121 results on '"Chondrodysplasia Punctata, Rhizomelic"'
Search Results
2. Rhizomelic Chondrodysplasia Punctata Registry
- Author
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RhizoKids International and Michael Bober, Director of Skeletal Dysplasia Program
- Published
- 2023
3. A First-in-Human Phase 1 Study of Plasmalogen Precursor PPI-1011 in Healthy Adult Volunteers to Assess Safety, Tolerability, and Pharmacokinetics
- Author
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BioPharma Services, Inc
- Published
- 2023
4. RCDP Natural History Study
- Published
- 2019
5. Expanding the genotypic and phenotypic landscapes of rhizomelic chondrodysplasia punctata type 3 (RCDP3) with two novel families, and a review of the literature
- Author
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Ezgi Gökpınar İli, Alper Gezdirici, Erminia Di Pietro, Christine Yergeau, and Nancy Braverman
- Subjects
Chondrodysplasia Punctata ,Chondrodysplasia Punctata, Rhizomelic ,Genotype ,Intellectual Disability ,Plasmalogens ,Genetics ,Humans ,Genetics (clinical) - Abstract
Rhizomelic chondrodysplasia punctata (RCDP) are a group of peroxisomal disorders caused by plasmalogen synthesis defects. Patients with RCDP present with rhizomelic short stature, characteristic punctate epiphyseal calcifications, congenital cataracts, severe intellectual disability, seizures, and facial dysmorphism. Pathogenic variants in AGPS result in RCDP type 3 (RCDP3) which is an extremely rare disorder characterized by isolated ADHAPS deficiency. Six patients with RCDP3 have been identified, upto-date. We report two new patients with RCDP3 and their novel variants, c.154dupG (p.Ala52GlyfsTer6) and c.637+1GA, in the AGPS gene. We also present a review of previously reported RCDP3 patients.
- Published
- 2022
6. Rhizomelic Chondro-Dysplasia Punctate (RCDP)
- Author
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Vykuntaraju K, Gowda, Varunvenkat M, Srinivasa, and Dhananjaya K, Vamyanmane
- Subjects
Rare Diseases ,Chondrodysplasia Punctata, Rhizomelic ,Humans - Published
- 2022
7. Oral batyl alcohol supplementation rescues decreased cardiac conduction in ether phospholipid‐deficient mice
- Author
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Johannes Berger, Xaver Koenig, Christian Lüchtenborg, Fabian Dorninger, Claus M. Fischer, Karlheinz Hilber, Fatma Asli Erdem, Peter J. Rothauer, Vaibhavkumar S. Gawali, Britta Bruegger, Michael Schranz, Janine Ebner, and Hannes Todt
- Subjects
Male ,medicine.medical_specialty ,electrocardiography ,Plasmalogens ,Phospholipid ,Administration, Oral ,Glyceryl Ethers ,arrhythmia ,Nerve conduction velocity ,Mice ,cardiac impulse conduction ,03 medical and health sciences ,chemistry.chemical_compound ,QRS complex ,Ductus arteriosus ,Internal medicine ,Cardiac conduction ,Genetics ,Animals ,Medicine ,Mitral valve prolapse ,cardiovascular diseases ,Genetics (clinical) ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,medicine.diagnostic_test ,business.industry ,030305 genetics & heredity ,Phospholipid Ethers ,Arrhythmias, Cardiac ,Original Articles ,batyl alcohol ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Dietary Supplements ,cardiovascular system ,Original Article ,rhizomelic chondrodysplasia punctata ,business ,Electrocardiography - Abstract
Plasmalogens (Pls) are a class of membrane phospholipids which serve a number of essential biological functions. Deficiency of Pls is associated with common disorders such as Alzheimer's disease or ischemic heart disease. A complete lack of Pls due to genetically determined defective biosynthesis gives rise to rhizomelic chondrodysplasia punctata (RCDP), characterized by a number of severe disabling pathologic features and death in early childhood. Frequent cardiac manifestations of RCDP include septal defects, mitral valve prolapse, and patent ductus arteriosus. In a mouse model of RCDP, reduced nerve conduction velocity was partially rescued by dietary oral supplementation of the Pls precursor batyl alcohol (BA). Here, we examine the impact of Pls deficiency on cardiac impulse conduction in a similar mouse model (Gnpat KO). In‐vivo electrocardiographic recordings showed that the duration of the QRS complex was significantly longer in Gnpat KO mice than in age‐ and sex‐matched wild‐type animals, indicative of reduced cardiac conduction velocity. Oral supplementation of BA for 2 months resulted in normalization of cardiac Pls levels and of the QRS duration in Gnpat KO mice but not in untreated animals. BA treatment had no effect on the QRS duration in age‐matched wild‐type mice. These data suggest that Pls deficiency is associated with increased ventricular conduction time which can be rescued by oral BA supplementation.
- Published
- 2020
8. A new GNPAT variant of foetal rhizomelic chondrodysplasia punctata
- Author
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Elisabetta Pelo, Adalgisa Cordisco, Roberto Biagiotti, and Mariarosaria Di Tommaso
- Subjects
Adult ,Pathology ,medicine.medical_specialty ,RNA Splicing ,Prenatal diagnosis ,Biology ,QH426-470 ,medicine.disease_cause ,Ultrasonography, Prenatal ,Clinical Reports ,symbols.namesake ,Cataracts ,medicine ,Genetics ,Humans ,Molecular Biology ,Genetics (clinical) ,Sanger sequencing ,Mutation ,Rhizomelic chondrodysplasia punctata ,Clinical Report ,prenatal diagnosis ,Chondrodysplasia Punctata, Rhizomelic ,Cartilage ,Rhizomelia ,GNPAT ,medicine.disease ,medicine.anatomical_structure ,RNA splicing ,symbols ,Female ,rhizomelic chondrodysplasia punctata ,Acyltransferases - Abstract
Background Rhizomelic chondrodysplasia punctata (RCDP) is a clinical entity resulting from defects of peroxisomal metabolism whose clinical phenotype is characterized by rhizomelia, calcified foci in periarticular cartilage, coronal lesions of vertebral bodies, cataracts and severe cognitive delay. Usually, survival does not exceed the first decade of life. Transmission is autosomal recessive and is related to mutations in the PEX7, GNPAT or AGPS. Methods A detailed description of the prenatal ultrasound signs of RCDP found in two successive pregnancies in a consanguineous couple is reported. Molecular genetic investigations included the study of the coding regions and the exon–intron junctions of the GNPAT (high‐throughput amplification and sequencing performed with Roche NimbleGen SeqCap Target kit on Illumina platform); the confirmation test was carried out by amplification and Sanger sequencing with automatic capillary sequencer. Results In addition to the typical prenatal ultrasound signs described in the literature in association with RCDP, the presence of prefrontal oedema, never previously described, has been detected in both pregnancies. Moreover, genetic investigations have found a new splicing variant c.924+1G>A of the homozygous GNPAT. Conclusion The role of mutation in the GNPAT suggests a likely association with the clinical phenotype., Rhizomelic chondrodysplasia punctata (RCDP) is a rare developmental disorder, characterized by rhizomelic bone shortening and epiphyseal stippling, microcephaly, characteristic facial features and severe psychomotor retardation. Transmission is autosomal recessive and is related to mutations in the PEX7, GNPAT or AGPS genes. A fetal diagnosis of RCDP with a new mutation of the GNPAT gene is reported.
- Published
- 2021
9. Genetic epidemiology approach to estimating birth incidence and current disease prevalence for rhizomelic chondrodysplasia punctata
- Author
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Shawn Ritchie, Tarik Luisman, Tara C. Smith, and Karen E. Malone
- Subjects
Adult ,medicine.medical_specialty ,Pediatrics ,AGPS ,Epidemiology ,Prevalence ,Disease ,Plasmalogen ,03 medical and health sciences ,FAR1 ,0302 clinical medicine ,Germany ,medicine ,Humans ,Pharmacology (medical) ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Molecular Epidemiology ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,business.industry ,Incidence (epidemiology) ,Incidence ,Research ,GNPAT ,General Medicine ,PEX7 ,medicine.disease ,PEX5 ,Human genetics ,Europe ,Genetic epidemiology ,Italy ,Spain ,Medicine ,France ,business ,Rare disease ,030217 neurology & neurosurgery ,Rhizomelic chondrodysplasia punctate - Abstract
Background Rhizomelic chondrodysplasia punctata (RCDP) is an inherited ultra-rare disease which results in severely impaired physical and mental development. Mutations in one of five genes involved in plasmalogen biosynthesis have been reported to drive disease pathology. Estimates of disease incidence have been extremely challenging due to the rarity of the disorder, preventing an understanding of the unmet medical need. To address this, we have prepared a disease incidence and prevalence model based on genetic epidemiology approaches to estimate the total number of RCDP patients affected, and their demographic characteristics. Results Extraction of allelic frequencies for known and predicted pathogenic variants in PEX7, GNPAT, AGPS, FAR1, PEX5 (limited to the PTS2 domain encoding region) genes, from large-scale human genetic diversity datasets (TopMed and gnomAD) revealed the mutational landscape contributing to the RCDP patient population in the US and Europe. We computed genetic prevalence to derive birth incidence for RCDP and modeled the impact to life expectancy to obtain high confidence estimates of disease prevalence. Our population genetics-based model indicates PEX7 variants are expected to contribute to the majority of RCDP cases in both the US and Europe; closely aligning with clinical reports. Furthermore, this model provides estimates for RCDP subtypes due to mutations in other genes, including exceedingly rare subtypes. Conclusion In total, the estimated number of RCDP patients in the US and the five largest European countries (UK, Germany, France, Italy and Spain) is between 516 and 847 patients, all under the age of 35 years old. This model provides a quantitative framework for better understanding the unmet medical need in RCDP, to help guide disease awareness and diagnosis efforts for this specific patient group.
