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Nancy Braverman - One of the best experts on this subject based on the ideXlab platform.
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clinical biochemical and molecular characterization of mild nonclassic Rhizomelic Chondrodysplasia Punctata
Journal of Inherited Metabolic Disease, 2021Co-Authors: Wedad Fallatah, Erminia Di Pietro, Hans R Waterham, Bwee Tien Pollthe, Monica Schouten, Christine Yergeau, Marc Engelen, Nancy BravermanAbstract:Rhizomelic Chondrodysplasia Punctata (RCDP) is a heterogenous group of disorders due to defects in genes encoding peroxisomal proteins required for plasmalogen (PL) biosynthesis, specifically PEX7 and PEX5 receptors, or GNPAT, AGPS and FAR1 enzymes. Most patients have congenital cataract and skeletal dysplasia. In the classic form, there is profound growth restriction and psychomotor delays, with most patients not advancing past infantile developmental milestones. Disease severity correlates to erythrocyte PL levels, which are almost undetectable in severe (classic) RCDP. In milder (nonclassic) forms, residual PL levels are associated with improved growth and development. However, the clinical course of this milder group remains largely unknown as only a few cases were reported. Using as inclusion criteria the ability to communicate and walk, we identified 16 individuals from five countries, ages 5-37 years, and describe their clinical, biochemical and molecular profiles. The average age at diagnosis was 2.6 years and most had cataract, growth deficiency, joint contractures, and developmental delays. Other major symptoms were learning disability (87%), behavioral issues (56%), seizures (43%), and cardiac defects (31%). All patients had decreased C16:0 PL levels that were higher than in classic RCDP, and up to 43% of average controls. Plasma phytanic acid levels were elevated in most patients. There were several common, and four novel, PEX7, and GNPAT hypomorphic alleles in this cohort. These results can be used to support earlier diagnosis and improve management in patients with mild RCDP.
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clinical biochemical and molecular characterization of mild nonclassic Rhizomelic Chondrodysplasia Punctata
Journal of Inherited Metabolic Disease, 2020Co-Authors: Wedad Fallatah, Erminia Di Pietro, Hans R Waterham, Bwee Tien Pollthe, Monica Schouten, Christine Yergeau, Marc Engelen, Nancy BravermanAbstract:Rhizomelic Chondrodysplasia Punctata (RCDP) is a heterogenous group of disorders due to defects in genes encoding peroxisomal proteins required for plasmalogen (PL) biosynthesis, specifically PEX7 and PEX5 receptors, or GNPAT, AGPS and FAR1 enzymes. Most patients have congenital cataract and skeletal dysplasia. In the classic form, there is profound growth restriction and psychomotor delays, with most patients not advancing past infantile developmental milestones. Disease severity correlates to erythrocyte PL levels, which are almost undetectable in severe (classic) RCDP. In milder (nonclassic) forms, residual PL levels are associated with improved growth and development. However, the clinical course of this milder group remains largely unknown as only a few cases were reported. Using as inclusion criteria the ability to communicate and walk, we identified 16 individuals from 5 countries, ages 5 -37 years, and describe their clinical, biochemical and molecular profiles. The average age at diagnosis was 2.6 years and most had cataract, growth deficiency, joint contractures and developmental delays. Other major symptoms were learning disability (87%), behavioral issues (56%), seizures (43%) and cardiac defects ( 31% ). All patients had decreased C16:0 PL levels that were higher than in classic RCDP, and up to 43 % of average controls. Plasma phytanic acid levels were elevated in most patients. There were several common, and 4 novel, PEX7 and GNPAT hypomorphic alleles in this cohort. These results can be used to support earlier diagnosis and improve management in patients with mild RCDP. This article is protected by copyright. All rights reserved.
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oral administration of a synthetic vinyl ether plasmalogen normalizes open field activity in a mouse model of Rhizomelic Chondrodysplasia Punctata
Disease Models & Mechanisms, 2020Co-Authors: Wedad Fallatah, Tara Smith, Dushmanthi Jayasinghe, Shawn Ritchie, Erminia Di Pietro, Nancy BravermanAbstract:ABSTRACT Rhizomelic Chondrodysplasia Punctata (RCDP) is a rare genetic disorder caused by mutations in peroxisomal genes essential for plasmalogen biosynthesis. Plasmalogens are a class of membrane glycerophospholipids containing a vinyl-ether-linked fatty alcohol at the sn-1 position that affect functions including vesicular transport, membrane protein function and free radical scavenging. A logical rationale for the treatment of RCDP is therefore the therapeutic augmentation of plasmalogens. The objective of this work was to provide a preliminary characterization of a novel vinyl-ether synthetic plasmalogen, PPI-1040, in support of its potential utility as an oral therapeutic option for RCDP. First, wild-type mice were treated with 13C6-labeled PPI-1040, which showed that the sn-1 vinyl-ether and the sn-3 phosphoethanolamine groups remained intact during digestion and absorption. Next, a 4-week treatment of adult plasmalogen-deficient Pex7hypo/null mice with PPI-1040 showed normalization of plasmalogen levels in plasma, and variable increases in plasmalogen levels in erythrocytes and peripheral tissues (liver, small intestine, skeletal muscle and heart). Augmentation was not observed in brain, lung and kidney. Functionally, PPI-1040 treatment normalized the hyperactive behavior observed in the Pex7hypo/null mice as determined by open field test, with a significant inverse correlation between activity and plasma plasmalogen levels. Parallel treatment with an equal amount of ether plasmalogen precursor, PPI-1011, did not effectively augment plasmalogen levels or reduce hyperactivity. Our findings show, for the first time, that a synthetic vinyl-ether plasmalogen is orally bioavailable and can improve plasmalogen levels in an RCDP mouse model. Further exploration of its clinical utility is warranted. This article has an associated First Person interview with the joint first authors of the paper.
