المؤلفون: Rebecca Schüle, Teepu Siddique, Han-Xiang Deng, Yi Yang, Sandra Donkervoort, Magnus Hansson, Ricardo E. Madrid, Nailah Siddique, Ludger Schöls, Ingemar Björkhem

المصدر: Journal of Lipid Research, Vol 51, Iss 4, Pp 819-823 (2010)

مصطلحات موضوعية: oxysterol, 27-hydroxycholesterol, 25-hydroxycholesterol, CYP27A1, neurodegeneration, Biochemistry, QD415-436

الوصف: Patients with a recessively inherited “pure” hereditary spastic paresis (SPG5) have mutations in the gene coding for the oxysterol 7 α hydroxylase (CYP7B1). One of the expected metabolic consequences of such mutations is accumulation of oxysterol substrates due to decreased enzyme activity. In accordance with this, we demonstrate here that four patients with the SPG5 disease have 6- to 9-fold increased plasma levels of 27-hydroxycholesterol. A much higher increase, 30- to 50-fold, was found in cerebrospinal fluid. The plasma levels of 25-hydroxycholesterol were increased about 100-fold. There were no measurable levels of this oxysterol in cerebrospinal fluid. The pattern of bile acids in serum was normal, suggesting a normal bile acid synthesis. The findings are discussed in relation to two transgenic mouse models with increased levels of 27-hydroxy cholesterol in the circulation but without neurological symptoms: the cyp27a1 transgenic mouse and the cyp7b1 knockout mouse. The absolute plasma levels of 27-hydroxycholesterol in the latter models are, however, only about 20% of those in the SPG5 patients. If the accumulation of 27-hydroxycholesterol is an important pathogenetic factor, a reduction of its levels may reduce or prevent the neurological symptoms. A possible strategy to achieve this is discussed.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0022227520304910Test; https://doaj.org/toc/0022-2275Test

الوصول الحر: https://doaj.org/article/300106a2af6740e5ab5d485950716129Test

المؤلفون: Ann Löfgren, Ricardo E. Madrid, Jonathan Baets, Vincent Timmerman

المصدر: Neuromuscular disorders

مصطلحات موضوعية: Adult, Pathology, medicine.medical_specialty, Mutation, Missense, Schwann cell, Sural nerve, Biology, Mice, Myelin, Sural Nerve, Charcot-Marie-Tooth Disease, medicine, Animals, Humans, Axon, Remyelination, Genetics (clinical), Onion bulb formation, Nerve biopsy, medicine.diagnostic_test, Exons, Anatomy, medicine.anatomical_structure, nervous system, Neurology, Pediatrics, Perinatology and Child Health, Mesaxon, Female, Human medicine, Neurology (clinical), Myelin Proteins

الوصف: We describe a patient with a longstanding history of hypertrophic neuropathy of DejerineSottas type, ultimately diagnosed with CMT1E disease due to a new p.Leu18Arg missense mutation in the first transmembrane domain of the PMP22 gene. The patient never walked independently and was wheelchair bound by age 18 years. Her parents and son were unaffected. Her peroneal muscular atrophy syndrome presented with scoliosis, bilateral hearing loss, pes planus, distal sensory loss and generalized areflexia. A nerve biopsy at age 26 years showed nerve hypertrophy, myelin uncompaction, defects in mesaxon formation, Schwann cells with irregular outline, axons incompletely surrounded by Schwann cell processes and very short internodes interspersed with denuded axons. Large, mostly denervated, onion bulb formations were also prominent. These findings indicate that demyelination continues undeterred in the advanced stages of the disease and is followed by remyelination attempts that recapitulate the early defects in Schwann cell/axon interaction seen in the Trembler-J mouse, which carries a mutation in the same transmembrane domain.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::68029bc385d90dcc6d3b8190b39e375bTest
https://doi.org/10.1016/j.nmd.2012.12.005Test

المؤلفون: Ingemar Björkhem, Magnus Hansson, Ludger Schöls, Han Xiang Deng, Ricardo E. Madrid, Teepu Siddique, Sandra Donkervoort, Rebecca Schüle, Yi Yang, Nailah Siddique

