic use , Peroxisome Proliferator-Activated Receptors/agonists , Sjogren-Larsson Syndrome/drug therapy , Aldehyde Oxidoreductases/genetics , Cells, Cultured , Fibroblasts/drug effects , Fibroblasts/enzymology , Humans , Hypolipidemic Agents/pharmacology , Sjogren-Larsson Syndrome/enzymology , Up-Regulation
10.
Neuropediatrics ; 37(2): 95-8, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16773508

ABSTRACT

We present a rare case of peroxisomal acyl-CoA oxidase deficiency that was not detected by the common metabolic screening program for peroxisomal disorders. The patient presented with a typical MRI pattern showing pachygyria, perisylvian polymicrogyria, cerebral and cerebellar white matter abnormalities, and facial dysmorphia, progressive psychomotor retardation, deafness, retinopathy, peripheral neuropathy, and infantile seizures strongly indicative for a peroxisomal disorder. Yet, repetitive measurements of very long-chain fatty acids (VLCFAs) and phytanic acid in serum and plasma as well as plasmalogens in erythrocytes revealed normal values apparently excluding a peroxisomal defect (methods of measurement published by Moser and co-workers in 1980 [4 ] and 1981 [2 ]). Subsequent biochemical investigation in cultured skin fibroblasts of the patient, however, revealed elevated concentrations of VLCFAs, deficient oxidation of C26:0, but normal oxidation of both phytanic acid and pristanic acid and normal DE NOVO plasmalogen synthesis, indicative for a defect in the peroxisomal beta-oxidation system. Enzymatic studies in these fibroblasts pointed to peroxisomal acyl-CoA oxidase deficiency and subsequent molecular analyses revealed a homozygous acceptor splice site mutation IVS3-1G>A in the ACOX1 gene (MIM *609751).


Subject(s)
Acyl-CoA Oxidase/deficiency , Fatty Acids/metabolism , Peroxisomal Disorders/diagnosis , Peroxisomal Disorders/metabolism , Acyl-CoA Oxidase/genetics , Humans , Infant , Male , Peroxisomal Disorders/genetics
11.
Am J Hum Genet ; 78(6): 1046-52, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16685654

ABSTRACT

In this report, we describe the first known patient with a deficiency of sterol carrier protein X (SCPx), a peroxisomal enzyme with thiolase activity, which is required for the breakdown of branched-chain fatty acids. The patient presented with torticollis and dystonic head tremor as well as slight cerebellar signs with intention tremor, nystagmus, hyposmia, and azoospermia. Magnetic resonance imaging showed leukencephalopathy and involvement of the thalamus and pons. Metabolite analyses of plasma revealed an accumulation of the branched-chain fatty acid pristanic acid, and abnormal bile alcohol glucuronides were excreted in urine. In cultured skin fibroblasts, the thiolytic activity of SCPx was deficient, and no SCPx protein could be detected by western blotting. Mutation analysis revealed a homozygous 1-nucleotide insertion, 545_546insA, leading to a frameshift and premature stop codon (I184fsX7).


Subject(s)
Carrier Proteins/genetics , Dementia, Vascular/diagnosis , Dystonia/diagnosis , Polyneuropathies/diagnosis , Torticollis/diagnosis , Adult , Carrier Proteins/blood , Codon, Nonsense , Dementia, Vascular/genetics , Dystonia/genetics , Fatty Acids/blood , Frameshift Mutation , Glucuronides/urine , Humans , Magnetic Resonance Imaging , Male , Polyneuropathies/genetics , Pons/pathology , Syndrome , Thalamus/pathology , Torticollis/genetics
12.
FEBS Lett ; 580(8): 2092-6, 2006 Apr 03.
Article in English | MEDLINE | ID: mdl-16546181

ABSTRACT

Phytol is a naturally occurring precursor of phytanic acid. The last step in the conversion of phytol to phytanoyl-CoA is the reduction of phytenoyl-CoA mediated by an, as yet, unidentified enzyme. A candidate for this reaction is a previously described peroxisomal trans-2-enoyl-CoA reductase (TER). To investigate this, human TER was expressed in E. coli as an MBP-fusion protein. The purified recombinant protein was shown to have high reductase activity towards trans-phytenoyl-CoA, but not towards the peroxisomal beta-oxidation intermediates C24:1-CoA and pristenoyl-CoA. In conclusion, our results show that human TER is responsible for the reduction of phytenoyl-CoA to phytanoyl-CoA in peroxisomes.