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growth charts for individuals with Rhizomelic Chondrodysplasia Punctata
American Journal of Medical Genetics Part A, 2017Co-Authors: Angela L Duker, Nancy Braverman, Tim Niiler, Grant Eldridge, Nga Brereton, Michael B BoberAbstract:Rhizomelic Chondrodysplasia Punctata (RCDP) is a class of peroxisomal disorders characterized by defective plasmalogen biosynthesis. There are multiple recognized types of RCDP, all of which have autosomal recessive inheritance, and their associated genes are known: RCDP type 1 with PEX7, RCDP type 2 with GNPAT, RCDP type 3 with AGPS, RCDP type 4 with FAR1, and RCDP type 5 with PEX5. Among other medical/developmental issues, plasmalogen deficiency has a direct effect on bone growth and results in postnatal growth failure, the severity of which corresponds to the degree of plasmalogen deficiency. In order to document growth in patients with RCDP, we present detailed growth curves for length, weight, and head circumference derived from retrospective data from 23 individuals with RCDP types 1 and 2 confirmed by molecular and/or biochemical studies. We stratified growth curves by age as well as by plasmalogen level, with those with higher plasmalogens grouped as "non-classic." The growth charts presented here provide guidance to families and physician caretakers on the natural course of growth in individuals with RCDP during infancy into early childhood, and thus will have particular utility in setting expectations and guiding optimal feeding interventions in this population.© 2016 Wiley Periodicals, Inc.
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Rhizomelic Chondrodysplasia Punctata Type 1 Caused by a Novel Mutation in the PEX7 Gene.
Journal of clinical research in pediatric endocrinology, 2015Co-Authors: Abdullah Çim, Erminia Di Pietro, Salih Coşkun, Orhan Görükmez, Hatice Yüksel, Ünal Uluca, François Plourde, Nancy BravermanAbstract:Peroxisomes are involved in various metabolic reactions. Rhizomelic Chondrodysplasia Punctata (RCDP) type 1 is one of the peroxisomal biogenesis disorders caused by mutations in the PEX7 gene and is inherited in an autosomal recessive manner. We present a nine-year-old boy with skeletal abnormalities and dysmorphic facial appearance. The patient was born to parents who were first cousins. Very-long-chain fatty acids and pristanic acid levels were in the normal range, but an elevated phytanic acid level was detected by gas chromatography/mass spectrometry. The PEX7 gene was sequenced in the patient and his parents. A novel homozygous mutation, c.192delT (p.F64Lfs*10), was identified in the patient and was present in heterozygosity in both parents. In conclusion, the clinical presentation and peroxisome profile of the patient suggest that this novel mutation leads to RCDP type 1.
Hans R Waterham - One of the best experts on this subject based on the ideXlab platform.
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clinical biochemical and molecular characterization of mild nonclassic Rhizomelic Chondrodysplasia Punctata
Journal of Inherited Metabolic Disease, 2021Co-Authors: Wedad Fallatah, Erminia Di Pietro, Hans R Waterham, Bwee Tien Pollthe, Monica Schouten, Christine Yergeau, Marc Engelen, Nancy BravermanAbstract:Rhizomelic Chondrodysplasia Punctata (RCDP) is a heterogenous group of disorders due to defects in genes encoding peroxisomal proteins required for plasmalogen (PL) biosynthesis, specifically PEX7 and PEX5 receptors, or GNPAT, AGPS and FAR1 enzymes. Most patients have congenital cataract and skeletal dysplasia. In the classic form, there is profound growth restriction and psychomotor delays, with most patients not advancing past infantile developmental milestones. Disease severity correlates to erythrocyte PL levels, which are almost undetectable in severe (classic) RCDP. In milder (nonclassic) forms, residual PL levels are associated with improved growth and development. However, the clinical course of this milder group remains largely unknown as only a few cases were reported. Using as inclusion criteria the ability to communicate and walk, we identified 16 individuals from five countries, ages 5-37 years, and describe their clinical, biochemical and molecular profiles. The average age at diagnosis was 2.6 years and most had cataract, growth deficiency, joint contractures, and developmental delays. Other major symptoms were learning disability (87%), behavioral issues (56%), seizures (43%), and cardiac defects (31%). All patients had decreased C16:0 PL levels that were higher than in classic RCDP, and up to 43% of average controls. Plasma phytanic acid levels were elevated in most patients. There were several common, and four novel, PEX7, and GNPAT hypomorphic alleles in this cohort. These results can be used to support earlier diagnosis and improve management in patients with mild RCDP.