- Published
- 2021
10. Plasmalogens regulate the AKT-ULK1 signaling pathway to control the position of the axon initial segment
- Author
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Luís S. Granadeiro, Diogo Bessa-Neto, Tiago Ferreira da Silva, Liliana L. Luz, Boris V. Safronov, and Pedro Brites
- Subjects
Rhizomelic chondrodysplasia punctata ,Plasmalogen ,Chondrodysplasia Punctata, Rhizomelic ,Akt/PKB signaling pathway ,General Neuroscience ,Plasmalogens ,Intracellular Signaling Peptides and Proteins ,Biology ,medicine.disease ,Axon initial segment ,medicine.anatomical_structure ,Peroxisomal disorder ,medicine ,Autophagy-Related Protein-1 Homolog ,Humans ,Neuron ,Signal transduction ,Protein kinase B ,Neuroscience ,Proto-Oncogene Proteins c-akt ,Axon Initial Segment ,Signal Transduction - Abstract
The axon initial segment (AIS) is a specialized region in neurons that encompasses two essential functions, the generation of action potentials and the regulation of the axodendritic polarity. The mechanism controlling the position of the axon initial segment to allow plasticity and regulation of neuron excitability is unclear. Here we demonstrate that plasmalogens, the most abundant ether-phospholipid, are essential for the homeostatic positioning of the AIS. Plasmalogen deficiency is a hallmark of Rhizomelic Chondrodysplasia Punctata (RCDP) and Zellweger spectrum disorders, but Alzheimer's and Parkinson's disease, are also characterized by plasmalogen defects. Neurons lacking plasmalogens displaced the AIS to more distal positions and were characterized by reduced excitability. Treatment with a short-chain alkyl glycerol was able to rescue AIS positioning. Plasmalogen deficiency impaired AKT activation, and we show that inhibition of AKT phosphorylation at Ser473 and Thr308 is sufficient to induce a distal relocation of the AIS. Pathway analysis revealed that downstream of AKT, overtly active ULK1 mediates AIS repositioning. Rescuing the impaired AKT signaling pathway was able to normalize AIS position independently of the biochemical defect. These results unveil a previously unknown mechanism that couples the phospholipid composition of the neuronal membrane to the positional assembly of the AIS.
- Published
- 2021
11. Clinical, biochemical, and molecular characterization of mild (nonclassic) rhizomelic chondrodysplasia punctata
- Author
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Wedad Fallatah, Monica Schouten, Hans R. Waterham, Marc Engelen, Bwee Tien Poll-The, Nancy Braverman, Erminia Di Pietro, Christine Yergeau, Neurology, Paediatric Neurology, ANS - Cellular & Molecular Mechanisms, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Laboratory Genetic Metabolic Diseases
- Subjects
Adult ,Male ,Phytanic acid ,Plasmalogen ,peroxisomal disorders ,Adolescent ,Physiology ,plasmalogen ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,Peroxisomal disorder ,Genetics ,medicine ,Humans ,Allele ,Growth Charts ,Child ,Genetics (clinical) ,Genetic Association Studies ,030304 developmental biology ,Psychomotor learning ,0303 health sciences ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,business.industry ,030305 genetics & heredity ,rhizomelic chondrodysplasia punctata (RCDP) ,medicine.disease ,mild (nonclassic) phenotype ,chemistry ,Dysplasia ,Child, Preschool ,Cohort ,Female ,business - Abstract
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.
- Published
- 2020
12. General Movements and Developmental Functioning in an Individual with Rhizomelic Chondrodysplasia Punctata within the First Months of the Life: A Case Report
- Author
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Akmer Mutlu, Bilge Nur Yardımcı-Lokmanoğlu, and Ayşe Livanelioğlu
- Subjects
musculoskeletal diseases ,030506 rehabilitation ,Pediatrics ,medicine.medical_specialty ,Movement ,Physical Therapy, Sports Therapy and Rehabilitation ,Gestational Age ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Occupational Therapy ,medicine ,Humans ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,Rehabilitation ,Infant, Newborn ,Infant ,General Medicine ,musculoskeletal system ,medicine.disease ,General movements ,Pediatrics, Perinatology and Child Health ,Fidgety movements ,Female ,sense organs ,0305 other medical science ,030217 neurology & neurosurgery - Abstract
Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive inherited disorder. Individuals with RCDP have a wide range of neurodevelopmental outcomes, but there are limited descriptions of their early motor development before 5 months of age. This study aimed to describe in detail the age-specific spontaneous movements and examine the developmental functioning in an individual with RCDP.A female infant (born at 39 weeks' gestation), diagnosed with RCDP at 3 weeks of age, was assessed at 4 and 16 weeks for general movements (GMs) and concurrent motor repertoire; the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III) was also applied at the same ages.At 4 weeks, the infant showed poor repertoire GMs, with a detailed General Movement Optimality Score of 16/42. At 16 weeks, age-specific fidgety movements were absent, and the movement character was monotonous and stiff; the detailed Motor Optimality Score was severely reduced (7/28). All Bayley-III scores were2 SD, that is70 indicating severe developmental delay.Functional assessments such as the GM assessment and age-specific detailed assessment could be complementary to neuroimaging assessments to predict the neurodevelopmental outcomes in infants with RCDP.
- Published
- 2020
13. Rhizomelic chondrodysplasia punctata morbidity and mortality, an update
- Author
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Angela L. Duker, Michael B. Bober, Dagmar Kinderman, Bwee Tien Poll-The, Monica Schouten, Tim Niiler, Nancy Braverman, Paediatric Neurology, AGEM - Inborn errors of metabolism, and Amsterdam Neuroscience - Cellular & Molecular Mechanisms
- Subjects
Pediatrics ,medicine.medical_specialty ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,business.industry ,Infant, Newborn ,Infant ,medicine.disease ,Ultrasonography, Prenatal ,Pregnancy ,Child, Preschool ,Genetics ,medicine ,Humans ,Female ,Chondrodysplasia punctata ,Morbidity ,Ultrasonography ,Child ,business ,Genetics (clinical) - Published
- 2020
14. Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata
- Author
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Shawn Ritchie, Dushmanthi Jayasinghe, Wedad Fallatah, Erminia Di Pietro, Tara C. Smith, Wei Cui, and Nancy Braverman
- Subjects
0301 basic medicine ,medicine.medical_specialty ,rcdp ,Vinyl Compounds ,Docosahexaenoic Acids ,Plasmalogen ,Plasmalogens ,Neuroscience (miscellaneous) ,peroxisomal disorder ,Administration, Oral ,Biological Availability ,Medicine (miscellaneous) ,lcsh:Medicine ,plasmalogen ,Motor Activity ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Drug Stability ,Immunology and Microbiology (miscellaneous) ,Oral administration ,Internal medicine ,Peroxisomal disorder ,medicine ,lcsh:Pathology ,Animals ,Peroxisomal Targeting Signal 2 Receptor ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,Chemistry ,ppi-1040 ,lcsh:R ,Skeletal muscle ,Peroxisome ,medicine.disease ,3. Good health ,Mice, Inbred C57BL ,Vesicular transport protein ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Membrane protein ,rhizomelic chondrodysplasia punctata ,030217 neurology & neurosurgery ,Research Article ,lcsh:RB1-214 - 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., Summary: This article shows, for the first time, that a synthetic vinyl-ether plasmalogen is orally bioavailable and bioactive in vivo following administration in animals.
- Published
- 2020
15. Rhizomelic Chondro-Dysplasia Punctate (RCDP).
- Author
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Gowda VK, Srinivasa VM, and Vamyanmane DK
- Subjects
- Humans, Chondrodysplasia Punctata, Rhizomelic, Rare Diseases
- Published
- 2022
16. The type-2 peroxisomal targeting signal
- Author
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Markus Kunze
- Subjects
0301 basic medicine ,Signal peptide ,Amino Acid Motifs ,Peptide ,03 medical and health sciences ,0302 clinical medicine ,Protein Domains ,medicine ,Peroxisomes ,Humans ,Receptor ,Protein Structure, Quaternary ,Molecular Biology ,Peroxisomal targeting signal ,Peroxisomal Targeting Signal 2 Receptor ,chemistry.chemical_classification ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,Membrane Proteins ,Cell Biology ,Peroxisome ,medicine.disease ,Transport protein ,Cell biology ,Cytosol ,Protein Transport ,030104 developmental biology ,chemistry ,030217 neurology & neurosurgery - Abstract
The type-2 peroxisomal targeting signal (PTS2) is one of two peptide motifs destining soluble proteins for peroxisomes. This signal acts as amphiphilic α-helix exposing the side chains of all conserved residues to the same side. PTS2 motifs are recognized by a bipartite protein complex consisting of the receptor PEX7 and a co-receptor. Cargo-loaded receptor complexes are translocated across the peroxisomal membrane by a transient pore and inside peroxisomes, cargo proteins are released and processed in many, but not all species. The components of the bipartite receptor are re-exported into the cytosol by a ubiquitin-mediated and ATP-driven export mechanism. Structurally, PTS2 motifs resemble other N-terminal targeting signals, whereas the functional relation to the second peroxisomal targeting signal (PTS1) is unclear. Although only a few PTS2-carrying proteins are known in humans, subjects lacking a functional import mechanism for these proteins suffer from the severe inherited disease rhizomelic chondrodysplasia punctata.
- Published
- 2019
17. Cervical Spine Deformities in Children With Rhizomelic Chondrodysplasia Punctata
- Author
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Oussama Abousamra, Vinay Kandula, William G. Mackenzie, Kenneth J. Rogers, Michael B. Bober, and Angela L. Duker
- Subjects
Male ,medicine.medical_specialty ,Spinal canal stenosis ,Constriction, Pathologic ,Spinal Cord Diseases ,03 medical and health sciences ,0302 clinical medicine ,Lumbar ,Spinal Stenosis ,medicine ,Humans ,Orthopedics and Sports Medicine ,Chondrodysplasia punctata ,030222 orthopedics ,Lumbar Vertebrae ,medicine.diagnostic_test ,Chondrodysplasia Punctata, Rhizomelic ,business.industry ,Cervical spinal stenosis ,Infant ,Magnetic resonance imaging ,General Medicine ,medicine.disease ,Magnetic Resonance Imaging ,Sagittal plane ,Stenosis ,medicine.anatomical_structure ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Cervical Vertebrae ,Female ,Radiology ,business ,Myelomalacia ,Spinal Canal ,Spinal Cord Compression ,030217 neurology & neurosurgery - Abstract
Background Cervical spine deformity in rhizomelic chondrodysplasia punctata (RCDP) has been described with different findings reported in the literature. However, available literature provides limited data from a few cases with magnetic resonance imaging (MRI) of the cervical spine. Our report describes the MRI findings in a group of children with RCDP, aiming to reach a better understanding of this pathology. Methods An Institutional Review Board-approved RCDP Registry was created at our institution with the goal of identifying pertinent medical issues over the lifespan of individuals with RCDP. Records of children within the registry were evaluated, and magnetic resonance images obtained between 2004 and 2015, were available for review. The levels of spinal canal stenosis were recorded and the severity of the stenosis was decided based on adults' parameters. Cord compression and myelomalacia were confirmed on the axial images. Sagittal lumbar spine magnetic resonance images were also evaluated when available, and the presence of tethered cord and fatty filum was recorded. Results Twenty-six children (15 boys and 11 girls) were identified in the RCDP Registry. Eleven children (6 boys and 5 girls) had sagittal MRI of the cervical spine available for review. Age at the time of MRI study was variable (1 wk to 32 mo). All patients except 1 had stenosis of the cervical spinal canal. Myelomalacia of the cord was noted only in this patient. Conclusions This study suggests that, in children with RCDP, cervical spinal stenosis and cord compression are a real risk, and children with this diagnosis should have monitoring for these issues. Tethered cord is also a possible finding that needs to be evaluated. Full sagittal spine MRI is necessary to detect the possible deformities at the cervical and lumbar levels.