Subject(s)
NADH, NADPH Oxidoreductases/metabolism , Peroxisomes/enzymology , Phytol/metabolism , Coenzyme A/metabolism , Gene Expression , Humans , NADH, NADPH Oxidoreductases/isolation & purification , Oxidoreductases Acting on CH-CH Group Donors , Phytanic Acid/analogs & derivatives , Phytanic Acid/metabolism , Recombinant Fusion Proteins/isolation & purification , Recombinant Fusion Proteins/metabolism , Substrate Specificity
13.
J Lipid Res ; 46(4): 716-26, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15654129

ABSTRACT

Branched-chain fatty acids (such as phytanic and pristanic acid) are ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARalpha) in vitro. To investigate the effects of these physiological compounds in vivo, wild-type and PPARalpha-deficient (PPARalpha-/-) mice were fed a phytol-enriched diet. This resulted in increased plasma and liver levels of the phytol metabolites phytanic and pristanic acid. In wild-type mice, plasma fatty acid levels decreased after phytol feeding, whereas in PPARalpha-/- mice, the already elevated fatty acid levels increased. In addition, PPARalpha-/- mice were found to be carnitine deficient in both plasma and liver. Dietary phytol increased liver free carnitine in wild-type animals but not in PPARalpha-/- mice. Investigation of carnitine biosynthesis revealed that PPARalpha is likely involved in the regulation of carnitine homeostasis. Furthermore, phytol feeding resulted in a PPARalpha-dependent induction of various peroxisomal and mitochondrial beta-oxidation enzymes. In addition, a PPARalpha-independent induction of catalase, phytanoyl-CoA hydroxylase, carnitine octanoyltransferase, peroxisomal 3-ketoacyl-CoA thiolase, and straight-chain acyl-CoA oxidase was observed. In conclusion, branched-chain fatty acids are physiologically relevant ligands of PPARalpha in mice. These findings are especially relevant for disorders in which branched-chain fatty acids accumulate, such as Refsum disease and peroxisome biogenesis disorders.


Subject(s)
Diet , Fatty Acids/metabolism , PPAR alpha/metabolism , Phytol/pharmacology , Signal Transduction/drug effects , Animals , Carnitine/biosynthesis , Gene Deletion , Liver/drug effects , Liver/metabolism , Mice , Mice, Knockout , Mitochondria, Liver/metabolism , Oxidation-Reduction , PPAR alpha/deficiency , PPAR alpha/genetics , Peroxisomes/enzymology , Phytol/metabolism
16.
Neurology ; 62(11): 2077-81, 2004 Jun 08.
Article in English | MEDLINE | ID: mdl-15184617

ABSTRACT

OBJECTIVE: To determine the enzymatic defect in a patient with ataxia, dysarthric speech, dry skin, hypotonia, and absent reflexes. The patient was previously diagnosed with a presumed deficiency of trihydroxycholestanoyl-CoA oxidase. BACKGROUND: Peroxisomes harbor a variety of metabolic functions, including fatty acid beta-oxidation, etherphospholipid biosynthesis, phytanic acid alpha-oxidation, and L-pipecolic acid oxidation. This patient was previously described with an isolated peroxisomal beta-oxidation defect caused by a deficiency of the enzyme trihydroxycholestanoyl-CoA oxidase. This was based on the pattern of accumulating metabolites. METHODS: Measurement of beta-oxidation enzymes, peroxisomal biochemical analysis in body fluids and cultured skin fibroblasts, and DNA analysis of the PEX12 gene were performed. RESULTS: An isolated beta-oxidation defect in this patient was excluded by measurement of the various beta-oxidation enzymes. The authors found that the patient had a peroxisome biogenesis disorder caused by mutations in the PEX12 gene, although all peroxisomal functions in cultured skin fibroblasts were normal. CONCLUSIONS: The absence of clear peroxisomal abnormalities in the patient's fibroblasts, including a normal peroxisomal localization of catalase, implies that even when all peroxisomal functions in fibroblasts are normal, a peroxisome biogenesis disorder cannot be fully excluded, and further studies may be needed. In addition, the authors' findings imply that there is no longer evidence for the existence of trihydroxycholestanoyl-CoA oxidase deficiency as a distinct disease entity.


