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Ronald J.a. Wanders - One of the best experts on this subject based on the ideXlab platform.
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Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients.
American journal of medical genetics. Part A, 2004Co-Authors: B. T. Poll-the, Jeannette Gootjes, Ronald J.a. Wanders, Hans R. Waterham, Marinus Duran, Johannis B.c. De Klerk, Ronald J.c. Admiraal, Liesbeth J Maillette De Buy Wenniger-prick, Peter G. BarthAbstract:The peroxisome biogenesis disorders (PBDs) with generalized peroxisomal dysfunction include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and Infantile Refsum Disease (IRD). There is clinical, biochemical, and genetic overlap among the three phenotypes, also known as Zellweger spectrum disorders. Clinical distinctions between the phenotypes are not sharply defined. Only limited sources are available to serve as a background for prognosis in PBD, especially in case of prolonged survival. We delineated the natural history of 31 PBD patients (age 1.2-24 years) through systematic clinical and biochemical investigations. We excluded classical ZS from our study, and included all patients with a biochemically confirmed generalized peroxisomal disorder over 1 year of age, irrespective of the previously diagnosed phenotype. The initial clinical suspicion, age at diagnosis, growth, development, neurological symptoms, organ involvements, and survival are summarized. Common to all patients were cognitive and motor dysfunction, retinopathy, sensorineural hearing impairment, and hepatic involvement. Many patients showed postnatal growth failure, 10 patients displayed hyperoxaluria of whom 4 had renal stones. Motor skills ranged from sitting with support to normal gait. Speech development ranged from non-verbal expression to grammatical speech and comprehensive reading. The neurodevelopmental course was variable with stable course, rapid decline with leukodystrophy, spinocerebellar syndrome, and slow decline over a wide range of faculties as outcome profiles. At the molecular level, 21 patients had mutations in the PEX1 gene. The two most common PEX1 mutations were the G843D (c.2528G-->A) missense and the c.2097insT frameshift mutation. Patients having the G843D/G843D or the G843D/c.2097insT genotypes were compared. Patients homozygous for G843D generally had a better developmental outcome. However, one patient who was homozygous for the "mild" G843D mutation had an early lethal Disease, whereas two other patients had a phenotype overlapping with the G843D/c.2097insT group. This indicates that next to the PEX1 genotype other yet unknown factors determine the ultimate phenotype.
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Peroxisome biogenesis disorders with prolonged survival: Phenotypic expression in a cohort of 31 patients
American Journal of Medical Genetics, 2004Co-Authors: B. T. Poll-the, Jeannette Gootjes, Ronald J.a. Wanders, Hans R. Waterham, Marinus Duran, Johannis B.c. De Klerk, Liesbeth J. Maillette De Buy Wenniger-prick, Ronald J.c. Admiraal, Peter G. BarthAbstract:The peroxisome biogenesis disorders (PBDs) with generalized peroxisomal dysfunction include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and Infantile Refsum Disease (IRD). There is clinical, biochemical, and genetic overlap among the three phenotypes, also known as Zellweger spectrum disorders. Clinical distinctions between the phenotypes are not sharply defined. Only limited sources are available to serve as a background for prognosis in PBD, especially in case of prolonged survival. We delineated the natural history of 31 PBD patients (age 1.2-24 years) through systematic clinical and biochemical investigations. We excluded classical ZS from our study, and included all patients with a biochemically confirmed generalized peroxisomal disorder over 1 year of age, irrespective of the previously diagnosed phenotype. The initial clinical suspicion, age at diagnosis, growth, development, neurological symptoms, organ involvements, and survival are summarized. Common to all patients were cognitive and motor dysfunction, retinopathy, sensorineural hearing impairment, and hepatic involvement. Many patients showed postnatal growth failure, 10 patients displayed hyperoxaluria of whom 4 had renal stones. Motor skills ranged from sitting with support to normal gait. Speech development ranged from non-verbal expression to grammatical speech and comprehensive reading. The neurodevelopmental course was variable with stable course, rapid decline with leukodystrophy, spinocerebellar syndrome, and slow decline over a wide range of faculties as outcome profiles. At the molecular level, 21 patients had mutations in the PEX1 gene. The two most common PEX1 mutations were the G843D (c.2528G-->A) missense and the c.2097insT frameshift mutation. Patients having the G843D/G843D or the G843D/c.2097insT genotypes were compared. Patients homozygous for G843D generally had a better developmental outcome. However, one patient who was homozygous for the "mild" G843D mutation had an early lethal Disease, whereas two other patients had a phenotype overlapping with the G843D/c.2097insT group. This indicates that next to the PEX1 genotype other yet unknown factors determine the ultimate phenotyp
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Novel Mutations in the PEX2 Gene of Four Unrelated Patients with a Peroxisome Biogenesis Disorder