المصدر: Journal of Lipid Research, Vol 51, Iss 4, Pp 819-823 (2010)

مصطلحات موضوعية: Genetically modified mouse, Adult, Male, Parents, medicine.medical_specialty, Heterozygote, CYP7B1, Oxysterol, 27-hydroxycholesterol, 25-hydroxycholesterol, Cytochrome P450 Family 7, tau Proteins, QD415-436, Biology, Cholesterol 7 alpha-hydroxylase, Biochemistry, Bile Acids and Salts, chemistry.chemical_compound, Endocrinology, Cerebrospinal fluid, Internal medicine, CYP27A1, medicine, polycyclic compounds, Humans, Phosphorylation, Spastic Paraplegia, Hereditary, Homozygote, neurodegeneration, Neurodegenerative Diseases, Cell Biology, Middle Aged, Hydroxycholesterols, chemistry, 27-Hydroxycholesterol, Knockout mouse, Steroid Hydroxylases, Female, lipids (amino acids, peptides, and proteins), oxysterol, Research Article

الوصف: Patients with a recessively inherited "pure" hereditary spastic paresis (SPG5) have mutations in the gene coding for the oxysterol 7 alpha hydroxylase (CYP7B1). One of the expected metabolic consequences of such mutations is accumulation of oxysterol substrates due to decreased enzyme activity. In accordance with this, we demonstrate here that four patients with the SPG5 disease have 6- to 9-fold increased plasma levels of 27-hydroxycholesterol. A much higher increase, 30- to 50-fold, was found in cerebrospinal fluid. The plasma levels of 25-hydroxycholesterol were increased about 100-fold. There were no measurable levels of this oxysterol in cerebrospinal fluid. The pattern of bile acids in serum was normal, suggesting a normal bile acid synthesis. The findings are discussed in relation to two transgenic mouse models with increased levels of 27-hydroxy cholesterol in the circulation but without neurological symptoms: the cyp27a1 transgenic mouse and the cyp7b1 knockout mouse. The absolute plasma levels of 27-hydroxycholesterol in the latter models are, however, only about 20% of those in the SPG5 patients. If the accumulation of 27-hydroxycholesterol is an important pathogenetic factor, a reduction of its levels may reduce or prevent the neurological symptoms. A possible strategy to achieve this is discussed.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::286674417628460a406502c178c416daTest
http://www.sciencedirect.com/science/article/pii/S0022227520304910Test

المؤلفون: Thomas T. Warner, Nigel G. Laing, Maria Tsaousidou, Philip A. Wilkinson, Andrew H. Crosby, Philippa J. Lamont, Heema Patel, Michael A. Patton, Ricardo E. Madrid, Fayçal Hentati, Afif Hentati, Michael A. Simpson, Yi Yang, Teepu Siddique, Karim Ouahchi

المصدر: The American Journal of Human Genetics. 82:510-515

مصطلحات موضوعية: Neuroactive steroid, CYP7B1, Molecular Sequence Data, Cytochrome P450 Family 7, Axonal loss, Biology, medicine.disease_cause, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Degenerative disease, Cytochrome P-450 Enzyme System, Report, Genetics, medicine, Homeostasis, Humans, Genetics(clinical), Amino Acid Sequence, Peptide sequence, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Base Sequence, Spastic Paraplegia, Hereditary, Chromosome Mapping, Sequence Analysis, DNA, medicine.disease, Pedigree, Cell biology, Cholesterol, Liver, Steroid Hydroxylases, 030217 neurology & neurosurgery, Oxidative stress

الوصف: The hereditary spastic paraplegias (HSPs) are a genetically and clinically heterogeneous group of upper-motor-neuron degenerative diseases characterized by selective axonal loss in the corticospinal tracts and dorsal columns. Although numerous mechanisms involving defective subcellular transportation, mitochondrial malfunction, and increased oxidative stress have been proposed, the pathogenic basis underlying the neuronal loss is unknown. We have performed linkage analysis to refine the extent of the SPG5 disease locus and conducted sequence analysis of the genes located within this region. This identified sequence alterations in the cytochrome P450-7B1 (CYP7B1) associated with this pure form of HSP. In the liver, CYP7B1 offers an alternative pathway for cholesterol degradation and also provides the primary metabolic route for the modification of dehydroepiandrosterone neurosteroids in the brain. These findings provide the first direct evidence of a pivotal role of altered cholesterol metabolism in the pathogenesis of motor-neuron degenerative disease and identify a potential for therapeutic intervention in this form of HSP.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fef6d7f2fcceaf5c92223804f9d9c1d9Test
https://doi.org/10.1016/j.ajhg.2007.10.001Test