- Published
- 2019
18. Growth charts for individuals with rhizomelic chondrodysplasia punctata
- Author
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Nancy Braverman, Grant Eldridge, Angela L. Duker, Nga Brereton, Michael B. Bober, and Tim Niiler
- Subjects
Male ,0301 basic medicine ,Adolescent ,Plasmalogen ,Postnatal growth failure ,Biology ,03 medical and health sciences ,Peroxisomal disorder ,Genetics ,medicine ,Humans ,In patient ,Registries ,Growth Charts ,Child ,Genetic Association Studies ,Genetics (clinical) ,Retrospective Studies ,Bone growth ,Natural course ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,Body Weight ,Infant ,Plasmalogen deficiency ,medicine.disease ,030104 developmental biology ,Child, Preschool ,Female - Abstract
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.
- Published
- 2016
19. Leukodystrophy caused by plasmalogen deficiency rescued by glyceryl 1-myristyl ether treatment
- Author
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Tiago Ferreira da Silva, Paul P. Van Veldhoven, Ana R. Malheiro, Barbara Correia, Pedro Brites, and Diogo Bessa‐Neto
- Subjects
0301 basic medicine ,Central Nervous System ,leukodystrophy ,peroxisomal disorders ,PROTEIN ,Glyceryl Ethers ,ASTROCYTES ,Myelin assembly ,Myelin ,Mice ,0302 clinical medicine ,Pathology ,Research Articles ,Myelin Sheath ,Mice, Knockout ,Rhizomelic chondrodysplasia punctata ,biology ,Chondrodysplasia Punctata, Rhizomelic ,Chemistry ,MICE DEFICIENT ,General Neuroscience ,Cell biology ,myelin ,Oligodendroglia ,medicine.anatomical_structure ,DIFFERENTIATION ,Spinal Cord ,MYELIN-ASSOCIATED GLYCOPROTEIN ,RHIZOMELIC CHONDRODYSPLASIA PUNCTATA ,Corrigendum ,Life Sciences & Biomedicine ,Plasmalogen ,Plasmalogens ,Clinical Neurology ,oligodendrocytes ,RAT-BRAIN ,Pathology and Forensic Medicine ,03 medical and health sciences ,Peroxisomal disorder ,medicine ,Peroxisomes ,Animals ,BIOSYNTHESIS ,Science & Technology ,Leukodystrophy ,CENTRAL-NERVOUS-SYSTEM ,Neurosciences ,Leukodystrophy, Metachromatic ,medicine.disease ,Oligodendrocyte ,Axons ,Myelin basic protein ,Disease Models, Animal ,030104 developmental biology ,nervous system ,biology.protein ,Neurology (clinical) ,Neurosciences & Neurology ,030217 neurology & neurosurgery ,Demyelinating Diseases - Abstract
Plasmalogens are the most abundant form of ether phospholipids in myelin and their deficiency causes Rhizomelic Chondrodysplasia Punctata (RCDP), a severe developmental disorder. Using the Gnpat-knockout (KO) mouse as a model of RCDP, we determined the consequences of a plasmalogen deficiency during myelination and myelin homeostasis in the central nervous system (CNS). We unraveled that the lack of plasmalogens causes a generalized hypomyelination in several CNS regions including the optic nerve, corpus callosum and spinal cord. The defect in myelin content evolved to a progressive demyelination concomitant with generalized astrocytosis and white matter-selective microgliosis. Oligodendrocyte precursor cells (OPC) and mature oligodendrocytes were abundant in the CNS of Gnpat KO mice during the active period of demyelination. Axonal loss was minimal in plasmalogen-deficient mice, although axonal damage was observed in spinal cords from aged Gnpat KO mice. Characterization of the plasmalogen-deficient myelin identified myelin basic protein and septin 7 as early markers of dysmyelination, whereas myelin-associated glycoprotein was associated with the active demyelination phase. Using in vitro myelination assays, we unraveled that the intrinsic capacity of oligodendrocytes to ensheath and initiate membrane wrapping requires plasmalogens. The defect in plasmalogens was rescued with glyceryl 1-myristyl ether [1-O-tetradecyl glycerol (1-O-TDG)], a novel alternative precursor in the plasmalogen biosynthesis pathway. 1-O-TDG treatment rescued myelination in plasmalogen-deficient oligodendrocytes and in mutant mice. Our results demonstrate the importance of plasmalogens for oligodendrocyte function and myelin assembly, and identified a novel strategy to promote myelination in nervous tissue. ispartof: BRAIN PATHOLOGY vol:29 issue:5 pages:622-639 ispartof: location:Switzerland status: published
- Published
- 2018
20. PRENATAL DIAGNOSIS OF RHIZOMELIC CHONDRODYSPLASIA PUNCTATA
- Author
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E, Erdogdu, N, Dilek, R, Arisoy, A E, Tahaoglu, T, Karacor, and C, Andan
- Subjects
Adult ,Chromosome Aberrations ,Chondrodysplasia Punctata, Rhizomelic ,Tibia ,DNA Mutational Analysis ,Infant, Newborn ,Genes, Recessive ,Humerus ,PHEX Phosphate Regulating Neutral Endopeptidase ,Ultrasonography, Prenatal ,Consanguinity ,Pregnancy ,Prenatal Diagnosis ,Humans ,Female ,Femur ,Peroxisomal Targeting Signal 2 Receptor - Published
- 2018
21. Stippled Calcifications over Bilateral Epiphyses of Humeri
- Author
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Chi-Nien Chen and Yu-Chen Lin
- Subjects
Chondrodysplasia Punctata, Rhizomelic ,business.industry ,Infant, Newborn ,Calcinosis ,Anatomy ,Humerus ,Diagnosis, Differential ,Radiography ,Pediatrics, Perinatology and Child Health ,Medicine ,Humans ,Female ,Genetic Testing ,business ,Epiphyses ,Peroxisomal Targeting Signal 2 Receptor - Published
- 2018
22. Plasmalogens regulate the AKT-ULK1 signaling pathway to control the position of the axon initial segment.
- Author
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Ferreira da Silva T, Granadeiro LS, Bessa-Neto D, Luz LL, Safronov BV, and Brites P
- Subjects
- Autophagy-Related Protein-1 Homolog, Chondrodysplasia Punctata, Rhizomelic, Humans, Intracellular Signaling Peptides and Proteins, Plasmalogens, Proto-Oncogene Proteins c-akt, Signal Transduction, Axon Initial Segment
- Abstract
The axon initial segment (AIS) is a specialized region in neurons that encompasses two essential functions, the generation of action potentials and the regulation of the axodendritic polarity. The mechanism controlling the position of the axon initial segment to allow plasticity and regulation of neuron excitability is unclear. Here we demonstrate that plasmalogens, the most abundant ether-phospholipid, are essential for the homeostatic positioning of the AIS. Plasmalogen deficiency is a hallmark of Rhizomelic Chondrodysplasia Punctata (RCDP) and Zellweger spectrum disorders, but Alzheimer's and Parkinson's disease, are also characterized by plasmalogen defects. Neurons lacking plasmalogens displaced the AIS to more distal positions and were characterized by reduced excitability. Treatment with a short-chain alkyl glycerol was able to rescue AIS positioning. Plasmalogen deficiency impaired AKT activation, and we show that inhibition of AKT phosphorylation at Ser473 and Thr308 is sufficient to induce a distal relocation of the AIS. Pathway analysis revealed that downstream of AKT, overtly active ULK1 mediates AIS repositioning. Rescuing the impaired AKT signaling pathway was able to normalize AIS position independently of the biochemical defect. These results unveil a previously unknown mechanism that couples the phospholipid composition of the neuronal membrane to the positional assembly of the AIS., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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23. Plasmalogens and fatty alcohols in rhizomelic chondrodysplasia punctata and Sjögren-Larsson syndrome
- Author
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Pedro Brites, Tiago Ferreira da Silva, and Ana R. Malheiro
- Subjects
Plasmalogen ,Plasmalogens ,Fatty alcohol ,Biology ,Antioxidants ,Mice ,Fatty aldehyde ,chemistry.chemical_compound ,Microsomes ,Lipid biosynthesis ,Peroxisomes ,Genetics ,medicine ,Animals ,Humans ,Alkylglycerone-phosphate synthase ,Genetics (clinical) ,chemistry.chemical_classification ,Aldehydes ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,Fatty Acids ,Fatty acid ,Peroxisome ,medicine.disease ,Aldehyde Oxidoreductases ,Sjogren-Larsson Syndrome ,chemistry ,Biochemistry ,Fatty Alcohols ,biology.gene - Abstract
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.
- Published
- 2014
24. Neonatal Rhizomelic Chondrodysplasia Punctata Type 1: Weaving Evidence Into Clinical Practice
- Author
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Jessica Landino, Amy J. Jnah, Sabine C. Iben, and Desi Newberry
- Subjects
Occupational therapy ,Adult ,Male ,medicine.medical_specialty ,Pediatrics ,Neurology ,Prenatal diagnosis ,Critical Care Nursing ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Prenatal Diagnosis ,Maternity and Midwifery ,medicine ,Humans ,Chondrodysplasia punctata ,Genetic Predisposition to Disease ,Peroxisomal Targeting Signal 2 Receptor ,030219 obstetrics & reproductive medicine ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,business.industry ,Cesarean Section ,Incidence (epidemiology) ,Infant, Newborn ,medicine.disease ,Prognosis ,Combined Modality Therapy ,Clinical Practice ,Apgar Score ,Female ,business ,030217 neurology & neurosurgery - Abstract
Rhizomelic chondrodysplasia punctata (RCDP) is a rare genetic peroxisome biogenesis disorder with a reported incidence of 1 in 100 000 live births. The 3 genetic subtypes of RCDP are acquired by an autosomal recessive inheritance pattern. RCDP type 1 accounts for greater than 90% of all aggregate cases. Differentiating between the 3 subtypes of RCDP, as well as disorders characterized by similar punctate cartilaginous changes, is essential to guide an appropriate postnatal plan of care. Management strategies are focused toward associated clinical manifestations and require an interdisciplinary approach including ophthalmology, cardiovascular, endocrine, physical and occupational therapy, and neurology. Purposeful and frequent collaboration among all members of the neonatal/pediatric interdisciplinary team is necessary to optimize outcomes for the neonate and the family unit. The purpose of this article is to anticipate the needs of both patients with known and prenatal diagnosis of RCDP type 1 and patients with suspected clinical diagnosis of RCDP type 1 in the immediate neonatal period and to guide the appropriate plan of care. This article presents a case report of type I RCDP, as well as describes genetic influences, symptoms, diagnosis, management, and prognosis.