Pediatric Research, 2004Co-Authors: Jeannette Gootjes, Hanna Mandel, Yasuyuki Suzuki, Hans R. Waterham, Orly Elpeleg, François Eyskens, Delphine Mitanchez, Noboyuki Shimozawa, Ronald J.a. WandersAbstract:The peroxisome biogenesis disorders (PBDs) form a genetically and clinically heterogeneous group of disorders due to defects in at least 11 distinct genes. The prototype of this group of disorders is Zellweger syndrome (ZS) with neonatal adrenoleukodystrophy (NALD) and Infantile Refsum Disease (IRD) as milder variants. Common to PBDs are liver Disease, variable neurodevelopmental delay, retinopathy and perceptive deafness. PBD patients belonging to complementation group 10 (CG10) have mutations in the PEX2 gene ( PXMP3 ), which codes for a protein (PEX2) that contains two transmembrane domains and a zinc-binding domain considered to be important for its interaction with other proteins of the peroxisomal protein import machinery. We report on the identification of four PBD patients belonging to CG10. Sequence analysis of their PEX2 genes revealed 4 different mutations, 3 of which have not been reported before. Two of the patients had homozygous mutations leading to truncated proteins lacking both transmembrane domains and the zinc-binding domain. These mutations correlated well with their severe phenotypes. The third patient had a homozygous mutation leading to the absence of the zinc-binding domain (W223X) and the fourth patient had a homozygous mutation leading to the change of the second cysteine residue of the zinc-binding domain (C247R). Surprisingly, the patient lacking the domain had a mild phenotype, whereas the C247R patient had a severe phenotype. This might be due to an increased instability of PEX2 due to the R for C substitution or to a dominant negative effect on interacting proteins.
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Late onset white matter Disease in peroxisome biogenesis disorder.
Neurology, 2001Co-Authors: Peter G. Barth, Jeannette Gootjes, H. Bode, P. Vreken, Charles B. L. M. Majoie, Ronald J.a. WandersAbstract:Objective: To report late onset cerebral white matter Disease as a distinctive phenotype in peroxisome biogenesis disorder (PBD). Background: There is phenotypic and genetic overlap among the PBD known as Zellweger syndrome (ZS), Infantile Refsum Disease (IRD), and neonatal adrenoleukodystrophy (NALD). Distinctive external features are variable among these three disorders, and neurologic deficit has its onset at birth or in infancy. In a structured follow-up cohort of 25 patients with PBD, not including ZS, three patients had an unusual pattern of cerebral white matter Disease with onset past the age of 1, not conforming to any of the classic PBD phenotypes. Methods: Clinical phenotyping and follow-up, peroxisomal biochemical determinations in body fluids and fibroblasts, identification of affected PEX gene by genetic complementation in fibroblasts, and MRI studies. Results: Two unrelated patients with PBD without distinctive external features had normal neurodevelopmental milestones during their first year, followed by rapid deterioration including severe hypotonic pareses, seizures, retinopathy, and deafness. A third patient initially diagnosed with IRD developed cerebral white matter degeneration in the third year of life, complicating the original diagnosis. MRI in all three patients showed cerebral demyelination with sparing of subcortical fibers and pronounced central cerebellar demyelination. Conclusions: Late-onset cerebral white matter Disease may occur in PBD, either following IRD or following normal early development and in the absence of distinctive external features. Peroxisome biogenesis disorder should be included in the differential diagnosis of post-Infantile onset of cerebral white matter Disease.
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Disorders of peroxisome biogenesis due to mutations in PEX1: phenotypes and PEX1 protein levels
American journal of human genetics, 2001Co-Authors: Claudia Walter, Peter G. Barth, Jeannette Gootjes, Petra A.w. Mooijer, Herma Portsteffen, Christina Klein, Hans R. Waterham, Jörg T. Epplen, Wolf-h. Kunau, Ronald J.a. WandersAbstract:Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and Infantile Refsum Disease (IRD) are clinically overlapping syndromes, collectively called “peroxisome biogenesis disorders” (PBDs), with clinical features being most severe in ZS and least pronounced in IRD. Inheritance of these disorders is autosomal recessive. The peroxisome biogenesis disorders are genetically heterogeneous, having at least 12 different complementation groups (CGs). The gene affected in CG1 is PEX1. Approximately 65% of the patients with PBD harbor mutations in PEX1. In the present study, we used SSCP analysis to evaluate a series of patients belonging to CG1 for mutations in PEX1 and studied phenotype-genotype correlations. A complete lack of PEX1 protein was found to be associated with severe ZS; however, residual amounts of PEX1 protein were found in patients with the milder phenotypes, NALD and IRD. The majority of these latter patients carried at least one copy of the common G843D allele. When patient fibroblasts harboring this allele were grown at 30°C, a two- to threefold increase in PEX1 protein levels was observed, associated with a recovery of peroxisomal function. This suggests that the G843D missense mutation results in a misfolded protein, which is more stable at lower temperatures. We conclude that the search for the factors and/or mechanisms that determine the stability of mutant PEX1 protein by high-throughput procedures will be a first step in the development of therapeutic strategies for patients with mild PBDs.