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clinical biochemical and molecular characterization of mild nonclassic Rhizomelic Chondrodysplasia Punctata
Journal of Inherited Metabolic Disease, 2020Co-Authors: Wedad Fallatah, Erminia Di Pietro, Hans R Waterham, Bwee Tien Pollthe, Monica Schouten, Christine Yergeau, Marc Engelen, Nancy BravermanAbstract:Rhizomelic Chondrodysplasia Punctata (RCDP) is a heterogenous group of disorders due to defects in genes encoding peroxisomal proteins required for plasmalogen (PL) biosynthesis, specifically PEX7 and PEX5 receptors, or GNPAT, AGPS and FAR1 enzymes. Most patients have congenital cataract and skeletal dysplasia. In the classic form, there is profound growth restriction and psychomotor delays, with most patients not advancing past infantile developmental milestones. Disease severity correlates to erythrocyte PL levels, which are almost undetectable in severe (classic) RCDP. In milder (nonclassic) forms, residual PL levels are associated with improved growth and development. However, the clinical course of this milder group remains largely unknown as only a few cases were reported. Using as inclusion criteria the ability to communicate and walk, we identified 16 individuals from 5 countries, ages 5 -37 years, and describe their clinical, biochemical and molecular profiles. The average age at diagnosis was 2.6 years and most had cataract, growth deficiency, joint contractures and developmental delays. Other major symptoms were learning disability (87%), behavioral issues (56%), seizures (43%) and cardiac defects ( 31% ). All patients had decreased C16:0 PL levels that were higher than in classic RCDP, and up to 43 % of average controls. Plasma phytanic acid levels were elevated in most patients. There were several common, and 4 novel, PEX7 and GNPAT hypomorphic alleles in this cohort. These results can be used to support earlier diagnosis and improve management in patients with mild RCDP. This article is protected by copyright. All rights reserved.
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The neurology of Rhizomelic Chondrodysplasia Punctata
Orphanet journal of rare diseases, 2013Co-Authors: Annemieke M Bams-mengerink, Hans R Waterham, Johannes Htm Koelman, Peter G. Barth, B. T. Poll-theAbstract:Background To describe the neurologic profiles of Rhizomelic Chondrodysplasia Punctata (RCDP); a peroxisomal disorder clinically characterized by skeletal abnormalities, congenital cataracts, severe growth and developmental impairments and immobility of joints. Defective plasmalogen biosynthesis is the main biochemical feature.
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Rhizomelic Chondrodysplasia Punctata and cardiac pathology
Journal of Medical Genetics, 2013Co-Authors: Irene C Huffnagel, Sallyann B Clur, Annemieke M Bamsmengerink, Nico A Blom, Ronald J A Wanders, Hans R Waterham, Bwee Tien PolltheAbstract:Background Rhizomelic Chondrodysplasia Punctata (RCDP) is an autosomal recessive peroxisomal disorder characterised by rhizomelia, contractures, congenital cataracts, facial dysmorphia, severe psychomotor defects and growth retardation. Biochemically, the levels of plasmalogens (major constituents of cellular membranes) are low due to a genetic defect in their biosynthesis. Cardiac muscle contains high concentrations of plasmalogens. Recently cardiac dysfunction was found in a mouse model for RCDP with undetectable plasmalogen levels in all tissues including the heart. This suggests the importance of plasmalogens in normal cardiac development and function. Congenital heart disease (CHD), however, has not been recognised as a major characteristic of RCDP. Aims We aimed to determine the prevalence of CHD found in RCDP patients as well as to describe genetic, biochemical and cardiac correlations. Methods We included 23 patients with genetically proven RCDP. The genetic, biochemical and physical data were evaluated. Echocardiograms were reviewed. Results Cardiac data were available for 18 patients. 12 (52%) had CHD. All twelve had type 1 RCDP and 11 (92%) had the PEX 7 :c.875T>A mutation, of whom seven were homozygous (58%). Plasmalogen levels were significantly lower in the patients with CHD. Cardiac lesions included: septal defects (80% atrial), patent ductus arteriosus, pulmonary artery hypoplasia, tetralogy of Fallot and mitral valve prolapse (mostly older patients). Conclusions The CHD prevalence among RCDP patients was at least 52%, significantly higher than among the normal population. Plasmalogen levels were significantly lower in patients with CHD. Routine cardiac evaluation should be included in the clinical management of RCDP patients.