- Published
- 2017
25. Mild reduction of plasmalogens causes rhizomelic chondrodysplasia punctata: functional characterization of a novel mutation
- Author
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Yousef Shafeghati, Masanori Honsho, Yuichi Abe, Ryusuke Toyama, Yoshiteru Sato, Hajime Niwa, Masafumi Noguchi, Kamran Ghaedi, Ali Rahmanifar, and Yukio Fujiki
- Subjects
Models, Molecular ,Plasmalogen ,Protein Conformation ,DNA Mutational Analysis ,Plasmalogens ,Gene Expression ,medicine.disease_cause ,Cell Line ,Gene expression ,Genetics ,medicine ,Humans ,Missense mutation ,Alkylglycerone-phosphate synthase ,RNA, Messenger ,Receptor ,Genetics (clinical) ,Mutation ,Alkyl and Aryl Transferases ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,biology ,Fibroblasts ,Peroxisome ,medicine.disease ,Molecular biology ,Biochemistry ,Child, Preschool ,Female ,biology.gene - Abstract
Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive disorder due to the deficiency in ether lipid synthesis. RCDP type 1, the most prominent type, is caused by the dysfunction of the receptor of peroxisome targeting signal type 2, Pex7 (peroxisomal biogenesis factor 7), and the rest of the patients, RCDP types 2 and 3, have defects in peroxisomal enzymes catalyzing the initial two steps of alkyl-phospholipid synthesis, glyceronephosphate O-acyltransferase and alkylglycerone phosphate synthase (Agps). We herein investigated defects of two patients with RCDP type 3. Patient 1 had a novel missense mutation, T1533G, resulting in the I511M substitution in Agps. The plasmalogen level was mildly reduced, whereas the protein level and peroxisomal localization of Agps-I511M in fibroblasts were normal as in the control fibroblasts. Structure prediction analysis suggested that the mutated residue was located in the helix α15 on the surface of V-shaped active site tunnel in Agps, likely accounting for the mild defects of plasmalogen synthesis. These results strongly suggest that an individual with mildly affected level of plasmalogen synthesis develops RCDP. In fibroblasts from patient 2, the expression of AGPS mRNA and Agps protein was severely affected, thereby giving rise to the strong reduction of plasmalogen synthesis.
- Published
- 2014
26. General Movements and Developmental Functioning in an Individual with Rhizomelic Chondrodysplasia Punctata within the First Months of the Life: A Case Report.
- Author
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Yardımcı-Lokmanoğlu BN, Mutlu A, and Livanelioğlu A
- Subjects
- Female, Gestational Age, Humans, Infant, Infant, Newborn, Movement, Chondrodysplasia Punctata, Rhizomelic
- Abstract
Aims: Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive inherited disorder. Individuals with RCDP have a wide range of neurodevelopmental outcomes, but there are limited descriptions of their early motor development before 5 months of age. This study aimed to describe in detail the age-specific spontaneous movements and examine the developmental functioning in an individual with RCDP., Methods: A female infant (born at 39 weeks' gestation), diagnosed with RCDP at 3 weeks of age, was assessed at 4 and 16 weeks for general movements (GMs) and concurrent motor repertoire; the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III) was also applied at the same ages., Results: At 4 weeks, the infant showed poor repertoire GMs, with a detailed General Movement Optimality Score of 16/42. At 16 weeks, age-specific fidgety movements were absent, and the movement character was monotonous and stiff; the detailed Motor Optimality Score was severely reduced (7/28). All Bayley-III scores were <2 SD, that is <70 indicating severe developmental delay., Conclusion: Functional assessments such as the GM assessment and age-specific detailed assessment could be complementary to neuroimaging assessments to predict the neurodevelopmental outcomes in infants with RCDP.
- Published
- 2021
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27. Rhizomelic chondrodysplasia punctata and cardiac pathology
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Irene C. Huffnagel, Sally-Ann B. Clur, Hans R. Waterham, Ronald J.A. Wanders, Bwee Tien Poll-The, Nico A. Blom, Annemieke M Bams-Mengerink, Other departments, ACS - Amsterdam Cardiovascular Sciences, AII - Amsterdam institute for Infection and Immunity, APH - Amsterdam Public Health, Paediatric Cardiology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Genetic Metabolic Diseases, ANS - Amsterdam Neuroscience, Paediatric Neurology, and Neurology
- Subjects
Adult ,Heart Defects, Congenital ,Male ,medicine.medical_specialty ,Adolescent ,Plasmalogen ,Heart disease ,Plasmalogens ,Internal medicine ,Peroxisomal disorder ,Prevalence ,Genetics ,medicine ,Humans ,Mitral valve prolapse ,cardiovascular diseases ,Child ,Genetics (clinical) ,Tetralogy of Fallot ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,business.industry ,Myocardium ,Homozygote ,Rhizomelia ,Infant ,medicine.disease ,Endocrinology ,Child, Preschool ,Mutation ,Pediatrics, Perinatology and Child Health ,Cardiology ,Congenital cataracts ,cardiovascular system ,Female ,business - Abstract
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.
- Published
- 2013
28. Type 1 rhizomelic chondrodysplasia punctata with a homozygous PEX7 mutation
- Author
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Melek Pala Akdoğan, Serdar Ceylaner, Meliha Esra Bilici, Erdal Kurnaz, Zehra Aycan, and Nursel Muratoglu Sahin
- Subjects
0301 basic medicine ,Male ,Pathology ,medicine.medical_specialty ,Phytanic acid ,Endocrinology, Diabetes and Metabolism ,030105 genetics & heredity ,Gene mutation ,03 medical and health sciences ,chemistry.chemical_compound ,Endocrinology ,medicine ,Humans ,Tetralogy of Fallot ,Peroxisomal Targeting Signal 2 Receptor ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,Ossification ,business.industry ,Rhizomelia ,Homozygote ,Infant ,medicine.disease ,Bilateral Cataracts ,Phenotype ,chemistry ,Pediatrics, Perinatology and Child Health ,Mutation ,medicine.symptom ,business - Abstract
Background Rhizomelic chondrodysplasia punctata (RCDP) is a rare peroxisomal disease characterised by punctate calcifications of non-ossified cartilage epiphyseal centres. The main biochemical marker of all RCDP types is a decrease in the levels of plasmalogens. Additionally, the accumulation of phytanic acid can be used as a differential marker between types of RDCP. Due to the biochemical overlap between types 1 and 5 RCDP, a genetic analysis of these genes should be performed in patients to identify the type. Case presentation A 2-month-19-day-old male child presented with symptoms of limited movement and discomfort with movement in the extremities. His sister, who had similar clinical findings, was diagnosed with tetralogy of Fallot and died at 6 months of age. A physical examination revealed an atypical facial appearance, bilateral cataracts, sensitivity to touch in the extremities, shortness in the proximal segments of the long bones, limited movement in both knees and elbows and axial hypotonicity. Laboratory analyses revealed normal ammonia, lactate, plasma and urine amino acids, long chain fatty acids and phytanic acid levels. Rhizomelia, significant metaphyseal expansion, irregularities in the cortex, loss of ossification, fragmented appearance and punctate calcifications in both elbows, both knees and in the femoral epiphysis were seen on the skeletal survey. A homozygote p.L70W (c.209T>G) mutation was found in the PEX7 gene. Conclusions Plasma phytanic acid levels can be normal in a patient with type 1 RCDP that develops as a result of a PEX7 gene mutation, as in our case. A molecular genetic analysis and/or fibroblast culture must be conducted in clinically suspicious cases. While no cardiac pathology was found in our case, tetralogy of Fallot was present in his sister with similar clinical findings. The presence of different cardiological phenotypes in the sibling suggested that the genotype-phenotype correlation may not be complete in this disorder.
- Published
- 2016
29. [Peroxisomal disorder, rhizomelyc chondrodysplasia punctata type 1: case report]
- Author
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Cesar Leonardo, González-Ortiz, Sandra Bibiana, Jaimes Leguizamón, and Gustavo Adolfo, Contreras-García
- Subjects
Male ,Fatal Outcome ,Chondrodysplasia Punctata, Rhizomelic ,Humans ,Infant ,Genetic Counseling ,Peroxisomal Targeting Signal 2 Receptor - Abstract
Peroxisomal diseases are a group of monogenic disorders that include defects in peroxisome biogenesis or enzyme dificiencies. Rhizomelic chondrodysplasia punctata type 1 (RCDP1) belongs to the first group, caused by autosomal recessive mutations on PEX7 gene, encoding for PTS2 receptor. The aims of this report are to describe a genetic disease of low prevalence, explaining its main characteristics and the importance of the diagnostic approach and genetic counseling.13-month-old male infant with no medical history, family or consanguinity, demonstrate at birth upper limbs shortening. Surgery intervention at seven months old for bilateral cataract. Growth retardation, psychomotor retardation, minor craniofacial anomalies, rhyzomelic shortened upper limbs and lower limbs lesser degree. Punctata calcifications in patella cartilage. Also fatty acid phytanic and pristanic increased levels. Patient dead at age of 3 years.RCDP1 is a rare disease, with a prevalence of 1/100,000. Different mutations of PEX7 gene have been described, with variations in phenotype. The treatment is basically symptomatic and depends on the severity of clinical manifestations. The rhizomelic type has poor prognosis, most patients do not survive before the first decade of live. Genetic counseling is essential because it is consider a 25% risk of recurrence.
