28 results on '"Takata RI"'
Search Results
2. Central Core Disease: Facial Weakness Differentiating Biallelic from Monoallelic Forms.
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Cotta A, Souza LS, Carvalho E, Feitosa LN, Cunha A Jr, Navarro MM, Valicek J, Menezes MM, Neves SVN, Xavier-Neto R, Vargas AP, Takata RI, Paim JF, and Vainzof M
- Subjects
- High-Throughput Nucleotide Sequencing, Humans, Pedigree, Retrospective Studies, Ryanodine Receptor Calcium Release Channel genetics, Myopathy, Central Core genetics, Myopathy, Central Core pathology, Neuroblastoma
- Abstract
Central Core Disease (CCD) is a genetic neuromuscular disorder characterized by the presence of cores in muscle biopsy. The inheritance has been described as predominantly autosomal dominant (AD), and the disease may present as severe neonatal or mild adult forms. Here we report clinical and molecular data on a large cohort of Brazilian CCD patients, including a retrospective clinical analysis and molecular screening for RYR1 variants using Next-Generation Sequencing (NGS). We analyzed 27 patients from 19 unrelated families: four families (11 patients) with autosomal dominant inheritance (AD), two families (3 patients) with autosomal recessive (AR), and 13 sporadic cases. Biallelic RYR1 variants were found in six families (two AR and four sporadic cases) of the 14 molecularly analyzed families (~43%), suggesting a higher frequency of AR inheritance than expected. None of these cases presented a severe phenotype. Facial weakness was more common in biallelic than in monoallelic patients ( p = 0.0043) and might be a marker for AR forms. NGS is highly effective for the identification of RYR1 variants in CCD patients, allowing the discovery of a higher proportion of AR cases with biallelic mutations. These data have important implications for the genetic counseling of the families. more...
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- 2022
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3. Muscle fat replacement and modified ragged red fibers in two patients with reversible infantile respiratory chain deficiency.
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Cotta A, Carvalho E, da-Cunha-Junior A, Navarro MM, Paim JF, Valicek J, Baptista-Junior S, da Silveira EB, Lima MI, Carellos EVM, de-La-Rocque-Ferreira A, Takata RI, and Horvath R
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- Biopsy, Female, Humans, Infant, Infant, Newborn, Magnetic Resonance Imaging, Male, Mitochondrial Diseases diagnostic imaging, Mitochondrial Myopathies pathology, Muscle Hypotonia etiology, Mitochondrial Diseases pathology, Muscle, Skeletal pathology
- Abstract
Reversible infantile respiratory chain deficiency is a severe neonatal mitochondrial myopathy that resolves spontaneously. It is caused by the homoplasmic m.14674T>C mtDNA mutation and additional nuclear variants in genes interacting with mt-tRNAGlu have been detected in some patients. We present detailed clinical, imaging, and muscle biopsy findings in a boy and a girl with neonatal hypotonia, feeding difficulties, lactic acidosis, and ragged red fibers. Both patients show fat replacement on muscle imaging, which was mild in the boy, but severe in the girl, affecting mostly the posterior leg muscles. In addition to the homoplasmic m.14674T>C, both patients carried heterozygous variants in QRSL1 (c. 686T>G; p.Val299Gly) and EARS2 (c.358C>T; p.Arg120Trp), respectively. It is very important to recognize the clinical and morphological signs of reversible infantile respiratory chain deficiency as patients should receive intensive supportive care in the first 6 months of life. Understanding the mechanism of the spontaneous recovery may lead to novel therapeutic perspectives in other mitochondrial diseases., Competing Interests: Declaration of Competing Interest None RH was supported by the European Research Council [309548], the Wellcome Investigator Award [109915/Z/15/Z], the Medical Research Council (UK) [MR/N025431/1]; the Newton Fund [UK/Turkey, MR/N027302/1], the Lily Foundation and the Evelyn Trust. Summary: AC, EC, Ald-C-L, MMN, JFP, JV, SB-J, EBS, MIL, EVMC, AdLRF, RIT have no interest to declare. RH was supported by the European Research Council [309548], the Wellcome Investigator Award [109915/Z/15/Z], the Medical Research Council (UK) [MR/N025431/1]; the Newton Fund [UK/Turkey, MR/N027302/1], the Lily Foundation and the Evelyn Trust., (Copyright © 2021 Elsevier B.V. All rights reserved.) more...