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defective lipid remodeling of gpi anchors in peroxisomal disorders zellweger syndrome and Rhizomelic Chondrodysplasia Punctata
Journal of Lipid Research, 2012Co-Authors: Noriyuki Kanzawa, Ronald J A Wanders, Hans R Waterham, Nobuyuki Shimozawa, Kazutaka Ikeda, Yoshiko Murakami, Satoru Mukai, Morihisa Fujita, Yusuke Maeda, Ryo TaguchiAbstract:Many cell surface proteins in mammalian cells are anchored to the plasma membrane via glycosylphosphatidylinositol (GPI). The predominant form of mammalian GPI contains 1-alkyl-2-acyl phosphatidylinositol (PI), which is generated by lipid remodeling from diacyl PI. The conversion of diacyl PI to 1-alkyl-2-acyl PI occurs in the ER at the third intermediate in the GPI biosynthetic pathway. This lipid remodeling requires the alkyl-phospholipid biosynthetic pathway in peroxisome. Indeed, cells defective in dihydroxyacetone phosphate acyltransferase (DHAP-AT) or alkyl-DHAP synthase express only the diacyl form of GPI-anchored proteins. A defect in the alkyl-phospholipid biosynthetic pathway causes a peroxisomal disorder, Rhizomelic Chondrodysplasia Punctata (RCDP), and defective biogenesis of peroxisomes causes Zellweger syndrome, both of which are lethal genetic diseases with multiple clinical phenotypes such as psychomotor defects, mental retardation, and skeletal abnormalities. Here, we report that GPI lipid remodeling is defective in cells from patients with Zellweger syndrome having mutations in the peroxisomal biogenesis factors PEX5, PEX16, and PEX19 and in cells from patients with RCDP types 1, 2, and 3 caused by mutations in PEX7, DHAP-AT, and alkyl-DHAP synthase, respectively. Absence of the 1-alkyl-2-acyl form of GPI-anchored proteins might account for some of the complex phenotypes of these two major peroxisomal disorders.
Ronald J A Wanders - One of the best experts on this subject based on the ideXlab platform.
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Rhizomelic Chondrodysplasia Punctata and cardiac pathology
Journal of Medical Genetics, 2013Co-Authors: Irene C Huffnagel, Sallyann B Clur, Annemieke M Bamsmengerink, Nico A Blom, Ronald J A Wanders, Hans R Waterham, Bwee Tien PolltheAbstract:Background Rhizomelic Chondrodysplasia Punctata (RCDP) is an autosomal recessive peroxisomal disorder characterised by rhizomelia, contractures, congenital cataracts, facial dysmorphia, severe psychomotor defects and growth retardation. Biochemically, the levels of plasmalogens (major constituents of cellular membranes) are low due to a genetic defect in their biosynthesis. Cardiac muscle contains high concentrations of plasmalogens. Recently cardiac dysfunction was found in a mouse model for RCDP with undetectable plasmalogen levels in all tissues including the heart. This suggests the importance of plasmalogens in normal cardiac development and function. Congenital heart disease (CHD), however, has not been recognised as a major characteristic of RCDP. Aims We aimed to determine the prevalence of CHD found in RCDP patients as well as to describe genetic, biochemical and cardiac correlations. Methods We included 23 patients with genetically proven RCDP. The genetic, biochemical and physical data were evaluated. Echocardiograms were reviewed. Results Cardiac data were available for 18 patients. 12 (52%) had CHD. All twelve had type 1 RCDP and 11 (92%) had the PEX 7 :c.875T>A mutation, of whom seven were homozygous (58%). Plasmalogen levels were significantly lower in the patients with CHD. Cardiac lesions included: septal defects (80% atrial), patent ductus arteriosus, pulmonary artery hypoplasia, tetralogy of Fallot and mitral valve prolapse (mostly older patients). Conclusions The CHD prevalence among RCDP patients was at least 52%, significantly higher than among the normal population. Plasmalogen levels were significantly lower in patients with CHD. Routine cardiac evaluation should be included in the clinical management of RCDP patients.
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defective lipid remodeling of gpi anchors in peroxisomal disorders zellweger syndrome and Rhizomelic Chondrodysplasia Punctata
Journal of Lipid Research, 2012Co-Authors: Noriyuki Kanzawa, Ronald J A Wanders, Hans R Waterham, Nobuyuki Shimozawa, Kazutaka Ikeda, Yoshiko Murakami, Satoru Mukai, Morihisa Fujita, Yusuke Maeda, Ryo TaguchiAbstract:Many cell surface proteins in mammalian cells are anchored to the plasma membrane via glycosylphosphatidylinositol (GPI). The predominant form of mammalian GPI contains 1-alkyl-2-acyl phosphatidylinositol (PI), which is generated by lipid remodeling from diacyl PI. The conversion of diacyl PI to 1-alkyl-2-acyl PI occurs in the ER at the third intermediate in the GPI biosynthetic pathway. This lipid remodeling requires the alkyl-phospholipid biosynthetic pathway in peroxisome. Indeed, cells defective in dihydroxyacetone phosphate acyltransferase (DHAP-AT) or alkyl-DHAP synthase express only the diacyl form of GPI-anchored proteins. A defect in the alkyl-phospholipid biosynthetic pathway causes a peroxisomal disorder, Rhizomelic Chondrodysplasia Punctata (RCDP), and defective biogenesis of peroxisomes causes Zellweger syndrome, both of which are lethal genetic diseases with multiple clinical phenotypes such as psychomotor defects, mental retardation, and skeletal abnormalities. Here, we report that GPI lipid remodeling is defective in cells from patients with Zellweger syndrome having mutations in the peroxisomal biogenesis factors PEX5, PEX16, and PEX19 and in cells from patients with RCDP types 1, 2, and 3 caused by mutations in PEX7, DHAP-AT, and alkyl-DHAP synthase, respectively. Absence of the 1-alkyl-2-acyl form of GPI-anchored proteins might account for some of the complex phenotypes of these two major peroxisomal disorders.