- Published
- 2016
30. The importance of ether-phospholipids: A view from the perspective of mouse models
- Author
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Tiago Ferreira da Silva, Ana R. Malheiro, Pedro Brites, and Vera Sousa
- Subjects
Plasmalogen ,Knockout ,Plasmalogens ,Glucosamine 6-Phosphate N-Acetyltransferase ,Receptors, Cytoplasmic and Nuclear ,Peroxisome ,Biology ,Mice ,Peroxisomal disorder ,medicine ,Animals ,Humans ,Chondrodysplasia punctata ,Molecular Biology ,Peroxisomal Targeting Signal 2 Receptor ,Mice, Knockout ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,Nervous tissue ,medicine.disease ,Disease Models, Animal ,medicine.anatomical_structure ,Biochemistry ,Oxidative stress ,Disease mechanism ,Molecular Medicine ,Biogenesis - Abstract
Ether-phospholipids represent an important group of phospholipids characterized by an alkyl or an alkenyl bond at the sn-1 position of the glycerol backbone. Plasmalogens are the most abundant form of alkenyl-glycerophospholipids, and their synthesis requires functional peroxisomes. Defects in the biosynthesis of plasmalogens are the biochemical hallmark of the human peroxisomal disorder Rhizomelic Chondrodysplasia Punctata (RCDP), which is characterized by defects in eye, bone and nervous tissue. The generation and characterization of mouse models with defects in plasmalogen levels have significantly advanced our understanding of the role and importance of plasmalogens as well as pathogenetic mechanisms underlying RCDP. A review of the current mouse models and the description of the combined knowledge gathered from the histopathological and biochemical studies is presented and discussed. Further characterization of the role and functions of plasmalogens will contribute to the elucidation of disease pathogenesis in peroxisomal and non-peroxisomal disorders. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease.
- Published
- 2012
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31. Defective lipid remodeling of GPI anchors in peroxisomal disorders, Zellweger syndrome, and rhizomelic chondrodysplasia punctata
- Author
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Ryo Taguchi, Yusuke Maeda, Noriyuki Kanzawa, Taroh Kinoshita, Satoru Mukai, Yukio Fujiki, Hans R. Waterham, Kazutaka Ikeda, Nobuyuki Shimozawa, Yoshiko Murakami, Morihisa Fujita, Ronald J.A. Wanders, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Laboratory Genetic Metabolic Diseases
- Subjects
Glycosylphosphatidylinositols ,peroxisomal disorder ,Receptors, Cytoplasmic and Nuclear ,CHO Cells ,QD415-436 ,Biology ,medicine.disease_cause ,Transfection ,Biochemistry ,chemistry.chemical_compound ,Endocrinology ,Cricetinae ,Peroxisomal disorder ,medicine ,Peroxisomes ,Animals ,Humans ,Phosphatidylinositol ,Zellweger Syndrome ,Research Articles ,Cell Line, Transformed ,Peroxisomal Targeting Signal 2 Receptor ,Zellweger syndrome ,Mutation ,Rhizomelic chondrodysplasia punctata ,Alkyl and Aryl Transferases ,Chondrodysplasia Punctata, Rhizomelic ,Membrane Proteins ,Cell Biology ,Peroxisome ,Fibroblasts ,medicine.disease ,glycosylphosphatidylinositol ,chemistry ,Membrane protein ,lipids (amino acids, peptides, and proteins) ,rhizomelic chondrodysplasia punctata ,plasmalogens ,Biogenesis ,Acyltransferases - Abstract
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.(jlr) 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.-Kanzawa, N., N. Shimozawa, R. J. A. Wanders, K. Ikeda, Y. Murakami, H. R. Waterham, S. Mukai, M. Fujita, Y. Maeda, R. Taguchi, Y. Fujiki, and T. Kinoshita. Defective lipid remodeling of GPI anchors in peroxisomal disorders, Zellweger syndrome, and rhizomelic chondrodysplasia punctate. J. Lipid Res. 2012. 53: 653-663
- Published
- 2012
32. Impaired neurotransmission in ether lipid-deficient nerve terminals
- Author
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Britta Brügger, Alexander Brodde, Wilhelm W. Just, Johannes Berger, Andre Teigler, Wolf D. Lehmann, and Felix T. Wieland
- Subjects
medicine.medical_specialty ,Plasmalogens ,Presynaptic Terminals ,Glutamic Acid ,Biology ,Synaptic Transmission ,Article ,Exocytosis ,Lipid peroxidation ,Mice ,chemistry.chemical_compound ,Adenosine Triphosphate ,Cerebellum ,Malondialdehyde ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Genetics (clinical) ,Oligonucleotide Array Sequence Analysis ,Mice, Knockout ,chemistry.chemical_classification ,Reactive oxygen species ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,Gene Expression Profiling ,Phosphatidylethanolamines ,Glutamate receptor ,Brain ,General Medicine ,medicine.disease ,Acetylcholine ,Adenosine Diphosphate ,Oxidative Stress ,Adenosine diphosphate ,Ether lipid ,Endocrinology ,chemistry ,Calcium ,Lipid Peroxidation ,Synaptic Vesicles ,Acyltransferases ,Synaptosomes ,medicine.drug - Abstract
Isolated defects of ether lipid (EL) biosynthesis in humans cause rhizomelic chondrodysplasia punctata type 2 and type 3, serious peroxisomal disorders. Using a previously described mouse model [Rodemer, C., Thai, T.P., Brugger, B., Kaercher, T., Werner, H., Nave, K.A., Wieland, F., Gorgas, K., and Just, W.W. (2003) Inactivation of ether lipid biosynthesis causes male infertility, defects in eye development and optic nerve hypoplasia in mice. Hum. Mol. Genet., 12, 1881-1895], we investigated the effect of EL deficiency in isolated murine nerve terminals (synaptosomes) on the pre-synaptic release of the neurotransmitters (NTs) glutamate and acetylcholine. Both Ca(2+)-dependent exocytosis and Ca(2+)-independent efflux of the transmitters were affected. EL-deficient synaptosomes respire at a reduced rate and exhibit a lowered adenosin-5'-triphosphate/adenosine diphosphate (ATP/ADP) ratio. Consequently, ATP-driven processes, such as synaptic vesicle cycling and maintenance of Na(+), K(+) and Ca(2+) homeostasis, might be disturbed. Analyzing reactive oxygen species in EL-deficient neural and non-neural tissues revealed that plasmalogens (PLs), the most abundant EL species in mammalian central nervous system, considerably contribute to the generation of the lipid peroxidation product malondialdehyde. Although EL-deficient tissue contains less lipid peroxidation products, fibroblasts lacking ELs are more susceptible to induced oxidative stress. In summary, these results suggest that due to the reduced energy state of EL-deficient tissue, the Ca(2+)-independent efflux of NTs increases while the Ca(2+)-dependent release declines. Furthermore, lack of PLs is mainly compensated for by an increase in the concentration of phosphatidylethanolamine and results in a significantly lowered level of lipid peroxidation products in the brain cortex and cerebellum.
- Published
- 2012
33. Peroxisomal Leukoencephalopathy
- Author
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Bwee Tien Poll-The, Marc Engelen, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Neuroscience, Paediatric Neurology, and Neurology
- Subjects
Male ,Peroxisomal Disorders ,Chondrodysplasia Punctata, Rhizomelic ,Neurology ,Leukoencephalopathies ,Humans ,Female ,Neurology (clinical) ,Adrenoleukodystrophy ,Zellweger Syndrome ,Magnetic Resonance Imaging - Abstract
Peroxisomal leukoencephalopathies include diseases belonging to the Zellweger spectrum and the rhizomelic chondrodysplasia punctata spectrum, as well as some single enzyme defects of peroxisomal beta-oxidation. The authors present information on the clinical and diagnostic approach, and the characteristics of brain magnetic resonance imaging (MRI) in these diseases. MRIs of patients belonging to the Zellweger spectrum may show developmental anomalies and regressive changes consisting of abnormal cerebral white matter. Involvement of the central white matter of the cerebellar hemispheres is frequently seen. The leukoencephalopathy is progressive, with or without peripheral nerve involvement, in patients with a prolonged course of the disease. MRI characteristics in the severe phenotype of rhizomelic chondrodysplasia punctata include supratentorial white matter abnormalities, with a parietooccipital predominance. Demyelinative lesions are the hallmark of the cerebral form of X-linked adrenoleukodystrophy and may appear in a similar way in patients with adrenomyeloneuropathy progressing to a cerebral form. The diagnosis of a peroxisomal disorder can be determined by a battery of biochemical assays in blood and/or urine, and should be confirmed in cultured fibroblasts and DNA analysis. Treatment of the peroxisomal leukoencephalopathies is largely symptomatic, except for boys affected by the cerebral form of X-linked adrenoleukodystrophy in whom a bone marrow/hematopoietic stem cell transplant can be lifesaving, at least in the early stages of the disease
- Published
- 2012
34. Clinical and molecular analysis of UAE fibrochondrogenesis patients expands the phenotype and reveals two COL11A1 homozygous null mutations
- Author
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Nadia Akawi, Lihadh Al-Gazali, and Bassam R. Ali
- Subjects
Male ,United Arab Emirates ,Biology ,Gene mutation ,Collagen Type XI ,medicine.disease_cause ,Consanguinity ,Exon ,Life Expectancy ,Genetics ,medicine ,Humans ,Family ,Child ,Marshall syndrome ,Genetics (clinical) ,Mutation ,Chondrodysplasia Punctata, Rhizomelic ,Stickler Syndrome Type 2 ,Homozygote ,Infant, Newborn ,Chromosome Mapping ,Infant ,medicine.disease ,Disease gene identification ,Stop codon ,Pedigree ,Phenotype ,Child, Preschool ,Female ,Fibrochondrogenesis - Abstract
Akawi NA, Al-Gazali L, Ali BR. Clinical and molecular analysis of UAE fibrochondrogenesis patients expands the phenotype and reveals two COL11A1 homozygous null mutations. Fibrochondrogenesis is documented to be a neonatally lethal rare recessively inherited disorder characterized by short-limbed skeletal dysplasia. Here we report two patients from two unrelated consanguineous Emirati families who have unexpectedly survived till the ages of 3 and 6 years. These patients show additional symptoms which include developmental delay, profound sensory–neural deafness, severe myopia and progressive severe skeletal abnormalities. Linkage of fibrochondrogenesis in the Emirati families to chromosome 1 has been established using homozygosity mapping confirming recent findings by Tompson et al. in 2010. Screening of the COL11A1 gene revealed two null homozygous mutations [c.4084C>T (p.R1362X) and c.3708+437T>G] in the aforementioned two families. The c.4084C>T mutation is predicted to introduce a stop codon at position Arg1362, whereas the c.3708+437T>G mutation causes the activation of an intronic pseudoexon between exons 48 and 49. This resulted in the insertion of 50 nucleotides into the mRNA. The carriers of these mutations display ocular defects with normal hearing. In conclusion, our data shall improve the overall understanding of fibrochondrogenesis especially in surviving homozygous patients and, at least partly, explain the phenotypic variability associated with COL11A1 gene mutations.