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- 2021
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4. Clinical, imaging, morphologic, and molecular features of X-linked VMA21-related myopathy in two unrelated Brazilian families.
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Cotta A, Carvalho E, da-Cunha-Junior AL, Navarro MM, Menezes MM, Paim JF, Valicek J, Lima MI, Velloso-Filho R, Freire-Lyra MH, Takata RI, Inoue M, Okubo M, Iida A, and Nishino I
- Subjects
- Brazil, Humans, Muscle, Skeletal metabolism, Muscular Diseases diagnostic imaging, Muscular Diseases genetics, Vacuolar Proton-Translocating ATPases metabolism
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- 2020
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5. Early-onset coenzyme Q10 deficiency associated with ataxia and respiratory chain dysfunction due to novel pathogenic COQ8A variants, including a large intragenic deletion.
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Cotta A, Alston CL, Baptista-Junior S, Paim JF, Carvalho E, Navarro MM, Appleton M, Ng YS, Valicek J, da-Cunha-Junior AL, Lima MI, de la Rocque Ferreira A, Takata RI, Hargreaves IP, Gorman GS, McFarland R, Pierre G, and Taylor RW more...
- Abstract
Coenzyme Q10 (CoQ10) deficiency is a clinically and genetically heterogeneous subtype of mitochondrial disease. We report two girls with ataxia and mitochondrial respiratory chain deficiency who were shown to have primary CoQ10 deficiency. Muscle histochemistry displayed signs of mitochondrial dysfunction-ragged red fibers, mitochondrial paracrystalline inclusions, and lipid deposits while biochemical analyses revealed complex II+III respiratory chain deficiencies. MRI brain demonstrated cerebral and cerebellar atrophy. Targeted molecular analysis identified a homozygous c.1015G>A, p.(Ala339Thr) COQ8A variant in subject 1, while subject 2 was found to harbor a single heterozygous c.1029_1030delinsCA variant predicting a p.Gln343_Val344delinsHisMet amino acid substitution. Subsequent investigations identified a large-scale COQ8A deletion in trans to the c.1029_1030delinsCA allele. A skin biopsy facilitated cDNA studies that confirmed exon skipping in the fibroblast derived COQ8A mRNA transcript. This report expands the molecular genetic spectrum associated with COQ8A -related mitochondrial disease and highlights the importance of thorough investigation of candidate pathogenic variants to establish phase. Rapid diagnosis is of the utmost importance as patients may benefit from therapeutic CoQ10 supplementation., Competing Interests: The authors have no conflicts of interest to disclose. All authors have read and approved the submitted manuscript., (© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.) more...
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- 2020
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6. Modelling the pathogenesis of X-linked distal hereditary motor neuropathy using patient-derived iPSCs.
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Perez-Siles G, Cutrupi A, Ellis M, Kuriakose J, La Fontaine S, Mao D, Uesugi M, Takata RI, Speck-Martins CE, Nicholson G, and Kennerson ML
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- Amino Acid Sequence, Base Sequence, Cell Differentiation, Copper metabolism, Copper-Transporting ATPases genetics, Down-Regulation genetics, Energy Metabolism, Fibroblasts metabolism, Fibroblasts pathology, Homeostasis, Humans, Karyotype, Mitochondria metabolism, Motor Neurons pathology, Mutation genetics, Phenotype, Spinal Cord pathology, Genetic Diseases, X-Linked pathology, Induced Pluripotent Stem Cells pathology, Models, Biological, Muscular Atrophy, Spinal pathology
- Abstract
ATP7A encodes a copper-transporting P-type ATPase and is one of 23 genes in which mutations produce distal hereditary motor neuropathy (dHMN), a group of diseases characterized by length-dependent axonal degeneration of motor neurons. We have generated induced pluripotent stem cell (iPSC)-derived motor neurons from a patient with the p.T994I ATP7A gene mutation as an in vitro model for X-linked dHMN (dHMNX). Patient motor neurons show a marked reduction of ATP7A protein levels in the soma when compared to control motor neurons and failed to upregulate expression of ATP7A under copper-loading conditions. These results recapitulate previous findings obtained in dHMNX patient fibroblasts and in primary cells from a rodent model of dHMNX, indicating that patient iPSC-derived motor neurons will be an important resource for studying the role of copper in the pathogenic processes that lead to axonal degeneration in dHMNX., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.) more...