Nobuyuki Shimozawa - One of the best experts on this subject based on the ideXlab platform.
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living donor liver transplantation from a heterozygous parent for Infantile Refsum Disease
Pediatrics, 2016Co-Authors: Masatoshi Matsunami, Nobuyuki Shimozawa, Akinari Fukuda, Tadayuki Kumagai, Masaya Kubota, Pin Fee Chong, Mureo KasaharaAbstract:Infantile Refsum Disease (IRD) is a rare autosomal recessive disorder of peroxisome biogenesis characterized by generalized peroxisomal metabolic dysfunction, including accumulation of very long-chain fatty acids (VLCFAs) and phytanic acid (PA), as well as decreased plasmalogen contents (PL). An effective therapy for this intractable Disease has not been established, and only supportive management with docosahexaenoic acid supplementation and low PA diet has been reported so far. A boy of 3 years and 8 months presented with facial dysmorphism, transaminitis, and psychomotor retardation. Biochemical analysis showed elevated PA and VLCFAs, with reduced PL in the serum. Immunofluorescence study of fibroblasts from the patient indicated a mosaic pattern of catalase-positive and -negative particles, and molecular analysis revealed compound heterozygous mutations of PEX6 The failure of medical management to prevent the progression of clinical symptoms and abnormal biochemistry prompted us to consider liver transplantation (LT). With the chances of receiving a deceased donor liver being poor, we performed a living-donor LT from the patient's heterozygous mother. At 6-month follow-up, the patient's serum PA levels had normalized. VLCFAs and PL levels had declined and increased, respectively. To the best of our knowledge, this is the second reported case in which IRD was treated by living-donor LT by using a heterozygous donor. Only long-term follow-up will reveal if there is any clinical improvement in the present case. With the liver being a major site for peroxisomal pathways, its replacement by LT may work as a form of partial enzyme therapy for patients with IRD.
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newly identified milder phenotype of peroxisome biogenesis disorder caused by mutated pex3 gene
Brain & Development, 2013Co-Authors: Shuji Matsui, Masuko Funahashi, Ayako Honda, Nobuyuki ShimozawaAbstract:We identified the first patient with Infantile Refsum Disease (IRD), a milder phenotype of peroxisome biogenesis disorder (PBD) caused by a mutated PEX3, and investigated the clinical, molecular and cellular characterization in this patient. The patient presented psychomotor regression, late-onset leukodystrophy, peripheral neuropathy, hearing impairment, a renal cyst, and renal hypertension and survived until the age of 36. Furthermore, fibroblasts from the patient indicated a mosaic pattern of catalase-positive particles (peroxisomes) and numerous peroxisomal membrane structures. Molecular analysis was homozygous for the D347Y mutation and reduced gene expression of PEX3 which encodes a peroxisomal membrane protein, pex3p, involved in peroxisome assembly at the early stage of peroxisomal membrane vesicle formation, therefore, patients with a mutated PEX3 gene have been reported to have only a severe phenotype of Zellweger syndrome and no or less peroxisomal remnant membrane structure. This is not only a newly identified milder PBD caused by a mutated PEX3 gene but also the first report of a Japanese patient with IRD who had not been diagnosed until over 30years of age, which suggests there must be more variant PBD in patients with degenerative neurologic disorder, and to bring them to light is necessary.