- Published
- 2011
35. Rhizomelic chrondrodysplasia punctata type 2 resulting from paternal isodisomy of chromosome 1
- Author
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Sarah Monsonego, Maria Descartes, Steven J. Steinberg, Graeme Nimmo, Nancy Braverman, and Judith Franklin
- Subjects
Male ,Proband ,DNA Mutational Analysis ,Molecular Sequence Data ,Limb Deformities, Congenital ,Uniparental inheritance ,Biology ,medicine.disease_cause ,Fathers ,Pregnancy ,Peroxisomal disorder ,Genetics ,medicine ,Humans ,Chondrodysplasia punctata ,Genetics (clinical) ,Mutation ,Rhizomelic chondrodysplasia punctata ,Base Sequence ,Chondrodysplasia Punctata, Rhizomelic ,Infant, Newborn ,Infant ,Uniparental Disomy ,medicine.disease ,Uniparental disomy ,Pedigree ,Radiography ,Chromosomes, Human, Pair 1 ,Female ,Genomic imprinting ,Hand Deformities, Congenital - Abstract
Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal-recessive disorder resulting from mutations in one of three peroxisomal genes essential for ether lipid biosynthesis, PEX7 (RCDP1), GNPAT (RCDP2), and AGPS (RCDP3). Affected patients have characteristic features including shortening of the proximal long bones, epiphyseal stippling, bilateral cataracts, growth and developmental delays. Whereas the majority of patients have RCDP type 1, around 5% have RCDP type 2 or 3. We identified a patient with RCDP type 2 and an apparent homozygous deletion, c.1428delC, after full sequencing of his GNPAT genes. The father was heterozygous for this mutation, while sequencing of the maternal GNPAT genes revealed only wild-type sequence. Southern analyses performed on parental gDNA did not show evidence of a maternal gene deletion. Amplification and fragment analysis of dinucleotide repeat markers spanning chromosome 1 in the patient and both parents revealed paternal uniparental inheritance. We discuss the potential mechanisms causing uniparental disomy (UPD) in this patient and review the literature on chromosome 1 UPD. The absence of non-RCDP clinical features in this patient was consistent with previous literature supporting the absence of imprinted genes on chromosome 1. This first description of RCDP caused by UPD dramatically changes the parental recurrence risk, highlighting the value of obtaining parental genotypes when the proband has a putative homozygous mutation by sequence analysis.
- Published
- 2010
36. Chondrodysplasia punctata: a clinical diagnostic and radiological review
- Author
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Lyn S. Chitty, Christine Hall, Sahar Mansour, and Irving M
- Subjects
Chondrodysplasia Punctata, Rhizomelic ,business.industry ,General Medicine ,Guideline ,medicine.disease ,Bioinformatics ,Pathology and Forensic Medicine ,Diagnosis, Differential ,Radiography ,carbohydrates (lipids) ,Cholesterol ,Pediatrics, Perinatology and Child Health ,Peroxisomes ,Humans ,Medicine ,lipids (amino acids, peptides, and proteins) ,Chondrodysplasia punctata ,Cholesterol metabolism ,Anatomy ,business ,Genetics (clinical) - Abstract
Chondrodysplasia punctata (CDP) is associated with a number of disorders, including inborn errors of metabolism, involving peroxisomal and cholesterol pathways, embryopathy and chromosomal abnormalities. Several classification systems of the different types of CDP have been suggested earlier. More recently, the biochemical and molecular basis of a number of CDP syndromes has recently been elucidated and a new aetiological classification has emerged. Here we provide an updated version with an overview of the different types of CDP, a discussion of the aetiology and a description of the clinical and radiographic findings. An investigative guideline to help determine the exact diagnosis in new cases is also presented.
- Published
- 2008
37. The Crucial Step in Ether Phospholipid Biosynthesis: Structural Basis of a Noncanonical Reaction Associated with a Peroxisomal Disorder
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Elena Carpanelli, Francesca Mattiroli, Alessandro Aliverti, Andrea Mattevi, V. Pandini, Alessandro Coda, and A. Razeto
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Models, Molecular ,Protein Conformation ,Crystallography, X-Ray ,Spectrum Analysis, Raman ,Protein Structure, Secondary ,Substrate Specificity ,Peroxisomal Disorders ,chemistry.chemical_compound ,Protein structure ,Structural Biology ,Dictyostelium ,Conserved Sequence ,Flavin adenine dinucleotide ,Rhizomelic chondrodysplasia punctata ,biology ,Chondrodysplasia Punctata, Rhizomelic ,Molecular Structure ,Phospholipid Ethers ,Recombinant Proteins ,Covalent bond ,Flavin-Adenine Dinucleotide ,Dimerization ,Protein Binding ,Stereochemistry ,Phenylalanine ,Molecular Sequence Data ,Ether ,Flavin group ,Models, Biological ,Cofactor ,Catalysis ,Lipid Metabolism, Inborn Errors ,Peroxisomal disorder ,medicine ,Animals ,Humans ,Histidine ,Amino Acid Sequence ,Molecular Biology ,Alkyl and Aryl Transferases ,Binding Sites ,Sequence Homology, Amino Acid ,Hydrogen Bonding ,medicine.disease ,Protein Structure, Tertiary ,chemistry ,Amino Acid Substitution ,Models, Chemical ,biology.protein ,Tyrosine ,CELLBIO - Abstract
SummaryEther phospholipids are essential constituents of eukaryotic cell membranes. Rhizomelic chondrodysplasia punctata type 3 is a severe peroxisomal disorder caused by inborn deficiency of alkyldihydroxyacetonephosphate synthase (ADPS). The enzyme carries out the most characteristic step in ether phospholipid biosynthesis: formation of the ether bond. The crystal structure of ADPS from Dictyostelium discoideum shows a fatty-alcohol molecule bound in a narrow hydrophobic tunnel, specific for aliphatic chains of 16 carbons. Access to the tunnel is controlled by a flexible loop and a gating helix at the protein-membrane interface. Structural and mutagenesis investigations identify a cluster of hydrophilic catalytic residues, including an essential tyrosine, possibly involved in substrate proton abstraction, and the arginine that is mutated in ADPS-deficient patients. We propose that ether bond formation might be orchestrated through a covalent imine intermediate with the flavin, accounting for the noncanonical employment of a flavin cofactor in a nonredox reaction.
- Published
- 2007
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38. Targeted carrier screening for four recessive disorders: High detection rate within a founder population
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Janneke M. C. van Eeten-Nijman, Egbert J.W. Redeker, Hanne Meijers-Heijboer, Phillis Lakeman, Winnie Ottenhof, Cecile P. E. Ottenheim, Inge B. Mathijssen, Merel C. van Maarle, Lidewij Henneman, Human genetics, EMGO - Quality of care, Human Genetics, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology Endocrinology Metabolism, Other Research, Cancer Center Amsterdam, and Amsterdam Reproduction & Development (AR&D)
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Population ,Genetic Carrier Screening ,Genes, Recessive ,Genetic Counseling ,Carrier testing ,Young Adult ,Pregnancy ,Genetics ,medicine ,Humans ,Outpatient clinic ,Genetic Testing ,Family history ,education ,Genetics (clinical) ,Netherlands ,Peroxisomal Targeting Signal 2 Receptor ,Genetic testing ,Arthrogryposis ,education.field_of_study ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,medicine.diagnostic_test ,business.industry ,General Medicine ,Middle Aged ,Osteogenesis Imperfecta ,medicine.disease ,Founder Effect ,Pedigree ,Olivopontocerebellar Atrophies ,Female ,business ,Founder effect - Abstract
In a genetically isolated community in the Netherlands four severe recessive genetic disorders occur at relatively high frequency (pontocerebellar hypoplasia type 2 (PCH2), fetal akinesia deformation sequence (FADS), rhizomelic chondrodysplasia punctata type 1 (RCDP1), and osteogenesis imperfecta (OI) type IIB/III. Over the past decades multiple patients with these disorders have been identified. This warranted the start of a preconception outpatient clinic, in 2012, aimed at couples planning a pregnancy. The aim of our study was to evaluate the offer of targeted genetic carrier screening as a method to identify high-risk couples for having affected offspring in this high-risk subpopulation. In one year, 203 individuals (92 couples and 19 individuals) were counseled. In total, 65 of 196 (33.2%) tested individuals were carriers of at least one disease, five (7.7%) of them being carriers of two diseases. Carrier frequencies of PCH2, FADS, RCDP1, and OI were 14.3%, 11.2%, 6.1%, and 4.1% respectively. In individuals with a positive family history for one of the diseases, the carrier frequency was 57.8%; for those with a negative family history this was 25.8%. Four PCH2 carrier-couples were identified. Thus, targeted (preconception) carrier screening in this genetically isolated population in which a high prevalence of specific disorders occurs detects a high number of carriers, and is likely to be more effective compared to cascade genetic testing. Our findings and set-up can be seen as a model for carrier screening in other high-risk subpopulations and contributes to the discussion about the way carrier screening can be offered and organized in the general population.
- Published
- 2015
39. A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform
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Kristine Stadskleiv, Sacha Ferdinandusse, Tuva Barøy, Else Merckoll, Petter Strømme, Eirik Frengen, Merel S. Ebberink, Ronald J.A. Wanders, Doriana Misceo, Jostein Westvik, Hans R. Waterham, Berit Woldseth, Nick Wood, Bjørn Tvedt, John H. Walter, Asbjørn Holmgren, Janet Koster, Timothy P. Hughes, Laboratory Genetic Metabolic Diseases, Other departments, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
- Subjects
Adult ,Male ,Plasmalogen ,Adolescent ,Peroxisome-Targeting Signal 1 Receptor ,Receptors, Cytoplasmic and Nuclear ,Biology ,medicine.disease_cause ,Frameshift mutation ,Exon ,Genetics ,medicine ,Peroxisomes ,Humans ,Protein Isoforms ,Exome ,Child ,Frameshift Mutation ,Molecular Biology ,Peroxisomal targeting signal ,Genetics (clinical) ,Mutation ,Zellweger syndrome ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,Peroxisomal matrix ,Infant ,General Medicine ,Sequence Analysis, DNA ,medicine.disease ,Pedigree ,Protein Transport ,Female - Abstract
Import of peroxisomal matrix proteins, crucial for peroxisome biogenesis, is mediated by the cytosolic receptors PEX5 and PEX7 that recognize proteins carrying peroxisomal targeting signals 1 or 2 (PTS1 or PTS2), respectively. Mutations in PEX5 or 12 other PEX genes cause peroxisome biogenesis disorders, collectively named the Zellweger spectrum disorders (ZSDs), whereas mutations in PEX7 cause rhizomelic chondrodysplasia punctata type 1 (RCDP1). Three additional RCDP types, RCDP2-3-4, are caused, respectively, by mutations in GNPAT, AGPS and FAR1, encoding enzymes involved in plasmalogen biosynthesis. Here we report a fifth type of RCDP (RCDP5) caused by a novel mutation in PEX5. In four patients with RCDP from two independent families, we identified a homozygous frame shift mutation c.722dupA (p.Val242Glyfs(∗)33) in PEX5 (GenBank: NM_001131023.1). PEX5 encodes two isoforms, PEX5L and PEX5S, and we show that the c.722dupA mutation, located in the PEX5L-specific exon 9, results in loss of PEX5L only. Both PEX5 isoforms recognize PTS1-tagged proteins, but PEX5L is also a co-receptor for PTS2-tagged proteins. Previous patients with PEX5 mutations had ZSD, mainly due to deficient import of PTS1-tagged proteins. Similarly to mutations in PEX7, loss of PEX5L results in deficient import of PTS2-tagged proteins only, thus causing RCDP instead of ZSD. We demonstrate that PEX5L expression restores the import of PTS2-tagged proteins in patient fibroblasts. Due to the biochemical overlap between RCDP1 and RCDP5, sequencing of PEX7 and exon 9 in PEX5 should be performed in patients with a selective defect in the import of PTS2-tagged proteins.
