1/25. prenatal diagnosis of peroxisomal D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-coa dehydrogenase bifunctional protein deficiency.The prenatal diagnosis of peroxisomal D-3-hydroxyacyl-coenzyme a (CoA) dehydratase/D-3-hydroxyacyl-coa dehydrogenase bifunctional protein (D-BP) deficiency was performed by peroxisomal beta-oxidation assay, indirect immunofluorescence staining, immunoblot analysis, and gene analysis of cultured amniocytes obtained from a fetus at 16 weeks' gestational age. beta-Oxidation activity, measured by [1-14C] lignoceric acid oxidation, was markedly decreased compared with the controls. Large peroxisomes were readily identified by immunofluorescence staining with anti-human catalase, as was found in the reported patients. Immunoreactive D-BP material was absent on immunoblot analysis and immunofluorescence staining with anti-human D-BP. reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed the presence of the same 237-bp deletion in the cDNA as that detected in a sibling (the proband). The autopsied fetus showed the characteristic facial appearance and D-BP was deficient on immunoblot and immunohistopathological studies of the fetal tissues. No neuronal migration disorder was identified. This seems to be the first prenatal diagnosis of D-BP deficiency.- - - - - - - - - - ranking = 1keywords = protein deficiency, deficiency, protein (Clic here for more details about this article) |
2/25. peroxisomal disorders: clinical and biochemical studies in 15 children and prenatal diagnosis in 7 families.We describe the main clinical and biochemical findings in 15 patients with peroxisomal disorders, together with the results of 11 prenatal investigations for zellweger syndrome. The initial laboratory diagnosis depended in most cases on demonstration of elevated very long chain fatty acids in plasma, but follow-up studies using cultured fibroblasts were essential for complete classification. The patient group comprises nine cases of zellweger syndrome, one of neonatal adrenoleucodystrophy, two of infantile refsum disease, one of bifunctional protein deficiency, and two of rhizomelic chondrodysplasia punctata. The study illustrates the clinical and biochemical variability of this group of patients and the detailed studies that are required for classification.- - - - - - - - - - ranking = 0.24999592593177keywords = protein deficiency, deficiency, protein (Clic here for more details about this article) |
3/25. Diagnosis and follow-up of a case of peroxisomal disorder with peroxisomal mosaicism.Peroxisomal disorder phenotypes are the result of mutations that cause defective peroxisomal assembly or alterations in the import mechanism of peroxisomal proteins that lead to multiple peroxisomal dysfunctions, or the result of a peroxisomal enzymatic deficiency with a single peroxisomal dysfunction. With complementation analysis, 16 groups have been found. Assignment of the genetic defect has been described for some of the complementation groups. We describe the clinical evolution and follow-up over 10 years of a patient who belongs to complementation group 4, although he showed a milder clinical course. It has been found in fibroblasts different peroxisome populations, normal processing and expression of beta-oxidation PTS1 and PTS2 proteins, abnormal ALD protein distribution and normal plasmalogen biosynthesis; abnormal beta-oxidation metabolites have also been detected in serum. Ultrastructural studies in liver showed peroxisomal mosaicism as in fibroblasts. It has been taken into account that peroxisomal mosaicism may lead to variability in peroxisomal diagnostic parameters, making difficult the final diagnosis in these patients.- - - - - - - - - - ranking = 1.3355417563715E-5keywords = deficiency, protein (Clic here for more details about this article) |
4/25. Molecular mechanism of detectable catalase-containing particles, peroxisomes, in fibroblasts from a PEX2-defective patient.patients with peroxisome biogenesis disorders (PBD) can be identified by detection of peroxisomes in their fibroblasts, by means of immunocytochemical staining using an anti-catalase antibody. We report here data on three PBD patients with newly identified mutations (del550C and del642G) in the PEX2 gene which encodes a 35-kDa peroxisomal membrane protein containing two membrane-spanning and a C-terminal cysteine-rich region. Some of the fibroblasts from the patient with the del642G mutation contained numerous catalase-containing particles, whereas no fibroblasts containing such particles were found in the patient with the del550C mutation. We confirmed that the del642G mutation caused a partial defect in peroxisome synthesis and import by expression of the mutated PEX2 into PEX2-defective CHO mutant cells. We propose that the two putative membrane-spanning segments in Pex2p are important domains for peroxisome assembly and import and that a defect in one of these domains severely affects PBD patients. Furthermore, a defect in the C-terminal portion of Pex2p exposed to the cytosol containing a RING finger motif caused the mild phenotype, residual enzyme activities, and mosaic detectable peroxisomes in fibroblasts from the patient.- - - - - - - - - - ranking = 2.0829124382565E-6keywords = protein (Clic here for more details about this article) |