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mri of the brain and cervical spinal cord in Rhizomelic Chondrodysplasia Punctata
Neurology, 2006Co-Authors: Annemieke M Bamsmengerink, Ronald J A Wanders, Peter G. Barth, Charles B L M Majoie, M Duran, J L K Van Hove, C D Scheurer, Bwee Tien PolltheAbstract:Background: The classic Rhizomelic Chondrodysplasia Punctata (RCDP) phenotype involves a typical facial appearance, cataracts, skeletal dysplasia causing disproportionate somatic growth failure, microcephaly, and severe psychomotor defects. Biochemical abnormalities include impaired plasmalogen biosynthesis in all forms of RCDP and accumulation of phytanic acid in RCDP type 1. A subset of patients has a milder clinical and biochemical phenotype, with less severe neurologic impairment and an incomplete deficiency in plasmalogens. The impact of plasmalogen deficiency on neurologic function is severe, causing spasticity and mental defects, but its pathomechanism is still unknown. The authors specifically focused on myelination because myelin is rich in ethanolamine plasmalogens. Objective: To define the neuroimaging characteristics of the genetic peroxisomal disorder RCDP. Methods: Twenty-one MR images of the brain and cervical spine of 11 patients were evaluated and correlated with neurologic and biochemical profiles. Results: No abnormalities on MRI were seen in the patients with a mild phenotype of RCDP, whereas delayed myelination, ventricular enlargement and increased subarachnoidal spaces, supratentorial myelin abnormalities, and cerebellar atrophy were observed in patients with the severe phenotype of both RCDP type 1 and 3. The severity of both the MRI abnormalities and the clinical phenotype is correlated with the plasmalogen level. Conclusions: The severe phenotype of Rhizomelic Chondrodysplasia Punctata (RCDP) is accompanied by a specific pattern of both developmental and regressive MRI abnormalities. Plasmalogen levels seem to play an important role in the pathophysiology of CNS abnormalities in RCDP. Increased phytanic acid appears not to be the cause of cerebellar atrophy.
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mutational spectrum in the pex7 gene and functional analysis of mutant alleles in 78 patients with Rhizomelic Chondrodysplasia Punctata type 1
American Journal of Human Genetics, 2002Co-Authors: Alison M Motley, Eveline M. Hogenhout, Ronald J A Wanders, Pedro Brites, Janet Haasjes, H F Tabak, Lisya Gerez, Rob Benne, Hans R WaterhamAbstract:Rhizomelic Chondrodysplasia Punctata (RCDP) is a genetically heterogeneous, autosomal recessive disorder of peroxisomal metabolism that is clinically characterized by symmetrical shortening of the proximal long bones, cataracts, periarticular calcifications, multiple joint contractures, and psychomotor retardation. Most patients with RCDP have mutations in the PEX7 gene encoding peroxin 7, the cytosolic PTS2-receptor protein required for targeting a subset of enzymes to peroxisomes. These enzymes are deficient in cells of patients with RCDP, because of their mislocalization to the cytoplasm. We report the mutational spectrum in the PEX7 gene of 78 patients (including five pairs of sibs) clinically and biochemically diagnosed with RCDP type I. We found 22 different mutations, including 18 novel ones. Furthermore, we show by functional analysis that disease severity correlates with PEX7 allele activity: expression of eight different alleles from patients with severe RCDP failed to restore the targeting defect in RCDP fibroblasts, whereas two alleles found only in patients with mild disease complemented the targeting defect upon overexpression. Surprisingly, one of the mild alleles comprises a duplication of nucleotides 45–52, which is predicted to lead to a frameshift at codon 17 and an absence of functional peroxin 7. The ability of this allele to complement the targeting defect in RCDP cells suggests that frame restoration occurs, resulting in full-length functional peroxin 7, which leads to amelioration of the predicted severe phenotype. This was confirmed in vitro by expression of the eight-nucleotide duplication–containing sequence fused in different reading frames to the coding sequence of firefly luciferase in COS cells.
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abnormal myelin formation in Rhizomelic Chondrodysplasia Punctata type 2 dhapat deficiency
Developmental Medicine & Child Neurology, 2000Co-Authors: Laszlo Sztriha, Rob Ofman, Ronald J A Wanders, Lihadh Algazali, Michael Nork, Gilles G LestringantAbstract:The case of a Yemeni girl with isolated peroxisomal acyl-CoA:dihydroxyacetonephosphate acyltransferase (DHAPAT) deficiency is reported. She had Rhizomelic Chondrodysplasia Punctata, microcephaly, failure to thrive, delayed motor and mental development, and spastic quadriplegia. Deficient de novo plasmalogen synthesis in her fibroblasts as a result of low DHAPAT activity was found, while her very-long-chain fatty acid profile, phytanic acid concentration, alkyl-dihydroxyacetonephosphate synthase (alkyl-DHAP synthase) activity, and peroxisomal 3-ketoacyl-CoA thiolase protein were normal. A mutation in her DHAPAT complementary DNA resulted in the substitution of an arginine residue in the protein at position 211 by a histidine (R211H). Magnetic resonance imaging showed abnormal white matter signal in the centrum semiovale involving the arcuate fibers, while the corpus callosum was normal. DHAPAT and alkyl-DHAP synthase initiate the synthesis of plasmalogens, which are major constituents of myelin phospholipids. The reported girl's abnormal formation of myelin is probably related to the inadequacy of plasmalogen biosynthesis, which is likely to be due to deficient DHAPAT activity.