- Published
- 2015
40. Peroxisome biogenesis disorders
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Steven J. Steinberg, Hugo W. Moser, Nancy Braverman, Gabriele Dodt, Gerald V. Raymond, and Ann B. Moser
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Rhizomelic chondrodysplasia punctata ,Molecular Sequence Data ,Plasmalogens ,Neonatal adrenoleukodystrophy ,Biology ,behavioral disciplines and activities ,Peroxisomal Disorders ,medicine ,Peroxisomes ,Humans ,Chondrodysplasia punctata ,Amino Acid Sequence ,Refsum Disease, Infantile ,Zellweger Syndrome ,Molecular Biology ,Zellweger syndrome ,Chondrodysplasia Punctata, Rhizomelic ,Membrane Proteins ,Cell Biology ,Peroxisome ,Infantile refsum disease ,medicine.disease ,Infantile Refsum disease ,Biochemistry ,Pipecolic Acids ,PEX1 ,PEX ,PEX6 - Abstract
Defects in PEX genes impair peroxisome assembly and multiple metabolic pathways confined to this organelle, thus providing the biochemical and molecular bases of the peroxisome biogenesis disorders (PBD). PBD are divided into two types—Zellweger syndrome spectrum (ZSS) and rhizomelic chondrodysplasia punctata (RCDP). Biochemical studies performed in blood and urine are used to screen for the PBD. DNA testing is possible for all of the disorders, but is more challenging for the ZSS since 12 PEX genes are known to be associated with this spectrum of PBD. In contrast, PBD-RCDP is associated with defects in the PEX7 gene alone. Studies of the cellular and molecular defects in PBD patients have contributed significantly to our understanding of the role of each PEX gene in peroxisome assembly.
- Published
- 2006
- Full Text
- View/download PDF
41. MRI of the brain and cervical spinal cord in rhizomelic chondrodysplasia punctata
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C. D. Scheurer, J. L. K. Van Hove, Ronald J.A. Wanders, B. T. Poll-The, Peter G. Barth, Marinus Duran, Charles B. L. M. Majoie, A. M. Bams-Mengerink, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ANS - Amsterdam Neuroscience, Paediatric Neurology, ACS - Amsterdam Cardiovascular Sciences, Radiology and Nuclear Medicine, Laboratory Genetic Metabolic Diseases, and Neurology
- Subjects
Adult ,medicine.medical_specialty ,Microcephaly ,Pathology ,Plasmalogen ,Biology ,Cohort Studies ,Internal medicine ,Peroxisomal disorder ,medicine ,Humans ,Chondrodysplasia punctata ,Spasticity ,Child ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,Brain ,Infant ,medicine.disease ,Osteochondrodysplasia ,Magnetic Resonance Imaging ,Endocrinology ,Phenotype ,Spinal Cord ,nervous system ,Child, Preschool ,Cervical Vertebrae ,Cerebellar atrophy ,Female ,Neurology (clinical) ,medicine.symptom - Abstract
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.
- Published
- 2006
42. Phytanic acid: production from phytol, its breakdown and role in human disease
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Ronald J.A. Wanders and D. M. van den Brink
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medicine.medical_specialty ,Phytanic acid ,Biology ,Peroxisomal Disorders ,Cellular and Molecular Neuroscience ,Phytol ,chemistry.chemical_compound ,Internal medicine ,medicine ,Alpha oxidation ,Peroxisomes ,Humans ,Molecular Biology ,Pharmacology ,chemistry.chemical_classification ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,Fatty acid ,Cell Biology ,Peroxisome ,medicine.disease ,Aldehyde Oxidoreductases ,Phytanic Acid ,Protein Transport ,Enzyme ,Refsum disease ,Endocrinology ,chemistry ,Biochemistry ,Molecular Medicine ,Refsum Disease ,Oxidation-Reduction - Abstract
Phytanic acid is a branched-chain fatty acid that accumulates in a variety of metabolic disorders. High levels of phytanic acid found in patients can exceed the millimolar range and lead to severe symptoms. Degradation of phytanic acid takes place by alpha-oxidation inside the peroxisome. A deficiency of its breakdown, leading to elevated levels, can result from either a general peroxisomal dysfunction or from a defect in one of the enzymes involved in alpha-oxidation. Research on Refsum disease, belonging to the latter group of disorders and characterized by a deficiency of the first enzyme of alpha-oxidation, has extended our knowledge of phytanic acid metabolism and pathology of the disease greatly over the past few decades. This review will centre on this research on phytanic acid: its origin, the mechanism by which its alpha-oxidation takes place, its role in human disease and the way it is produced from phytol.
- Published
- 2006
43. Congenital heart defects common in rhizomelic chondrodysplasia punctata
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Michael B. Bober, Nancy Braverman, Grant Eldridge, and Angela L. Duker
- Subjects
0301 basic medicine ,Heart Defects, Congenital ,Male ,Pathology ,medicine.medical_specialty ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,Infant ,Receptors, Cytoplasmic and Nuclear ,Biology ,Peroxisomal Targeting Signal 2 Receptor ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,Child, Preschool ,Genetics ,medicine ,Peroxisomes ,Humans ,Chondrodysplasia punctata ,Female ,Child ,Genetics (clinical) ,Acyltransferases - Published
- 2014
44. Prenatal Ultrasonographic Diagnosis of Rhizomelic Chondrodysplasia punctata by Detection of Rhizomelic Shortening and Bilateral Cataracts
- Author
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Mustafa Basbug, Ibrahim Serdar Serin, Mehmet Tayyar, Bülent Özçelik, Mustafa Akcakus, and Tamer Gunes
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Adult ,musculoskeletal diseases ,Embryology ,Eye disease ,Limb Deformities, Congenital ,Prenatal diagnosis ,Cataract ,Ultrasonography, Prenatal ,Peroxisomal disorder ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Chondrodysplasia punctata ,Arthrography ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,Shoulder Joint ,business.industry ,Obstetrics and Gynecology ,General Medicine ,Anatomy ,medicine.disease ,Osteochondrodysplasia ,Bilateral Cataracts ,Pediatrics, Perinatology and Child Health ,Female ,Hip Joint ,sense organs ,business ,Epiphyseal stippling - Abstract
Antenatal sonographic diagnosis of rhizomelic chondrodysplasia punctata depends on recognization of the combination of rhizomelic bone shortening and epiphyseal stippling. This is the only report of prenatal ultrasonographic diagnosis of bilateral cataracts in a fetus with rhizomelic chondrodysplasia punctata (type 1). Also, this is the first report of severe rhizomelic limb shortening, and bilateral cataracts prior to the recognization of epiphyseal stippling. Copyright (C) 2005 S. Karger AG, Basel.
- Published
- 2005
45. Human peroxisomal disorders
- Author
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Marc Espeel, Frank Roels, and Marianne Depreter
- Subjects
Pathology ,medicine.medical_specialty ,Histology ,Immunocytochemistry ,Biology ,Peroxisomal Disorders ,Mice ,Peroxisomal disorder ,medicine ,Animals ,Humans ,Adrenoleukodystrophy ,Zellweger Syndrome ,Instrumentation ,Kidney ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,medicine.diagnostic_test ,Peroxisome ,medicine.disease ,Medical Laboratory Technology ,medicine.anatomical_structure ,Liver biopsy ,Refsum Disease ,Anatomy ,Biogenesis - Abstract
Peroxisomes are single membrane-bound cell organelles performing numerous metabolic functions. The present article aims to give an overview of our current knowledge about inherited peroxisomal disorders in which these organelles are lacking or one or more of their functions are impaired. They are multiorgan disorders and the nervous system is implicated in most. After a summary of the historical names and categories, each having distinct symptoms and prognosis, microscopic pathology is reviewed in detail. Data from the literature are added to experience in the authors' laboratory with 167 liver biopsy and autopsy samples from peroxisomal patients, and with a smaller number of chorion samples for prenatal diagnosis, adrenal-, kidney-, and brain samples. Various light and electron microscopic methods are used including enzyme- and immunocytochemistry, polarizing microscopy, and morphometry. Together with other laboratory investigations and clinical data, this approach continues to contribute to the diagnosis and further characterization of peroxisomal disorders, and the discovery of novel variants. When liver specimens are examined, three main groups including 9 novel variants (33 patients) are distinguished: (1) absence or (2) presence of peroxisomes, and (3) mosaic distribution of cells with and without peroxisomes (10 patients). Renal microcysts, polarizing trilamellar inclusions, and insoluble lipid in macrophages in liver, adrenal cortex, brain, and in interstitial cells of kidney are also valuable for classification. On a genetic basis, complementation of fibroblasts has classified peroxisome biogenesis disorders into 12 complementation groups. Peroxisome biogenesis genes (PEX), knock-out-mice, and induction of redundant genes are briefly reviewed, including some recent results with 4-phenylbutyrate. Finally, regulation of peroxisome expression during development and in cell cultures, and by physiological factors is discussed. Microsc. Res. Tech. 61:203–223, 2003. © 2003 Wiley-Liss, Inc.