5/25. Developmental and pathological expression of peroxisomal enzymes: their relationship of D-bifunctional protein deficiency and zellweger syndrome.We present the developmental changes of peroxisomal enzymes, catalase, L-bifunctional protein (L-BF) and D-bifunctional protein (D-BF), in the normal brains, and patients with D-BF deficiency, a new peroxisomal disease. D-BF immunoreactivity was observed in controls as early as 13 gestational weeks (GW) and increased with maturation. The adult pattern with fine granule staining of somata and dendrites became apparent in adolescence. L-BF appeared at 20 GW in the cerebral cortex and purkinje cells and positive glia appeared early in the white matter at 17 GW, and then increased with age. catalase-positive neurons were identified in the same manner as L-BF, D-BF deficiency in both fetus and infant showed markedly diminished enzyme immunoreactivity. patients demonstrate reduced D-BF expression. zellweger syndrome shows decreased expression for the three proteins. This study shows that the peroxisomal enzymes may be closely related to neuronal maturation and gliogenesis in human brain and to disturbance of neuronal migration as seen in zellweger syndrome significant. D-BF deficiency may exhibit a range of symptoms during the neonatal and early infantile periods some of which may be similar to zellweger syndrome.- - - - - - - - - - ranking = 1.0000112725051keywords = protein deficiency, deficiency, protein (Clic here for more details about this article) |
6/25. D-hydroxyacyl-CoA dehydrogenase deficiency. Identification of a new peroxisomal disorder with implications for other disorders of beta-oxidation.The second and third steps of peroxisomal beta-oxidation are catalysed by two multifunctional enzymes: D-bifunctional protein and L-bifunctional protein. Here we show that fibroblasts of a patient described as being deficient in the 3-hydroxyacyl-coa dehydrogenase component of D-bifunctional protein and fibroblasts of a patient described as being deficient in L-bifunctional protein do not complement one another. Using a newly developed method to measure the activity of D-bifunctional protein in fibroblast homogenates, we found that the activity of the D-bifunctional protein was completely deficient in the patient with presumed L-bifunctional protein deficiency.- - - - - - - - - - ranking = 0.25003685012739keywords = protein deficiency, deficiency, protein (Clic here for more details about this article) |
7/25. Two novel mutations in the adrenoleukodystrophy gene in two unrelated Japanese families and the long-term effect of bone marrow transplantation.We identified two novel missense mutations in exon 1 of adrenoleukodystrophy (ALD) gene in two unrelated Japanese families. The first, G(874)C transition results in Arg(163)Pro substitution in the cytoplasmic domain of the ALD protein in adrenomyeloneuropathy family. The second, C(679)G results in Ser(98)Trp substitution in the first transmembrane loop in childhood onset cerebral ALD family. Both mutations cause the substitution of polar amino acid (arginine and serine) with non-polar amino acid (proline and tryptophan). bone marrow transplantation (BMT) from his non-affected his younger sister was performed on a boy with childhood onset cerebral ALD who showed neurological deficit and brain MRI abnormalities. We evaluated the effect of BMT over a 6-year period in terms of neurological deficit, the level of very-long-chain fatty acids (VLCFA) in plasma and fibroblasts, and brain MRI. After BMT, patient's peripheral white blood cells were replaced by donor's XX ones carrying a normal ALD gene confirmed by in situ hybridization using satellite dna of the centromere of X and Y chromosomes as probes and the level of VLCFA in lymphocytes was within normal limit. However, his neurological state progressively deteriorated. BMT was not beneficial to him.- - - - - - - - - - ranking = 2.0829124382565E-6keywords = protein (Clic here for more details about this article) |