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- 2020
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7. LMNA-Related Muscular Dystrophy with Clinical Intrafamilial Variability.
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Cotta A, Paim JF, Carvalho E, Valicek J, da Cunha Junior AL, Navarro MM, Vargas AP, Lima MI, de Almeida CF, Takata RI, and Vainzof M
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- Adult, Diagnosis, Differential, Female, Genetic Testing, Heterozygote, Humans, Male, Middle Aged, Muscular Dystrophy, Emery-Dreifuss diagnostic imaging, Muscular Dystrophy, Emery-Dreifuss genetics, Mutation, Missense, Biological Variation, Population, Lamin Type A genetics, Muscular Dystrophy, Emery-Dreifuss pathology, Pedigree
- Abstract
The LMNA gene is associated to a huge broad of phenotypes, including congenital Emery-Dreifuss muscular dystrophy and late-onset LMNA-related muscular dystrophy. In these forms, muscle weakness, contractures, and cardiac impairment are common. In an autosomal dominant pedigree including 5 affected patients, NGS molecular analysis performed in 6 relatives identifies the heterozygous c.1129C>T p.Arg377Cys variant in the exon 6 of the LMNA gene in three of them. Clinical, laboratorial, imaging investigation of these affected patients showed a significant clinical variability: the father presented subclinical imaging muscular dystrophy masqueraded as radiculopathy. One of his sons presented cardiac arrhythmia, muscular weakness, elbow contractures, and intranuclear pseudoinclusions on muscle biopsy. A second son presented only decreased tendon reflexes. Two other brothers presenting myalgia and cramps were not carriers of the same mutation in the LMNA gene. Early diagnosis, considering these variable phenotype and genotype, is important for genetic counseling, as well as cardiac, and rehabilitation management. more...
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- 2019
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8. Analysis of mutations in EXT1 and EXT2 in Brazilian patients with multiple osteochondromas.
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Santos SCL, Rizzo IMPO, Takata RI, Speck-Martins CE, Brum JM, and Sollaci C
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- Adolescent, Adult, Aged, Base Sequence genetics, Brazil epidemiology, Child, Child, Preschool, Exons, Female, Humans, Male, Middle Aged, Mutation, N-Acetylglucosaminyltransferases physiology, Osteochondromatosis genetics, Prevalence, Sequence Deletion, Exostosin 2, Exostosin 1, Exostoses, Multiple Hereditary genetics, N-Acetylglucosaminyltransferases genetics
- Abstract
Background: Multiple osteochondromas is a dysplasia characterized by growth of two or more osteochondromas. It is genetically heterogeneous, caused by pathogenic variants in EXT1 or EXT2 genes in 70%-90% of patients. The EXT1 is more often mutated than EXT2 gene, with a variable prevalence between populations. There are no data about EXT1 and EXT2 pathogenic variants in patients with multiple osteochondromas in Brazilian population. The aim of this survey is to characterize these to determine the genotype profile of this population., Methods: DNA sequencing (Sanger Method) and MLPA analysis were performed to identify point mutations and deletions/duplications in the sample of 153 patients in 114 families., Results: Germline variants were identified in 83% of families in which EXT2 variants were detected in 46% and EXT1 in 37% of cases. No variants were detected in 17% of them. We identified 50 different variants, 33 (13 frameshift, 11 nonsense, 5 missense, 2 splice site mutation, and 2 large deletions) in EXT1 and 17 (6 frameshift, 6 splice site mutation, 3 nonsense, 1 missense, and 1 large deletion) in EXT2. Of all 50 variants, 31 (62%) were novel, including 20 out of 33 (60,6%) EXT1 and 11 out of 17 (64.7%) EXT2 alleles. The vast majority of variants (88%) were "loss-of-function" and two novel hotspots in EXT2 gene were observed in our study., Conclusion: The prevalence of variants detected in the EXT2 gene differs from other researches from Latin America, European, and Asian population. This uncommon prevalence could be related with the newly characterized variant hotspot sites detected in EXT2 gene (p.Ala409Profs*26 and p.Ser290*). A high number of novel variants were also identified indicating that Brazilian population has a unique genetic profile. Characterizing this population and establishing its genotype is essential to understand the molecular pathogenesis of this disease in Brazil., (© 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.) more...
- Published
- 2018
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9. The relative frequency of common neuromuscular diagnoses in a reference center.