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mutations in novel peroxin gene pex26 that cause peroxisome biogenesis disorders of complementation group 8 provide a genotype phenotype correlation
American Journal of Human Genetics, 2003Co-Authors: N Matsumoto, Nobuyuki Shimozawa, Yasuyuki Suzuki, Naomi Kondo, Shigehiko Tamura, Ann B Moser, Satomi Furuki, Non Miyata, Hugo W Moser, Yukio FujikiAbstract:The human disorders of peroxisome biogenesis (PBDs) are subdivided into 12 complementation groups (CGs). CG8 is one of the more common of these and is associated with varying phenotypes, ranging from the most severe, Zellweger syndrome (ZS), to the milder neonatal adrenoleukodystrophy (NALD) and Infantile Refsum Disease (IRD). PEX26, encoding the 305-amino-acid membrane peroxin, has been shown to be deficient in CG8. We studied the PEX26 genotype in fibroblasts of eight CG8 patients—four with the ZS phenotype, two with NALD, and two with IRD. Catalase was mostly cytosolic in all these cell lines, but import of the proteins that contained PTS1, the SKL peroxisome targeting sequence, was normal. Expression of PEX26 reestablished peroxisomes in all eight cell lines, confirming that PEX26 defects are pathogenic in CG8 patients. When cells were cultured at 30°C, catalase import was restored in the cell lines from patients with the NALD and IRD phenotypes, but to a much lesser extent in those with the ZS phenotype, indicating that temperature sensitivity varied inversely with the severity of the clinical phenotype. Several types of mutations were identified, including homozygous G89R mutations in two patients with ZS. Expression of these PEX26 mutations in pex26 Chinese hamster ovary cells resulted in cell phenotypes similar to those in the human cell lines. These findings confirm that the degree of temperature sensitivity in pex26 cell lines is predictive of the clinical phenotype in patients with PEX26 deficiency.
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Temperature-Sensitive Mutation of PEX6 in Peroxisome Biogenesis Disorders in Complementation Group C (CG-C): Comparative Study of PEX6 and PEX1
Pediatric Research, 2000Co-Authors: Atsushi Imamura, Yukio Fujiki, Ronald J.a. Wanders, Nobuyuki Shimozawa, Yasuyuki Suzuki, Zhongyi Zhang, Toshiro Tsukamoto, Tadao Orii, Takashi Osumi, Naomi KondoAbstract: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°C but not at 37°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.
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functional heterogeneity of c terminal peroxisome targeting signal 1 in pex5 defective patients
Biochemical and Biophysical Research Communications, 1999Co-Authors: Nobuyuki Shimozawa, Yukio Fujiki, Atsushi Imamura, Yasuyuki Suzuki, Zhongyi Zhang, Toshiro Tsukamoto, Tadao Orii, Takashi Osumi, P G Barth, Ronald J.a. WandersAbstract:To investigate mechanisms related to functions of the peroxisome targeting signal (PTS) 1 receptor, Pex5p, we analyzed peroxisome matrix protein import in fibroblasts from three patients with peroxisome biogenesis disorders, all with different mutations in the PEX5 gene. The patients 2-01 (Zellweger syndrome) and 2-05 (neonatal adrenoleukodystrophy) have the reported mutations, R390X and N489K, and patient 2-03 (Infantile Refsum Disease) has a newly identified mutation, S563W. Fibroblasts from 2-03 (S563W) were detected in both PTS1 and PTS2 imports despite the PEX5 defect, findings in contrast with fibroblasts from 2-05 (N489K) severely defective in PTS1 import and those from 2-01 (R390X) severely defective in both PTS1 and PTS2. The PTS1 receptor in 2-03 is functional for only the C-terminal -SKL sequence (acyl-CoA oxidase) and had little or no function for C-terminal -AKL (D-bifunctional protein and sterol carrier protein 2) and -KANL (catalase) sequences, respectively. After transfection of these mutated PEX5 cDNA into the PEX5-defective CHO mutant, transformants of ZP102 revealed that each mutation was responsible for each dysfunction of the PTS1 import. It seems apparent that -AKL and -KANL are poorer variants of PTS1 and are likely to be more susceptible to effects of mutation of its receptor, Pex5p.
Yukio Fujiki - One of the best experts on this subject based on the ideXlab platform.
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a temperature sensitive cho pex1 mutant with a novel mutation in the aaa walker a1 motif
Biochemical and Biophysical Research Communications, 2006Co-Authors: Wei Fan, Yukio FujikiAbstract:Abstract We herein isolated a peroxisome-deficient Chinese hamster ovary mutant, ZPEG252, import-defective of peroxisome targeting signal 1 (PTS1)- and PTS2-proteins at 37 °C. The impaired protein import was restored at 30 °C, indicating a temperature-sensitive phenotype, similar to that of cells derived from patients with milder peroxisome biogenesis disorders such as Infantile Refsum Disease. PEX1 expression complemented the mutant phenotype of ZPEG252. Reverse transcription-PCR analysis indicated one point mutation at nucleotide residue 1817 changing a codon (GGG) for Gly 606 to a codon (GAG) for Glu 606 in the sequence for the Walker A1 motif of the AAA cassettes. This novel mutant Pex1pG606E was severely affected in binding to Pex6p at 37 °C, but not at 30 °C. Pex1pG606E was localized to peroxisomes at 30 °C, whilst it was discernible in a cytosolic staining pattern at 37 °C. Together, our findings demonstrate that Walker A1 motif of Pex1p is essential for Pex1p–Pex6p interaction and Pex1p targeting to peroxisomes.