Ann B. Moser - One of the best experts on this subject based on the ideXlab platform.
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human disorders of peroxisome biogenesis zellweger spectrum and Rhizomelic Chondrodysplasia Punctata
2014Co-Authors: Nancy Braverman, Catherine Argyriou, Ann B. MoserAbstract:The human peroxisome biogenesis disorders (PBD) are caused by autosomal recessive mutations in any of the 14 PEX genes, which encode peroxins, or PEX proteins, that act cooperatively to assemble functional peroxisomes. Mutations in PEX genes affect the import of peroxisome matrix enzymes and formation of new peroxisomes. The consequences are multiple enzyme deficiencies causing developmental malformations and progressive postnatal tissue injury. The PBD are classified into two distinct groups: Zellweger spectrum disorders (ZSD) and Rhizomelic Chondrodysplasia Punctata spectrum type 1 (RCDP1). The term “spectrum” is preferred because there is a gradation of phenotypes from severe to mild in these disorders, as well as newly recognized atypical phenotypes. In general, the milder the phenotype, the greater are the residual functions of the defective peroxin.
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and Rhizomelic Chondrodysplasia Punctata 4
2014Co-Authors: Nancy Braverman, Catherine Argyriou, Ann B. MoserAbstract:The human peroxisome biogenesis disorders (PBD) are caused by autosomal recessive mutations in any of the 14 PEX genes, which encode peroxins, or PEX proteins, that act cooperatively to assemble functional peroxisomes. Mutations in PEX genes affect the import of peroxisome matrix enzymes and formation of new peroxisomes. The consequences are multiple enzyme deficiencies causing developmental malformations and progressive postnatal tissue injury. The PBD are classified into two distinct groups: Zellweger spectrum disorders (ZSD) and Rhizomelic Chondrodysplasia Punctata spectrum type 1 (RCDP1). The term “spectrum” is preferred because there is a gradation of phenotypes from severe to mild in these disorders, as well as newly recognized atypical phenotypes. In general, the milder the phenotype, the greater are the residual functions of the defective peroxin. Tissues most affected in the PBD include the brain, peripheral nerves, eye, liver, kidney, heart, adrenal glands, bone, and lung. The severe form is distinguished by developmental malformations and early demise. In the intermediate and milder phenotypes, malformations may not be present and prominent disease features reflect postnatal peroxisome dysfunction over time. It is this latter group of patients that would benefit most from targeted therapies. In this chapter, we will review clinical phenotypes, diagnoses, supportive management, and research approaches to developing targeted therapies. In the overall theme of
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Rhizomelic Chondrodysplasia Punctata type 1
2012Co-Authors: Nancy Braverman, Ann B. Moser, Steven J SteinbergAbstract:Clinical characteristics Rhizomelic Chondrodysplasia Punctata type 1 (RCDP1), a peroxisome biogenesis disorder (PBD) has a classic (severe) form and a nonclassic (mild) form. Classic (severe) RCDP1 is characterized by proximal shortening of the humerus (rhizomelia) and to a lesser degree the femur, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (Chondrodysplasia Punctata, or CDP), coronal clefts of the vertebral bodies, and cataracts that are usually present at birth or appear in the first few months of life. Birth weight, length, and head circumference are often at the lower range of normal; postnatal growth deficiency is profound. Intellectual disability is severe, and the majority of children develop seizures. Most affected children do not survive the first decade of life; a proportion die in the neonatal period. Nonclassic (mild) RCDP1 is characterized by congenital or childhood cataracts, CDP or infrequently, Chondrodysplasia manifesting only as mild epiphyseal changes, variable rhizomelia, and milder intellectual disability and growth restriction than classic RCDP1. Diagnosis/testing The diagnosis of RCDP1 is established in a proband with suggestive clinical, radiographic, and laboratory findings and biallelic pathogenic variants in PEX7 identified on molecular genetic testing. Management Treatment of manifestations: Classic (severe) RCDP1: Management is supportive and limited by the multiple handicaps present at birth and poor outcome. Poor feeding and recurrent aspiration may necessitate placement of a gastrostomy tube; attention to respiratory function and good pulmonary toilet. Cataract extraction may restore some vision. Physical therapy to improve contractures; orthopedic procedures may improve function in some individuals. Management of developmental delay/intellectual disability as per standard of care. Prevention of primary manifestations: Dietary restriction of phytanic acid to avoid the consequences of phytanic acid accumulation over time may benefit individuals with mild RCDP1. Surveillance: Frequent monitoring of growth, nutritional status, and developmental and educational needs; regular assessments for evidence of aspiration, respiratory insufficiency, seizure control, vision, hearing, contractures, and orthopedic complications. Genetic counseling RCDP1 is inherited in an autosomal recessive manner. If each parent is known to be heterozygous for a PEX7 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an unaffected carrier, and a 25% chance of inheriting both normal alleles. Molecular genetic carrier testing of at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible once the PEX7 pathogenic variants have been identified in an affected family member.