- Published
- 2003
46. Impaired neuronal migration and endochondral ossification in Pex7 knockout mice: a model for rhizomelic chondrodysplasia punctata
- Author
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Ingrid Ploegaert, Myriam Baes, Mieke Dewerchin, Vincent Everts, Pedro Brites, Petra A. W. Mooyer, Philippe Evrard, Pierre Gressens, Luc Schoonjans, Hans R. Waterham, Alison M Motley, Ronald J.A. Wanders, Peter Carmeliet, Marinus Duran, Laboratory Genetic Metabolic Diseases, Cell Biology and Histology, Paediatric Metabolic Diseases, and Parodontologie (OUD, ACTA)
- Subjects
medicine.medical_specialty ,Time Factors ,Plasmalogens ,Osteoclasts ,Receptors, Cytoplasmic and Nuclear ,Biology ,Mice ,Cell Movement ,Osteogenesis ,Phytol ,Internal medicine ,Peroxisomal disorder ,Genetics ,medicine ,Peroxisomes ,Animals ,Chondrodysplasia punctata ,Acetyl-CoA C-Acetyltransferase ,Molecular Biology ,Endochondral ossification ,Genetics (clinical) ,Cells, Cultured ,Peroxisomal Targeting Signal 2 Receptor ,Mice, Knockout ,Neurons ,Rhizomelic chondrodysplasia punctata ,Osteoblasts ,Chondrodysplasia Punctata, Rhizomelic ,Peroxisomal matrix ,Ossification ,Brain ,General Medicine ,Fibroblasts ,medicine.disease ,Diet ,Phytanic Acid ,Endocrinology ,Animals, Newborn ,Liver ,Knockout mouse ,Gene Targeting ,Mutation ,medicine.symptom ,Oxidation-Reduction - Abstract
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.
- Published
- 2003
47. Functional studies on human Pex7p: subcellular localization and interaction with proteins containing a peroxisome-targeting signal type 2 and other peroxins
- Author
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Guy P. Mannaerts, Karen Ghys, Marc Fransen, and Paul P. Van Veldhoven
- Subjects
Recombinant Fusion Proteins ,Peroxisomal Biogenesis Factor 2 ,Receptors, Cytoplasmic and Nuclear ,CHO Cells ,Plasma protein binding ,Protein Sorting Signals ,Biology ,Biochemistry ,Green fluorescent protein ,Mice ,Cricetinae ,Two-Hybrid System Techniques ,Peroxisomes ,medicine ,Animals ,Humans ,Molecular Biology ,Peroxisomal Targeting Signal 2 Receptor ,Rhizomelic chondrodysplasia punctata ,Base Sequence ,Chondrodysplasia Punctata, Rhizomelic ,Chinese hamster ovary cell ,Genetic Complementation Test ,Membrane Proteins ,Cell Biology ,Peroxisome ,medicine.disease ,Fusion protein ,Recombinant Proteins ,Phenotype ,Membrane protein ,Plasmids ,Protein Binding ,Subcellular Fractions ,Research Article - Abstract
Pex7p is a WD40-containing protein involved in peroxisomal import of proteins containing an N-terminal peroxisome-targeting signal (PTS2). The interaction of human recombinant Pex7p expressed in different hosts/systems with its PTS2 ligand and other peroxins was analysed using various experimental approaches. Specific binding of human Pex7p to PTS2 could be demonstrated only when Pex7p was formed in vitro by a coupled transcription/translation system or synthesized in vivo in Chinese hamster ovary K1 cells transfected with a construct coding for a Pex7p-green fluorescent protein (GFP) fusion protein. Apparently, no cofactors are required and only monomeric Pex7p binds to PTS2. The interaction is reduced upon cysteine alkylation and is impaired upon truncation of the N-terminus of Pex7p. Interaction of Pex7p with other peroxins could not be demonstrated in bacterial or yeast two-hybrid screens, or in pull-down binding assays. The GFP fusion proteins, tagged at either the N- or C-terminus, were able to restore PTS2 import in rhizomelic chondrodysplasia punctata fibroblasts, and Pex7p-GFP was located both in the lumen of peroxisomes and in the cytosol.
- Published
- 2002
48. Mutational Spectrum in the PEX7 Gene and Functional Analysis of Mutant Alleles in 78 Patients with Rhizomelic Chondrodysplasia Punctata Type 1
- Author
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Lisya Gerez, Pedro Brites, Rob Benne, Eveline M. Hogenhout, Janet Haasjes, Hans R. Waterham, Alison M Motley, Henk F. Tabak, Ronald J.A. Wanders, Faculteit der Geneeskunde, Laboratory Genetic Metabolic Diseases, Medical Biochemistry, and Paediatric Metabolic Diseases
- Subjects
Repetitive Sequences, Amino Acid ,musculoskeletal diseases ,Protein Folding ,DNA Mutational Analysis ,Molecular Sequence Data ,Receptors, Cytoplasmic and Nuclear ,Genes, Recessive ,Peroxin ,Biology ,medicine.disease_cause ,Protein Structure, Secondary ,Frameshift mutation ,Open Reading Frames ,Structure-Activity Relationship ,Genes, Reporter ,Peroxisomal disorder ,Genetics ,medicine ,Animals ,Humans ,Genetics(clinical) ,Chondrodysplasia punctata ,Amino Acid Sequence ,Allele ,Codon ,Frameshift Mutation ,Luciferases ,Alleles ,Genetics (clinical) ,Peroxisomal Targeting Signal 2 Receptor ,Mutation ,Rhizomelic chondrodysplasia punctata ,Chondrodysplasia Punctata, Rhizomelic ,Genetic heterogeneity ,Genetic Complementation Test ,Homozygote ,Articles ,Fibroblasts ,medicine.disease ,Phenotype ,COS Cells ,sense organs ,Sequence Alignment - Abstract
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.
- Published
- 2002
49. Homeostasis of phospholipids - The level of phosphatidylethanolamine tightly adapts to changes in ethanolamine plasmalogens
- Author
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Fabian, Dorninger, Alexander, Brodde, Nancy E, Braverman, Ann B, Moser, Wilhelm W, Just, Sonja, Forss-Petter, Britta, Brügger, and Johannes, Berger
- Subjects
RCDP, rhizomelic chondrodysplasia punctata ,Docosahexaenoic Acids ,Plasmalogens ,DHA, docosahexaenoic acid ,AA, arachidonic acid ,Peroxisome ,PE, phosphatidylethanolamine ,Severity of Illness Index ,Article ,Plasmalogen ,PC, phosphatidylcholine ,PUFA, polyunsaturated fatty acid ,Animals ,Homeostasis ,Humans ,Genetic Predisposition to Disease ,Gray Matter ,HDG, hexadecylglycerol ,Cells, Cultured ,PlsEtn, ethanolamine plasmalogen ,Mice, Knockout ,Arachidonic Acid ,SM, sphingomyelin ,Chondrodysplasia Punctata, Rhizomelic ,Phosphatidylethanolamines ,GNPAT, glyceronephosphate acyltransferase ,Fibroblasts ,Alzheimer's disease ,BA, batyl alcohol ,PS, phosphatidylserine ,Adaptation, Physiological ,Mice, Inbred C57BL ,Disease Models, Animal ,Docosahexaenoic acid ,Phenotype ,AGPS, alkylglycerone phosphate synthase ,CDP, cytidine diphosphate ,Compensation ,Acyltransferases - Abstract
Ethanolamine plasmalogens constitute a group of ether glycerophospholipids that, due to their unique biophysical and biochemical properties, are essential components of mammalian cellular membranes. Their importance is emphasized by the consequences of defects in plasmalogen biosynthesis, which in humans cause the fatal disease rhizomelic chondrodysplasia punctata (RCDP). In the present lipidomic study, we used fibroblasts derived from RCDP patients, as well as brain tissue from plasmalogen-deficient mice, to examine the compensatory mechanisms of lipid homeostasis in response to plasmalogen deficiency. Our results show that phosphatidylethanolamine (PE), a diacyl glycerophospholipid, which like ethanolamine plasmalogens carries the head group ethanolamine, is the main player in the adaptation to plasmalogen insufficiency. PE levels were tightly adjusted to the amount of ethanolamine plasmalogens so that their combined levels were kept constant. Similarly, the total amount of polyunsaturated fatty acids (PUFAs) in ethanolamine phospholipids was maintained upon plasmalogen deficiency. However, we found an increased incorporation of arachidonic acid at the expense of docosahexaenoic acid in the PE fraction of plasmalogen-deficient tissues. These data show that under conditions of reduced plasmalogen levels, the amount of total ethanolamine phospholipids is precisely maintained by a rise in PE. At the same time, a shift in the ratio between ω-6 and ω-3 PUFAs occurs, which might have unfavorable, long-term biological consequences. Therefore, our findings are not only of interest for RCDP but may have more widespread implications also for other disease conditions, as for example Alzheimer's disease, that have been associated with a decline in plasmalogens., Highlights • PE accurately compensates for the lack of plasmalogens in vitro and in vivo. • PE levels decrease to adapt to excess of ethanolamine plasmalogens (PlsEtn). • Plasmalogen deficiency favors incorporation of arachidonic acid into PE. • Docosahexaenoic acid in ethanolamine phospholipids decreases upon PlsEtn depletion.
- Published
- 2014
50. CUL4A-DDB1-Rbx1 E3 ligase controls the quality of the PTS2 receptor Pex7p
- Author
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Yukio Fujiki, Yasuhiro Miyauchi-Nanri, Satoru Mukai, and Kosuke Kuroda
- Subjects
RBX1 ,Receptors, Cytoplasmic and Nuclear ,CHO Cells ,medicine.disease_cause ,Biochemistry ,DDB1 ,Cricetulus ,Cricetinae ,medicine ,Animals ,Humans ,Molecular Biology ,Peroxisomal Targeting Signal 2 Receptor ,Genetics ,Mutation ,Rhizomelic chondrodysplasia punctata ,biology ,Chondrodysplasia Punctata, Rhizomelic ,Peroxisomal matrix ,Cell Biology ,medicine.disease ,Cullin Proteins ,Cell biology ,Ubiquitin ligase ,DNA-Binding Proteins ,HEK293 Cells ,biology.protein ,CUL4A ,Carrier Proteins ,HeLa Cells - Abstract
Pex7p is the cytosolic receptor for peroxisomal matrix proteins harbouring PTS2 (peroxisome-targeting signal type-2). Mutations in the PEX7 gene cause RCDP (rhizomelic chondrodysplasia punctata) type 1, a distinct PTS2-import-defective phenotype of peroxisome biogenesis disorders. The mechanisms by which the protein level and quality of Pex7p are controlled remain largely unknown. In the present study we show that dysfunctional Pex7p, including mutants from RCDP patients, is degraded by a ubiquitin-dependent proteasomal pathway involving the CRL4A (Cullin4A-RING ubiquitin ligase) complex. Furthermore, we demonstrate that the degradation of dysfunctional Pex7p is essential for maintaining normal PTS2 import, thereby suggesting that CRL4A functions as an E3 ligase in the quality control of Pex7p. Our results define a mechanism underlying Pex7p homoeostasis and highlight its importance for regulating PTS2 import. These findings may lead to a new approach to Pex7p-based therapies for the treatment of peroxisome biogenesis disorders such as RCDP.
- Published
- 2014
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