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Cotta A, Paim JF, Carvalho E, da-Cunha-Júnior AL, Navarro MM, Valicek J, Menezes MM, Nunes SV, Xavier-Neto R, Baptista S Junior, Lima LR, Takata RI, and Vargas AP
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- Biopsy, Female, Humans, Male, Neuromuscular Diseases genetics, Neuromuscular Diseases pathology, Retrospective Studies, Neuromuscular Diseases diagnosis
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The diagnostic procedure in neuromuscular patients is complex. Knowledge of the relative frequency of neuromuscular diseases within the investigated population is important to allow the neurologist to perform the most appropriate diagnostic tests., Objective: To report the relative frequency of common neuromuscular diagnoses in a reference center., Methods: A 17-year chart review of patients with suspicion of myopathy., Results: Among 3,412 examinations, 1,603 (46.98%) yielded confirmatory results: 782 (48.78%) underwent molecular studies, and 821 (51.21%) had muscle biopsies. The most frequent diagnoses were: dystrophinopathy 460 (28.70%), mitochondriopathy 330 (20.59%), spinal muscular atrophy 158 (9.86%), limb girdle muscular dystrophy 157 (9.79%), Steinert myotonic dystrophy 138 (8.61%), facioscapulohumeral muscular dystrophy 99 (6.17%), and other diagnoses 261 (16.28%)., Conclusion: Using the presently-available diagnostic techniques in this service, a specific limb girdle muscular dystrophy subtype diagnosis was reached in 61% of the patients. A neuromuscular-appropriate diagnosis is important for genetic counseling, rehabilitation orientation, and early treatment of respiratory and cardiac complications. more...
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- 2017
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10. Central core myopathy with autophagy.
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Cotta A, Paim JF, Pavanello RCM, Nogueira L, Leão LG, Xavier-Neto R, Navarro MM, Carvalho E, Valicek J, Silveira EB, Takata RI, and Vainzof M
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- Adult, DNA Mutational Analysis, Humans, Male, Muscle, Skeletal pathology, Mutation, Myopathy, Central Core genetics, Myopathy, Central Core pathology, Ryanodine Receptor Calcium Release Channel metabolism, Autophagy physiology, Muscle, Skeletal metabolism, Myopathy, Central Core metabolism, Ryanodine Receptor Calcium Release Channel genetics
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- 2017
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11. Phenotypic Variability of Dystrophinopathy Symptomatic Female Carriers.
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Cotta A, Paim JF, Carvalho E, Navarro MM, Valicek J, da-Cunha-Junior AL, Menezes MM, Nunes SV, Xavier-Neto R, da Silveira EB, Costa-E-Silva C, Takata RI, and Vargas AP
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- Adolescent, Adult, Aged, Female, Humans, Middle Aged, Retrospective Studies, Dystrophin genetics, Heterozygote, Muscular Dystrophies diagnostic imaging, Muscular Dystrophies genetics, Phenotype
- Abstract
Background: Dystrophinopathies are X-linked muscular dystrophies characterized by pathogenic mutations in the dystrophin gene. Symptomatic dystrophinopathy female carriers may present with limb-girdle weakness. The diagnosis may be challenging in the absence of affected male relatives. We aimed to describe the phenotypic variability in a series of molecular-confirmed female dystrophinopathy patients., Methods: This is a retrospective analysis of medical records from 1997 to 2015., Results: Ten female dystrophinopathy patients were selected, two with unusual phenotypes: one with early joint contractures muscular dystrophy and the other with very late onset myopathy. Muscle imaging studies demonstrated predominant asymmetric fat replacement. Muscle biopsy immunohistochemistry demonstrated clear mosaic pattern in two cases and only subtle reduction of dystrophin intensity in three., Conclusions: Adequate diagnosis is fundamental for genetic counseling and cardiologic follow-up. Female patients with dystrophinopathy may present unusual phenotypes such as early contractures and very late onset myopathy. more...
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- 2017
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12. Characterizing the molecular phenotype of an Atp7a(T985I) conditional knock in mouse model for X-linked distal hereditary motor neuropathy (dHMNX).
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Perez-Siles G, Grant A, Ellis M, Ly C, Kidambi A, Khalil M, Llanos RM, Fontaine SL, Strickland AV, Züchner S, Bermeo S, Neist E, Brennan-Speranza TC, Takata RI, Speck-Martins CE, Mercer JF, Nicholson GA, and Kennerson ML more...