8/25. temperature-sensitive mutation of PEX6 in peroxisome biogenesis disorders in complementation group C (CG-C): comparative study of PEX6 and PEX1.Peroxisome biogenesis disorders (PBD), including zellweger syndrome, neonatal adrenoleukodystrophy, and infantile refsum disease, are a group of genetically heterogeneous autosomal-recessive diseases caused by mutations in PEX genes that encode peroxins, proteins required for peroxisome biogenesis. zellweger syndrome patients present the most severe phenotype, whereas neonatal adrenoleukodystrophy patients are intermediate and infantile refsum disease patients have the mildest features. PEX6 is a causative gene for PBD of complementation group C (CG-C) and encodes the peroxin Pex6p, one of the ATPases associated with diverse cellular activities and a member of the same family of proteins as Pex1p, a causative protein for PBD of CG-E (CG1). Here, we identified the temperature sensitivity of peroxisomes in the fibroblasts of a patient with neonatal adrenoleukodystrophy in CG-C. peroxisomes were morphologically and biochemically formed at 30 degrees C but not at 37 degrees C. This patient was homozygous for a missense mutation, T-->C at nucleotide 170 resulting in a change from leucine to proline at amino acid 57 (L57P) in Pex6p. CG-C cell mutants (ZP92) in the Chinese hamster ovary transfected with L57P in HsPEX6 revealed the same temperature-sensitive phenotype. However, PEX1-deficient Chinese hamster ovary cell mutants (ZP101) transfected with L111P in PEX1, the counterpart to L57P in PEX6, showed no temperature sensitivity. In addition, ZP92 transfected with G708D in PEX6, the counterpart to the temperature-sensitive mutation G843D in PEX1, revealed no temperature-sensitive phenotype. These results indicate that L57P in Pex6p is a temperature-sensitive mutation causing the milder phenotype in a patient with PBD in CG-C. They also indicate that the amino acid residues responsible for temperature sensitivity do not seem to be conserved between Pex6p and Pex1p.- - - - - - - - - - ranking = 6.2487373147694E-6keywords = protein (Clic here for more details about this article) |
9/25. Fibroblast studies documenting a case of peroxisomal 2-methylacyl-CoA racemase deficiency: possible link between racemase deficiency and malabsorption and vitamin k deficiency.BACKGROUND: 2-Methylacyl-CoA racemase interconverts the 2-methyl group of pristanoyl-CoA or the 25-methyl group of hydroxylated cholestanoyl-CoAs, allowing further peroxisomal desaturation of these compounds in man by the branched chain acyl-coa oxidase, which recognise only the S-isomers. Hence, oxidation studies in fibroblasts, currently based on the use of racemic substrates such as [1-14C] pristanic acid, do not allow us to distinguish between a deficient racemase or an impaired oxidase. DESIGN: To evaluate the racemase activity directly, the 2R-isomer of[1-14C] pristanic acid, as well as the 2R-isomer of 2-methyl-[1-14C] hexadecanoic, a synthetic pristanic acid substitute, were prepared and their degradation by cultured human skin fibroblasts was compared to that of the racemic substrates. RESULTS: In fibroblasts in a young girl, presenting with elevated urinary levels of trihydroxycholestanoic acid metabolites but normal plasma levels of very long chain fatty acids, a partial deficient degradation of racemic [1-14C] pristanic acid was observed. Incorporation of 2R-[1-14C] pristanic acid in glycerolipids of the patient's fibroblasts proceeded normally, but breakdown was impaired. Similar findings were seen with the 2R-isomer of 2-methyl-[1-14C] hexadecanoic. These data, combined with the fact that the branched chain acyl-coa oxidase, catalyzing the first oxidation step of pristanic acid and bile acid intermediates in man, appeared normal, suggested a peroxisomal beta-oxidation defect in the patient at the level of 2-methylacyl-CoA racemase. CONCLUSION: Carboxy-labelled 2R-methyl branched chain fatty acids might be useful tools to document cases of racemase deficiencies. Because a brother of the patient died with a diagnosis of vitamin k deficiency, an impaired racemase might be responsible for other cases of unexplicable malabsorption.- - - - - - - - - - ranking = 9.2386843236295E-5keywords = deficiency (Clic here for more details about this article) |
10/25. A new defect of peroxisomal function involving pristanic acid: a case report.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.- - - - - - - - - - ranking = 7.1066802489457E-6keywords = deficiency (Clic here for more details about this article) |
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