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functional characterization of novel mutations in gnpat and agps causing Rhizomelic Chondrodysplasia Punctata rcdp types 2 and 3
Human Mutation, 2012Co-Authors: Brandon Itzkovitz, Ann B. Moser, Steve Steinberg, Sarn Jiralerspong, Graeme Nimmo, Melissa L Loscalzo, Dafne Dain Gandelman Horovitz, Ann Snowden, Nancy BravermanAbstract:Rhizomelic Chondrodysplasia Punctata (RCDP) is a disorder of peroxisome metabolism result-ing from a deficiency of plasmalogens, a specialized class of membrane phospholipids. Classically, patients have a skeletal dysplasia and profound mental retardation, al-though milder phenotypes are increasingly being iden-tified. It is commonly caused by defects in the peroxi-some transporter, PEX7 (RCDP1), and less frequently due to defects in the peroxisomal enzymes required to initi-ate plasmalogen synthesis, GNPAT (RCDP2) and AGPS (RCDP3). PEX7 transports AGPS into the peroxisome, where AGPS and GNPAT partner on the luminal mem-brane surface. The presence of AGPS is thought to be required for GNPAT activity. We present six additional probands with RCDP2 and RCDP3, and the novel muta-tions identified in them. Using cell lines from these and previously reported patients, we compared the amounts of both AGPS and GNPAT proteins present for the first time. We used protein modeling to predict the structural consequences ofAGPSmutations and transcript analysis to predict consequences ofGNPATmutations, and show that milder RCDP phenotypes are likely to be associated with residual protein function. In addition, we propose that full GNPAT activity depends not only on the pres-ence of AGPS, but also on the integrity of substrate chan-neling from GNPAT to AGPS.
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Rhizomelic Chondrodysplasia Punctata type 1: report of mutations in 3 children from India.
Journal of applied genetics, 2010Co-Authors: Shubha R. Phadke, Neerja Gupta, Katta M. Girisha, Madhulika Kabra, M. Maeda, E. Vidal, Ann B. Moser, Steve Steinberg, Ratna Dua Puri, Ishwar C. VermaAbstract:Rhizomelic Chondrodysplasia Punctata is a rare autosomal recessive disorder characterized by stippled epiphyses and Rhizomelic shortening of the long bones. We report 3 subjects of Rhizomelic Chondrodysplasia Punctata from India and thePEX7 mutations identified in them. The commonPEX7-L292X allele, whose high frequency is due to a founder effect in the northern European Caucasian population, was not identified in these patients. Instead, 2 novel alleles are described, including 64_65delGC, which was present on a singlePEX7 haplotype and could represent a common allele in the Indian population.
Pedro Brites - One of the best experts on this subject based on the ideXlab platform.
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Plasmalogens and fatty alcohols in Rhizomelic Chondrodysplasia Punctata and Sjögren-Larsson syndrome
Journal of Inherited Metabolic Disease, 2015Co-Authors: Ana R. Malheiro, Tiago Ferreira Da Silva, Pedro BritesAbstract:Plasmalogens are a special class of ether-phospholipids, best recognized by their vinyl-ether bond at the sn -1 position of the glycerobackbone and by the observation that their deficiency causes Rhizomelic Chondrodysplasia Punctata (RCDP). The complex plasmalogen biosynthetic pathway involves multiple enzymatic steps carried-out in peroxisomes and in the endoplasmic reticulum. The rate limiting step in the biosynthesis of plasmalogens resides in the formation of the fatty alcohol responsible for the formation of an intermediate with an alkyl-linked moiety. The regulation in the biosynthesis of plasmalogens also takes place at this step using a feedback mechanism to stimulate or inhibit the biosynthesis. As such, fatty alcohols play a relevant role in the formation of ether-phospholipids. These advances in our understanding of complex lipid biosynthesis brought two seemingly distinct disorders into the spotlight. Sjögren-Larsson syndrome (SLS) is caused by defects in the microsomal fatty aldehyde dehydrogenase (FALDH) leading to the accumulation of fatty alcohols and fatty aldehydes. In RCDP cells, the defect in plasmalogens is thought to generate a feedback signal to increase their biosynthesis, through the activity of fatty acid reductases to produce fatty alcohols. However, the enzymatic defects in either glyceronephosphate O-acyltransferase (GNPAT) or alkylglycerone phosphate synthase (AGPS) disrupt the biosynthesis and result in the accumulation of the fatty alcohols. A detailed characterization on the processes and enzymes that govern these intricate biosynthetic pathways, as well as, the metabolic characterization of defects along the pathway should increase our understanding of the causes and mechanisms behind these disorders.