المؤلفون: Arthur P. Hays, Christian Kubisch, Ricardo E. Madrid

المصدر: Neurology. 65:1301-1303

مصطلحات موضوعية: Adult, Male, medicine.medical_specialty, Caveolin 3, Rippling muscle disease, DNA Mutational Analysis, Muscle Fibers, Skeletal, Biology, Gene mutation, Caveolae, medicine.disease_cause, Achilles Tendon, Exon, Microscopy, Electron, Transmission, Muscular Diseases, Internal medicine, medicine, Humans, Point Mutation, Genetic Predisposition to Disease, Genetic Testing, Child, Muscle, Skeletal, Gene, Gait Disorders, Neurologic, Genes, Dominant, Early onset, Genetics, Mutation, Transition (genetics), Exons, Immunohistochemistry, Endocrinology, Neurology (clinical)

الوصف: The authors describe a family with autosomal dominant rippling muscle disease (RMD) and prominent early-onset toe walking. Molecular analysis revealed a novel heterozygous G > A transition at nucleotide position 136 in exon 2 of the caveolin-3 gene (CAV3). The role of Achilles tendon lengthening in more severe forms of RMD is discussed.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b72034f3ac7449727a78ce360208fb55Test
https://doi.org/10.1212/01.wnl.0000180963.85963.73Test

المؤلفون: Haluk Topaloglu, Els De Vriendt, Argirios Dinopoulos, Esra Battaloglu, Kim Van Hoorenbeeck, Berten Ceulemans, Vincent Timmerman, Patrick Van Bogaert, Jonathan Baets, A. Pou-Serradell, Michaela Auer-Grumbach, Albena Jordanova, Yesim Parman, Peter Van den Bergh, Ricardo E. Madrid, Andrzej Kochański, Magdalena Zimoń, Dagmara Kabzińska, K. Peeters, Laetitia Yperzeele, Geoffrey P. Miller, Gian Maria Fabrizi, Günther Bernert, Birdal Bilir, Peter De Jonghe, Ronen Spiegel, Fernand Pauly, Satu-Leena Sallinen, Tine Deconinck

المساهمون: Çocuk Sağlığı ve Hastalıkları, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie

المصدر: Brain, 134 (Pt 9
Brain
Brain : a journal of neurology, Vol. 134, no. 9, p. 2664-2676 (2011)

مصطلحات موضوعية: Génétique clinique, genotype-phenotype correlations, DNA Mutational Analysis, Disease, Charcot–Marie–Tooth disease, Dejerine-Sottas neuropathy, medicine.disease_cause, Bioinformatics, Cohort Studies, 0302 clinical medicine, Charcot-Marie-Tooth Disease, SH3TC2, Gene duplication, Age of Onset, Child, Genetics, 0303 health sciences, Mutation, early onset hereditary neuropathies, congenital hypomyelinating neuropathy, Dejerine–Sottas neuropathy, genotype–phenotype correlations, Middle Aged, Hypotonia, Phenotype, Child, Preschool, Hereditary Sensory and Motor Neuropathy -- genetics -- pathology -- physiopathology, medicine.symptom, Adult, Adolescent, Charcot-Marie-Tooth disease, 03 medical and health sciences, Young Adult, Neurologie, medicine, Humans, 030304 developmental biology, Aged, Genetic heterogeneity, business.industry, Infant, Original Articles, medicine.disease, Peripheral neuropathy, Charcot-Marie-Tooth Disease -- genetics -- pathology -- physiopathology, Neurology (clinical), Human medicine, Age of onset, business, Hereditary Sensory and Motor Neuropathy, 030217 neurology & neurosurgery