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mutations in the peroxin pex26p responsible for peroxisome biogenesis disorders of complementation group 8 impair its stability peroxisomal localization and interaction with the pex1p pex6p complex
Journal of Biological Chemistry, 2006Co-Authors: Satomi Furuki, Shigehiko Tamura, N Matsumoto, Ann B Moser, Non Miyata, Hugo W Moser, Yukio FujikiAbstract:Peroxisome biogenesis disorders (PBDs) are fatal autosomal recessive Diseases and are caused by impaired peroxisome biogenesis. PBDs are genetically heterogeneous and classified into 13 complementation groups (CGs). CG8 is one of the most common groups and has three clinical phenotypes, including Zellweger syndrome (ZS), neonatal adrenoleukodystrophy, and Infantile Refsum Disease (IRD). We recently isolated PEX26 as the pathogenic gene for PBD of CG8. Pex26p functions in recruiting to peroxisomes the complexes of the AAA ATPase peroxins, Pex1p and Pex6p. In the present work, we identified four distinct mutations in PEX26 from five patients of CG8 PBD including 2 with ZS and 3 with IRD, in addition to 7 mutant alleles in 8 patients in the first report describing the pathogenic PEX26 gene for CG8 PBD. Phenotype-genotype analyses revealed that temperature-sensitive (ts) peroxisome assembly gave rise to a milder IRD in contrast to the non-ts phenotype of the cells from ZS patients. Furthermore, we present several lines of evidence that show that the instability, insufficient binding to Pex1p x Pex6p complexes, or mislocalization of patient-derived Pex26p mutants is most likely responsible for the CG8 PBDs.
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mutations in novel peroxin gene pex26 that cause peroxisome biogenesis disorders of complementation group 8 provide a genotype phenotype correlation
American Journal of Human Genetics, 2003Co-Authors: N Matsumoto, Nobuyuki Shimozawa, Yasuyuki Suzuki, Naomi Kondo, Shigehiko Tamura, Ann B Moser, Satomi Furuki, Non Miyata, Hugo W Moser, Yukio FujikiAbstract:The human disorders of peroxisome biogenesis (PBDs) are subdivided into 12 complementation groups (CGs). CG8 is one of the more common of these and is associated with varying phenotypes, ranging from the most severe, Zellweger syndrome (ZS), to the milder neonatal adrenoleukodystrophy (NALD) and Infantile Refsum Disease (IRD). PEX26, encoding the 305-amino-acid membrane peroxin, has been shown to be deficient in CG8. We studied the PEX26 genotype in fibroblasts of eight CG8 patients—four with the ZS phenotype, two with NALD, and two with IRD. Catalase was mostly cytosolic in all these cell lines, but import of the proteins that contained PTS1, the SKL peroxisome targeting sequence, was normal. Expression of PEX26 reestablished peroxisomes in all eight cell lines, confirming that PEX26 defects are pathogenic in CG8 patients. When cells were cultured at 30°C, catalase import was restored in the cell lines from patients with the NALD and IRD phenotypes, but to a much lesser extent in those with the ZS phenotype, indicating that temperature sensitivity varied inversely with the severity of the clinical phenotype. Several types of mutations were identified, including homozygous G89R mutations in two patients with ZS. Expression of these PEX26 mutations in pex26 Chinese hamster ovary cells resulted in cell phenotypes similar to those in the human cell lines. These findings confirm that the degree of temperature sensitivity in pex26 cell lines is predictive of the clinical phenotype in patients with PEX26 deficiency.
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Temperature-Sensitive Mutation of PEX6 in Peroxisome Biogenesis Disorders in Complementation Group C (CG-C): Comparative Study of PEX6 and PEX1
Pediatric Research, 2000Co-Authors: Atsushi Imamura, Yukio Fujiki, Ronald J.a. Wanders, Nobuyuki Shimozawa, Yasuyuki Suzuki, Zhongyi Zhang, Toshiro Tsukamoto, Tadao Orii, Takashi Osumi, Naomi KondoAbstract: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°C but not at 37°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.