Subject(s)
Cholestanols/blood , Membrane Proteins/deficiency , Peroxisomes/metabolism , Amino Acid Sequence , Animals , Ataxia/enzymology , Ataxia/genetics , Catalase/analysis , Child, Preschool , Consensus Sequence , DNA Mutational Analysis , Diagnostic Errors , Dysarthria/enzymology , Dysarthria/genetics , Erythrocytes/metabolism , Female , Fibroblasts/enzymology , Fibroblasts/metabolism , Fibroblasts/ultrastructure , Fungi/genetics , Humans , Intellectual Disability/enzymology , Intellectual Disability/genetics , Mammals/genetics , Membrane Proteins/genetics , Molecular Sequence Data , Muscle Hypotonia/enzymology , Muscle Hypotonia/genetics , Oxidation-Reduction , Oxidoreductases/deficiency , Peroxisomes/physiology , Phytanic Acid/adverse effects , Phytanic Acid/blood , Sequence Alignment , Sequence Homology, Amino Acid
17.
Am J Hum Genet ; 70(6): 1589-93, 2002 Jun.
Article in English | MEDLINE | ID: mdl-11992265

ABSTRACT

In this report, we reinvestigate the only patient ever reported with a deficiency of peroxisomal 3-ketoacyl-CoA thiolase (THIO). At the time when they were described, the abnormalities in this patient, which included accumulation of very-long-chain fatty acids and the bile-acid intermediate trihydroxycholestanoic acid, were believed to be the logical consequence of a deficiency of the peroxisomal beta-oxidation enzyme THIO. In light of the current knowledge of the peroxisomal beta-oxidation system, however, the reported biochemical aberrations can no longer be explained by a deficiency of this thiolase. In this study, we show that the true defect in this patient is at the level of d-bifunctional protein (DBP). Immunoblot analysis revealed the absence of DBP in postmortem brain of the patient, whereas THIO was normally present. In addition, we found that the patient had a homozygous deletion of part of exon 3 and intron 3 of the DBP gene, resulting in skipping of exon 3 at the cDNA level. Our findings imply that the group of single-peroxisomal beta-oxidation-enzyme deficiencies is limited to straight-chain acyl-CoA oxidase, DBP, and alpha-methylacyl-CoA racemase deficiency and that there is no longer evidence for the existence of THIO deficiency as a distinct clinical entity.


Subject(s)
17-Hydroxysteroid Dehydrogenases , 3-Hydroxyacyl CoA Dehydrogenases/genetics , 3-Hydroxyacyl CoA Dehydrogenases/metabolism , Acetyl-CoA C-Acyltransferase/deficiency , Enoyl-CoA Hydratase , Hydro-Lyases/genetics , Hydro-Lyases/metabolism , Multienzyme Complexes/genetics , Multienzyme Complexes/metabolism , Peroxisomes/enzymology , 3-Hydroxyacyl CoA Dehydrogenases/chemistry , Amino Acid Sequence , Blotting, Western , Brain/enzymology , Brain/metabolism , Exons/genetics , Fibroblasts , Humans , Hydro-Lyases/chemistry , Introns/genetics , Kidney/enzymology , Kidney/metabolism , Multienzyme Complexes/chemistry , Peroxisomal Multifunctional Protein-2 , Peroxisomes/genetics , Zellweger Syndrome/enzymology , Zellweger Syndrome/metabolism
18.
J Lipid Res ; 43(3): 438-44, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11893780

ABSTRACT

Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid derived from dietary sources and broken down in the peroxisome to pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) via alpha-oxidation. Pristanic acid then undergoes beta-oxidation in peroxisomes. Phytanic acid naturally occurs as a mixture of (3S,7R,11R)- and (3R,7R,11R)-diastereomers. In contrast to the alpha-oxidation system, peroxisomal beta-oxidation is stereospecific and only accepts (2S)-isomers. Therefore, a racemase called alpha-methylacyl-CoA racemase is required to convert (2R)-pristanic acid into its (2S)-isomer. To further investigate the stereochemistry of the peroxisomal oxidation systems and their substrates, we have developed a method using gas-liquid chromatography-mass spectrometry to analyze the isomers of phytanic, pristanic, and trimethylundecanoic acid in plasma from patients with various peroxisomal fatty acid oxidation defects. In this study, we show that in plasma of patients with a peroxisomal beta-oxidation deficiency, the relative amounts of the two diastereomers of pristanic acid are almost equal, whereas in patients with a defect of alpha-methylacyl-CoA racemase, (2R)-pristanic acid is the predominant isomer. Furthermore, we show that in alpha-methylacyl-CoA racemase deficiency, not only pristanic acid accumulates, but also one of the metabolites of pristanic acid, 2610-trimethylundecanoic acid, providing direct in vivo evidence for the requirement of this racemase for the complete degradation of pristanic acid.