الوصف: Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine-Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot-Marie-Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot-Marie-Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot-Marie-Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset.
Journal Article
Research Support, Non-U.S. Gov't
SCOPUS: ar.j
info:eu-repo/semantics/published

وصف الملف: 2 full-text file(s): application/pdf; application/pdf; text/plain

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a38300dcc0daaeeed746ea51631b2759Test
http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/108357Test

المؤلفون: Carolyn M. Ritterson, Ken Inoue, James R. Lupski, Ricardo E. Madrid, Jennifer A. Lee, James Y. Garbern, Grace M. Hobson, Karen Sperle

المصدر: Annals of neurology. 59(2)

مصطلحات موضوعية: Male, Proteolipid protein 1, Pelizaeus-Merzbacher Disease, Proteolipids, DNA Mutational Analysis, Neural Conduction, Sural nerve, medicine.disease_cause, Microscopy, Electron, Transmission, Sural Nerve, Gene duplication, Gene silencing, Medicine, Humans, Genetics, Mutation, MARVEL Domain-Containing Proteins, business.industry, Reverse Transcriptase Polymerase Chain Reaction, Pelizaeus–Merzbacher disease, Membrane Proteins, Nucleic Acid Hybridization, Peripheral Nervous System Diseases, medicine.disease, Magnetic Resonance Imaging, Neurology, Electrophoresis, Polyacrylamide Gel, Neurology (clinical), business, Neuroscience, Comparative genomic hybridization

الوصف: Objective To report an association between spastic paraplegia type 2 with axonal peripheral neuropathy and apparent proteolipid protein gene (PLP1) silencing in a family. Methods Pulsed-field gel electrophoresis, custom array comparative genomic hybridization, and semi-quantitative multiplex polymerase chain reaction analyses were used to examine the PLP1 genomic region. Results Electrodiagnostic studies and a sural nerve biopsy showed features of a dystrophic axonal neuropathy. Molecular studies identified a small duplication downstream of PLP1. Interpretation We propose the duplication to result in PLP1 gene silencing by virtue of a position effect. Our observations suggest that genomic rearrangements that do not include PLP1 coding sequences should be considered as yet another potential mutational mechanism underlying PLP1-related dysmyelinating disorders. Ann Neurol 2005

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1f4ba132042a986bff5f89e2ef38fd69Test
https://pubmed.ncbi.nlm.nih.gov/16374829Test

المؤلفون: Jennifer A. Lee, Ricardo E. Madrid, Karen Sperle, Carolyn M. Ritterson, Grace M. Hobson, James Garbern, James R. Lupski, Ken Inoue

المصدر: Annals of Neurology; Feb2006, Vol. 59 Issue 2, p398-403, 6p

المؤلفون: Henryk M. Wiśniewski, Ricardo E. Madrid

المصدر: Journal of Neurocytology. 6:103-117

مصطلحات موضوعية: Histology, Guinea Pigs, Biology, Myelin, Dorsal root ganglion, Ganglia, Spinal, medicine, Animals, Demyelinating Disorder, Pathological, Myelin Sheath, General Neuroscience, Cell Biology, Anatomy, Spinal cord, Sciatic Nerve, Axons, medicine.anatomical_structure, Spinal Cord, nervous system, Nerve Degeneration, Sciatic nerve, Immune reaction, Axonal degeneration, Demyelinating Diseases

الوصف: Changes in the L7 and S1 segments of the spinal cord and the corresponding dorsal root ganglia (DRG), spinal roots and sciatic nerves of guinea pigs immunized with whole rabbit sciatic nerve in complete Freund's adjuvant have been studied and compared with the changes found in guinea pigs immunized with purified P.N.S. myelin. In both groups of animals, pathological changes were found in the posterior roots, DRG and root entry zones. In the posterior roots, axonal degeneration and segmental demyelination evolved in parallel, affected different populations of myelinated axons and showed no indication of interdependence. The aetiology of axonal degeneration in this and other demyelinating disorders is discussed. It is concluded that axons can be damaged by being in the vicinity of areas where cell-mediated immune reactions are taking place, i.e. as a consequence of the so-called 'bystander' effect.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c44b4c695af312abee2f0cf84d6caae1Test
https://doi.org/10.1007/bf01175417Test