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functional heterogeneity of c terminal peroxisome targeting signal 1 in pex5 defective patients
Biochemical and Biophysical Research Communications, 1999Co-Authors: Nobuyuki Shimozawa, Yukio Fujiki, Atsushi Imamura, Yasuyuki Suzuki, Zhongyi Zhang, Toshiro Tsukamoto, Tadao Orii, Takashi Osumi, P G Barth, Ronald J.a. WandersAbstract:To investigate mechanisms related to functions of the peroxisome targeting signal (PTS) 1 receptor, Pex5p, we analyzed peroxisome matrix protein import in fibroblasts from three patients with peroxisome biogenesis disorders, all with different mutations in the PEX5 gene. The patients 2-01 (Zellweger syndrome) and 2-05 (neonatal adrenoleukodystrophy) have the reported mutations, R390X and N489K, and patient 2-03 (Infantile Refsum Disease) has a newly identified mutation, S563W. Fibroblasts from 2-03 (S563W) were detected in both PTS1 and PTS2 imports despite the PEX5 defect, findings in contrast with fibroblasts from 2-05 (N489K) severely defective in PTS1 import and those from 2-01 (R390X) severely defective in both PTS1 and PTS2. The PTS1 receptor in 2-03 is functional for only the C-terminal -SKL sequence (acyl-CoA oxidase) and had little or no function for C-terminal -AKL (D-bifunctional protein and sterol carrier protein 2) and -KANL (catalase) sequences, respectively. After transfection of these mutated PEX5 cDNA into the PEX5-defective CHO mutant, transformants of ZP102 revealed that each mutation was responsible for each dysfunction of the PTS1 import. It seems apparent that -AKL and -KANL are poorer variants of PTS1 and are likely to be more susceptible to effects of mutation of its receptor, Pex5p.
Mariefrancoise Vincent - One of the best experts on this subject based on the ideXlab platform.
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orthotopic liver transplantation from a living related donor in an infant with a peroxisome biogenesis defect of the Infantile Refsum Disease type
Journal of Inherited Metabolic Disease, 2005Co-Authors: L Van Maldergem, Mariefrancoise Vincent, Jean-bernard Otte, Raymond Reding, A B Moser, Dominique Roland, Etienne SokalAbstract:Peroxisomal biogenesis defects include a number of severe neurodevelopmental disorders, among which Infantile Refsum Disease (IRD) occupies the mildest end of the spectrum. Although high docosahexaenoic acid (DHA) and low phytanic acid diets can correct some of the biochemical defects, they have not consistently altered the progressive course of the Disease. We carried out orthotopic liver transplantation (OLT) in a mildly symptomatic 6-month-old infant who was a sibling of a severely neurologically impaired older sister. After transplantation the clinical course of this young child appeared much improved by comparison to her older sister. She walked alone at 4 years, had acceptable social interaction and had a noticeable recovery of audition. After transplantation her biochemical parameters were significantly improved: phytanic acid and very long-chain fatty acid (VLCFA) serum concentrations decreased. Abnormal bile acids disappeared from plasma. Although the OLT did not result in a cure of the disorder, the clinical and biochemical results suggest that OLT should be considered in mildly symptomatic patients.
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hepatocyte transplantation in a 4 year old girl with peroxisomal biogenesis Disease technique safety and metabolic follow up
Transplantation, 2003Co-Authors: Etienne Sokal, Françoise Smets, Annick Bourgois, Jean-paul Buts, Dominique Latinne, Veerle Evrard, Jean-bernard Otte, Raymond Reding, Lionel Van Maldergem, Mariefrancoise VincentAbstract:Hepatocyte transplantation is an investigational alternative to orthotopic liver transplantation to treat liver based inborn errors of metabolism. We report successful hepatocyte transplantation in a 4-year-old girl with Infantile Refsum Disease. Hepatocytes were isolated from the left liver segment of two male donors using a classic two-step perfusion method. Fresh cells were transplanted first and then cryopreserved cells, for a total of 2 billion cells. Total bile acids and abnormal dihydroxycoprostanoic acid markedly decreased in the patient's serum, indicating resolution of cholestasis and re-population of liver cells. Pipecholic acid decreased by 40% and c26:c22 fatty acid ratio by 36% after 18 months. Donor chromosomes sequences were detected on biopsy posttransplant, indicating engraftment. Hepatocyte transplantation is a safe and promising technique in the treatment of rare inborn errors of metabolism. Future improvements of cell viability and prevention of apoptosis may increase engraftment and subsequent re-population.
Jeannette Gootjes - One of the best experts on this subject based on the ideXlab platform.