Subject(s)
Fatty Acids/metabolism , Mixed Function Oxygenases/metabolism , Oxidoreductases/metabolism , Peroxisomal Disorders/metabolism , Phytanic Acid/metabolism , Racemases and Epimerases/metabolism , Fatty Acids/blood , Fatty Acids/chemistry , Humans , Mixed Function Oxygenases/deficiency , Oxidation-Reduction , Oxidoreductases/deficiency , Peroxisomal Disorders/blood , Peroxisomal Disorders/enzymology , Phytanic Acid/blood , Phytanic Acid/chemistry , Racemases and Epimerases/deficiency , Refsum Disease/blood , Refsum Disease/enzymology , Refsum Disease/metabolism , Stereoisomerism
19.
J Neurol Neurosurg Psychiatry ; 72(3): 396-9, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11861706

ABSTRACT

AN adult onset novel disorder of peroxisomal function is described, characterised by retinitis pigmentosa resulting in progressive visual failure, learning difficulties, a peripheral neuropathy, and hypogonadism. The defect results in accumulation of pristanic acid, and the bile acid intermediates, dihydroxycholestanoic and trihydroxycholestanoic acid, and is due to a deficiency of alpha-methylacyl-CoA racemase, making this the first fully characterised description of this defect. Screening of patients with retinitis pigmentosa should be extended to include pristanic acid and/or bile acid intermediate concentrations, as dietary measures offer a potential treatment for the disorder.


Subject(s)
Abnormalities, Multiple/diagnosis , Fatty Acids/blood , Learning Disabilities/diagnosis , Peroxisomal Disorders/diagnosis , Racemases and Epimerases/deficiency , Retinitis Pigmentosa/diagnosis , Abnormalities, Multiple/enzymology , Abnormalities, Multiple/genetics , Chromosome Aberrations , Genes, Recessive/genetics , Humans , Learning Disabilities/enzymology , Learning Disabilities/genetics , Male , Middle Aged , Peroxisomal Disorders/enzymology , Peroxisomal Disorders/genetics , Retinitis Pigmentosa/enzymology , Retinitis Pigmentosa/genetics
20.
J Lipid Res ; 42(12): 1987-95, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11734571

ABSTRACT

DHA (C22:6n-3) is an important PUFA implicated in a number of (patho)physiological processes. For a long time, the exact mechanism of DHA formation has remained unclear, but now it is known that it involves the production of tetracosahexaenoic acid (C24:6n-3) from dietary linolenic acid (C18:3n-3) via a series of elongation and desaturation reactions, followed by beta-oxidation of C24:6n-3 to C22:6n-3. Although DHA is deficient in patients lacking peroxisomes, the intracellular site of retroconversion of C24:6n-3 has remained controversial. By making use of fibroblasts from patients with defined mitochondrial and peroxisomal fatty acid oxidation defects, we show in this article that peroxisomes, and not mitochondria, are involved in DHA formation by catalyzing the beta-oxidation of C24:6n-3 to C22:6n-3. Additional studies of fibroblasts from patients with X-linked adrenoleukodystrophy, straight-chain acyl-CoA oxidase (SCOX) deficiency, d-bifunctional protein (DBP) deficiency, and rhizomelic chondrodysplasia punctata type 1, and of fibroblasts from l-bifunctional protein and sterol carrier protein X (SCPx) knockout mice, show that the main enzymes involved in beta-oxidation of C24:6n-3 to C22:6n-3 are SCOX, DBP, and both 3-ketoacyl-CoA thiolase and SCPx. These findings are of importance for the treatment of patients with a defect in peroxisomal beta-oxidation.


Subject(s)
Docosahexaenoic Acids/metabolism , Peroxisomes/enzymology , Acetyl-CoA C-Acetyltransferase/deficiency , Acetyl-CoA C-Acetyltransferase/genetics , Acetyl-CoA C-Acyltransferase/genetics , Acetyl-CoA C-Acyltransferase/metabolism , Acyl-CoA Oxidase , Animals , Carnitine Acyltransferases/deficiency , Carnitine Acyltransferases/genetics , Carrier Proteins/genetics , Cell Line , Chromatography, High Pressure Liquid , Fibroblasts , Humans , Lipid Metabolism, Inborn Errors/enzymology , Lipid Metabolism, Inborn Errors/genetics , Lipid Metabolism, Inborn Errors/metabolism , Mice , Mice, Knockout , Mitochondria/metabolism , Oxidation-Reduction , Oxidoreductases/deficiency , Oxidoreductases/genetics , Radioisotopes , Zellweger Syndrome/metabolism
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