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impaired neuronal migration and endochondral ossification in pex7 knockout mice a model for Rhizomelic Chondrodysplasia Punctata
Human Molecular Genetics, 2003Co-Authors: Pedro Brites, Alison M Motley, Pierre Gressens, Petra A W Mooyer, Ingrid Ploegaert, Vincent Everts, Philippe Evrard, Peter Carmeliet, Mieke Dewerchin, Luc SchoonjansAbstract:Rhizomelic Chondrodysplasia Punctata is a human autosomal recessive disorder characterized by skeletal, eye and brain abnormalities. The disorder is caused by mutations in the PEX7 gene, which encodes the receptor for a class of peroxisomal matrix enzymes. We describe the generation and characterization of a Pex7 mouse knockout (Pex7(-/-)). Pex7(-/-) mice are born severely hypotonic and have a growth impairment. Mortality in Pex7(-/-) mice is highest in the perinatal period although some Pex7(-/-) mice survived beyond 18 months. Biochemically Pex7(-/-) mice display the abnormalities related to a Pex7 deficiency, i.e. a severe depletion of plasmalogens, impaired alpha-oxidation of phytanic acid and impaired beta-oxidation of very-long-chain fatty acids. In the intermediate zone of the developing cerebral cortex Pex7(-/-) mice have an increase in neuronal density. In vivo neuronal birthdating revealed that Pex7(-/-) mice have a delay in neuronal migration. Analysis of bone ossification in newborn Pex7(-/-) mice revealed a defect in ossification of distal bone elements of the limbs as well as parts of the skull and vertebrae. These findings demonstrate that Pex7 knockout mice provide an important model to study the role of peroxisomal functioning in the pathogenesis of the human disorder.
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Identification of PEX7 as the Second Gene Involved in Refsum Disease
American journal of human genetics, 2003Co-Authors: Pedro Brites, G A Jansen, Anthony S Wierzbicki, John Mitchell, Jacqueline De Belleroche, Janet Haasjes, Michelle Lambert-hamill, Hans R WaterhamAbstract: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 α-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.
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mutational spectrum in the pex7 gene and functional analysis of mutant alleles in 78 patients with Rhizomelic Chondrodysplasia Punctata type 1
American Journal of Human Genetics, 2002Co-Authors: Alison M Motley, Eveline M. Hogenhout, Ronald J A Wanders, Pedro Brites, Janet Haasjes, H F Tabak, Lisya Gerez, Rob Benne, Hans R WaterhamAbstract:Rhizomelic Chondrodysplasia Punctata (RCDP) is a genetically heterogeneous, autosomal recessive disorder of peroxisomal metabolism that is clinically characterized by symmetrical shortening of the proximal long bones, cataracts, periarticular calcifications, multiple joint contractures, and psychomotor retardation. Most patients with RCDP have mutations in the PEX7 gene encoding peroxin 7, the cytosolic PTS2-receptor protein required for targeting a subset of enzymes to peroxisomes. These enzymes are deficient in cells of patients with RCDP, because of their mislocalization to the cytoplasm. We report the mutational spectrum in the PEX7 gene of 78 patients (including five pairs of sibs) clinically and biochemically diagnosed with RCDP type I. We found 22 different mutations, including 18 novel ones. Furthermore, we show by functional analysis that disease severity correlates with PEX7 allele activity: expression of eight different alleles from patients with severe RCDP failed to restore the targeting defect in RCDP fibroblasts, whereas two alleles found only in patients with mild disease complemented the targeting defect upon overexpression. Surprisingly, one of the mild alleles comprises a duplication of nucleotides 45–52, which is predicted to lead to a frameshift at codon 17 and an absence of functional peroxin 7. The ability of this allele to complement the targeting defect in RCDP cells suggests that frame restoration occurs, resulting in full-length functional peroxin 7, which leads to amelioration of the predicted severe phenotype. This was confirmed in vitro by expression of the eight-nucleotide duplication–containing sequence fused in different reading frames to the coding sequence of firefly luciferase in COS cells.
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Rhizomelic Chondrodysplasia Punctata is a peroxisomal protein targeting disease caused by a non functional pts2 receptor
Nature Genetics, 1997Co-Authors: Alison M Motley, Eveline M. Hogenhout, Pedro Brites, Ewald H. Hettema, A Ten L M A Asbroek, Frits A Wijburg, Frank Baas, H S Heijmans, H F Tabak, Ronald J A WandersAbstract:Rhizomelic Chondrodysplasia Punctata (RCDP) is an autosomal recessive disease characterized clinically by a disproportionately short stature primarily affecting the proximal parts of the extremities, typical dysmorphic facial appearance, congenital contractures and severe growth and mental retardation. Although some patients have single enzyme deficiencies, the majority of RCDP patients (86%) belong to a single complementation group (CG11, also known as complementation group I, Amsterdam nomenclature1). Cells from CG11 show a tetrad of biochemical abnormalities: a deficiency of i) dihydroxyacetonephosphate acyltransferase, ii) alkyldihydroxyacetonephosphate synthase, iii) phytanic acid α-oxidation and iv) inability to import peroxisomal thiolase. These deficiencies indicate involvement of a component required for correct targeting of these peroxisomal proteins. Deficiencies in peroxisomal targeting are also found in Saccharomyces cerevisiae pex5 and pex7 mutants2–6, which show differential protein import deficiencies corresponding to two peroxisomal targeting sequences (PTS1 and PTS2). These mutants lack their PTS1 and PTS2 receptors, respectively. Like S. cerevisiae pex7 cells, RCDP cells from CG11 cannot import a PTS2 reporter protein7. Here we report the cloning of PEX7 encoding the human PTS2 receptor, based on its similarity to two yeast orthologues. All RCDP patients from CG11 with detectable PEX7 mRNA were found to contain mutations in PEX7. A mutation resulting in C-terminal truncation of PEX7 cosegregates with the disease and expression of PEX7 in RCDP fibroblasts from CG11 rescues the PTS2 protein import deficiency. These findings prove that mutations in PEX7 cause RCDP,CG11.