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HUMAN MUTATION 24:130^139 (2004) RESEARCH ARTICLE Identification of the Molecular Defect in Patients With Peroxisomal Mosaicism Using a Novel Method Involving Culturing of Cells at 401C: Implications for Other Inborn Errors of Metabolism
2013Co-Authors: Jeannette Gootjes, Petra A.w. Mooijer, Meral Topcu, Frank Schmohl, Conny Dekker, Hanna M, Martina Huemer, M. Von Schütz, Thorsten Marquardt, Jan A. SmeitinkAbstract:The peroxisome biogenesis disorders (PBDs), which comprise Zellweger syndrome (ZS), neonatal adrenoleukodystrophy, and Infantile Refsum Disease (IRD), represent a spectrum of Disease severity, with ZS being the most severe, and IRD the least severe disorder. The PBDs are caused by mutations in one of the at least 12 different PEX genes encoding proteins involved in the biogenesis of peroxisomes. We report the biochemical characteristics and molecular basis of a subset of atypical PBD patients. These patients were characterized by abnormal peroxisomal plasma metabolites, but otherwise normal to very mildly abnormal peroxisomal parameters in cultured skin fibroblasts, including a mosaic catalase immunofluorescence pattern in fibroblasts. Since this latter feature made standard complementation analysis impossible, we developed a novel complementation technique in which fibroblasts were cultured at 401C, which exacerbates the defect in peroxisome biogenesis. Using this method, we were able to assign eight patients to complementation group 3 (CG3), followed by the identification of a single homozygous c.959C4T (p.S320F) mutation in their PEX12 gene. We also investigated various peroxisomal biochemical parameters in fibroblasts at 301C, 371C, and 401C
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Peroxisome biogenesis disorders with prolonged survival: Phenotypic expression in a cohort of 31 patients
American Journal of Medical Genetics, 2004Co-Authors: B. T. Poll-the, Jeannette Gootjes, Ronald J.a. Wanders, Hans R. Waterham, Marinus Duran, Johannis B.c. De Klerk, Liesbeth J. Maillette De Buy Wenniger-prick, Ronald J.c. Admiraal, Peter G. BarthAbstract:The peroxisome biogenesis disorders (PBDs) with generalized peroxisomal dysfunction include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and Infantile Refsum Disease (IRD). There is clinical, biochemical, and genetic overlap among the three phenotypes, also known as Zellweger spectrum disorders. Clinical distinctions between the phenotypes are not sharply defined. Only limited sources are available to serve as a background for prognosis in PBD, especially in case of prolonged survival. We delineated the natural history of 31 PBD patients (age 1.2-24 years) through systematic clinical and biochemical investigations. We excluded classical ZS from our study, and included all patients with a biochemically confirmed generalized peroxisomal disorder over 1 year of age, irrespective of the previously diagnosed phenotype. The initial clinical suspicion, age at diagnosis, growth, development, neurological symptoms, organ involvements, and survival are summarized. Common to all patients were cognitive and motor dysfunction, retinopathy, sensorineural hearing impairment, and hepatic involvement. Many patients showed postnatal growth failure, 10 patients displayed hyperoxaluria of whom 4 had renal stones. Motor skills ranged from sitting with support to normal gait. Speech development ranged from non-verbal expression to grammatical speech and comprehensive reading. The neurodevelopmental course was variable with stable course, rapid decline with leukodystrophy, spinocerebellar syndrome, and slow decline over a wide range of faculties as outcome profiles. At the molecular level, 21 patients had mutations in the PEX1 gene. The two most common PEX1 mutations were the G843D (c.2528G-->A) missense and the c.2097insT frameshift mutation. Patients having the G843D/G843D or the G843D/c.2097insT genotypes were compared. Patients homozygous for G843D generally had a better developmental outcome. However, one patient who was homozygous for the "mild" G843D mutation had an early lethal Disease, whereas two other patients had a phenotype overlapping with the G843D/c.2097insT group. This indicates that next to the PEX1 genotype other yet unknown factors determine the ultimate phenotyp
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Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients.
American journal of medical genetics. Part A, 2004Co-Authors: B. T. Poll-the, Jeannette Gootjes, Ronald J.a. Wanders, Hans R. Waterham, Marinus Duran, Johannis B.c. De Klerk, Ronald J.c. Admiraal, Liesbeth J Maillette De Buy Wenniger-prick, Peter G. BarthAbstract:The peroxisome biogenesis disorders (PBDs) with generalized peroxisomal dysfunction include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and Infantile Refsum Disease (IRD). There is clinical, biochemical, and genetic overlap among the three phenotypes, also known as Zellweger spectrum disorders. Clinical distinctions between the phenotypes are not sharply defined. Only limited sources are available to serve as a background for prognosis in PBD, especially in case of prolonged survival. We delineated the natural history of 31 PBD patients (age 1.2-24 years) through systematic clinical and biochemical investigations. We excluded classical ZS from our study, and included all patients with a biochemically confirmed generalized peroxisomal disorder over 1 year of age, irrespective of the previously diagnosed phenotype. The initial clinical suspicion, age at diagnosis, growth, development, neurological symptoms, organ involvements, and survival are summarized. Common to all patients were cognitive and motor dysfunction, retinopathy, sensorineural hearing impairment, and hepatic involvement. Many patients showed postnatal growth failure, 10 patients displayed hyperoxaluria of whom 4 had renal stones. Motor skills ranged from sitting with support to normal gait. Speech development ranged from non-verbal expression to grammatical speech and comprehensive reading. The neurodevelopmental course was variable with stable course, rapid decline with leukodystrophy, spinocerebellar syndrome, and slow decline over a wide range of faculties as outcome profiles. At the molecular level, 21 patients had mutations in the PEX1 gene. The two most common PEX1 mutations were the G843D (c.2528G-->A) missense and the c.2097insT frameshift mutation. Patients having the G843D/G843D or the G843D/c.2097insT genotypes were compared. Patients homozygous for G843D generally had a better developmental outcome. However, one patient who was homozygous for the "mild" G843D mutation had an early lethal Disease, whereas two other patients had a phenotype overlapping with the G843D/c.2097insT group. This indicates that next to the PEX1 genotype other yet unknown factors determine the ultimate phenotype.
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Novel Mutations in the PEX2 Gene of Four Unrelated Patients with a Peroxisome Biogenesis Disorder
Pediatric Research, 2004Co-Authors: Jeannette Gootjes, Hanna Mandel, Yasuyuki Suzuki, Hans R. Waterham, Orly Elpeleg, François Eyskens, Delphine Mitanchez, Noboyuki Shimozawa, Ronald J.a. WandersAbstract:The peroxisome biogenesis disorders (PBDs) form a genetically and clinically heterogeneous group of disorders due to defects in at least 11 distinct genes. The prototype of this group of disorders is Zellweger syndrome (ZS) with neonatal adrenoleukodystrophy (NALD) and Infantile Refsum Disease (IRD) as milder variants. Common to PBDs are liver Disease, variable neurodevelopmental delay, retinopathy and perceptive deafness. PBD patients belonging to complementation group 10 (CG10) have mutations in the PEX2 gene ( PXMP3 ), which codes for a protein (PEX2) that contains two transmembrane domains and a zinc-binding domain considered to be important for its interaction with other proteins of the peroxisomal protein import machinery. We report on the identification of four PBD patients belonging to CG10. Sequence analysis of their PEX2 genes revealed 4 different mutations, 3 of which have not been reported before. Two of the patients had homozygous mutations leading to truncated proteins lacking both transmembrane domains and the zinc-binding domain. These mutations correlated well with their severe phenotypes. The third patient had a homozygous mutation leading to the absence of the zinc-binding domain (W223X) and the fourth patient had a homozygous mutation leading to the change of the second cysteine residue of the zinc-binding domain (C247R). Surprisingly, the patient lacking the domain had a mild phenotype, whereas the C247R patient had a severe phenotype. This might be due to an increased instability of PEX2 due to the R for C substitution or to a dominant negative effect on interacting proteins.
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Late onset white matter Disease in peroxisome biogenesis disorder.
Neurology, 2001Co-Authors: Peter G. Barth, Jeannette Gootjes, H. Bode, P. Vreken, Charles B. L. M. Majoie, Ronald J.a. WandersAbstract:Objective: To report late onset cerebral white matter Disease as a distinctive phenotype in peroxisome biogenesis disorder (PBD). Background: There is phenotypic and genetic overlap among the PBD known as Zellweger syndrome (ZS), Infantile Refsum Disease (IRD), and neonatal adrenoleukodystrophy (NALD). Distinctive external features are variable among these three disorders, and neurologic deficit has its onset at birth or in infancy. In a structured follow-up cohort of 25 patients with PBD, not including ZS, three patients had an unusual pattern of cerebral white matter Disease with onset past the age of 1, not conforming to any of the classic PBD phenotypes. Methods: Clinical phenotyping and follow-up, peroxisomal biochemical determinations in body fluids and fibroblasts, identification of affected PEX gene by genetic complementation in fibroblasts, and MRI studies. Results: Two unrelated patients with PBD without distinctive external features had normal neurodevelopmental milestones during their first year, followed by rapid deterioration including severe hypotonic pareses, seizures, retinopathy, and deafness. A third patient initially diagnosed with IRD developed cerebral white matter degeneration in the third year of life, complicating the original diagnosis. MRI in all three patients showed cerebral demyelination with sparing of subcortical fibers and pronounced central cerebellar demyelination. Conclusions: Late-onset cerebral white matter Disease may occur in PBD, either following IRD or following normal early development and in the absence of distinctive external features. Peroxisome biogenesis disorder should be included in the differential diagnosis of post-Infantile onset of cerebral white matter Disease.