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- Animals, Behavior, Animal, Cells, Cultured, Embryo, Mammalian cytology, Embryo, Mammalian metabolism, Female, Fibroblasts cytology, Fibroblasts metabolism, Genetic Diseases, X-Linked genetics, Genetic Diseases, X-Linked metabolism, Humans, Male, Mice, Mice, Inbred C57BL, Motor Neuron Disease genetics, Motor Neuron Disease metabolism, Myogenin metabolism, Myostatin metabolism, Copper metabolism, Copper-Transporting ATPases genetics, Genetic Diseases, X-Linked pathology, Motor Neuron Disease pathology, Mutation
- Abstract
ATP7A is a P-type ATPase essential for cellular copper (Cu) transport and homeostasis. Loss-of-function ATP7A mutations causing systemic Cu deficiency are associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome. We previously identified two rare ATP7A missense mutations (P1386S and T994I) leading to a non-fatal form of motor neuron disorder, X-linked distal hereditary motor neuropathy (dHMNX), without overt signs of systemic Cu deficiency. Recent investigations using a tissue specific Atp7a knock out model have demonstrated that Cu plays an essential role in motor neuron maintenance and function, however the underlying pathogenic mechanisms of ATP7A mutations causing axonal degeneration remain unknown. We have generated an Atp7a conditional knock in mouse model of dHMNX expressing Atp7a(T985I), the orthologue of the human ATP7A(T994I) identified in dHMNX patients. Although a degenerative motor phenotype is not observed, the knock in Atp7a(T985I/Y) mice show altered Cu levels within the peripheral and central nervous systems, an increased diameter of the muscle fibres and altered myogenin and myostatin gene expression. Atp7a(T985I/Y) mice have reduced Atp7a protein levels and recapitulate the defective trafficking and altered post-translational regulatory mechanisms observed in the human ATP7A(T994I) patient fibroblasts. Our model provides a unique opportunity to characterise the molecular phenotype of dHMNX and the time course of cellular events leading to the process of axonal degeneration in this disease. more...
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- 2016
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13. Limb girdle muscular dystrophy type 2G with myopathic-neurogenic motor unit potentials and a novel muscle image pattern.
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Cotta A, Paim JF, da-Cunha-Junior AL, Neto RX, Nunes SV, Navarro MM, Valicek J, Carvalho E, Yamamoto LU, Almeida CF, Braz SV, Takata RI, and Vainzof M
- Abstract
Background: Limb girdle muscular dystrophy type 2G (LGMD2G) is a subtype of autosomal recessive muscular dystrophy caused by mutations in the telethonin gene. There are few LGMD2G patients worldwide reported, and this is the first description associated with early tibialis anterior sparing on muscle image and myopathic-neurogenic motor unit potentials., Case Presentation: Here we report a 31 years old caucasian male patient with progressive gait disturbance, and severe lower limb proximal weakness since the age of 20 years, associated with subtle facial muscle weakness. Computed tomography demonstrated soleus, medial gastrocnemius, and diffuse thigh muscles involvement with tibialis anterior sparing. Electromyography disclosed both neurogenic and myopathic motor unit potentials. Muscle biopsy demonstrated large groups of atrophic and hypertrophic fibers, frequent fibers with intracytoplasmic rimmed vacuoles full of autophagic membrane and sarcoplasmic debris, and a total deficiency of telethonin. Molecular investigation identified the common homozygous c.157C > T in the TCAP gene., Conclusion: This report expands the phenotypic variability of telethoninopathy/ LGMD2G, including: 1) mixed neurogenic and myopathic motor unit potentials, 2) facial weakness, and 3) tibialis anterior sparing. Appropriate diagnosis in these cases is important for genetic counseling and prognosis. more...
- Published
- 2014
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14. Common recessive limb girdle muscular dystrophies differential diagnosis: why and how?
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Cotta A, Carvalho E, da-Cunha-Júnior AL, Paim JF, Navarro MM, Valicek J, Menezes MM, Nunes SV, Xavier Neto R, Takata RI, and Vargas AP
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- Biopsy, Diagnosis, Differential, Female, Humans, Male, Medical Illustration, Muscles diagnostic imaging, Muscles pathology, Muscular Dystrophies, Limb-Girdle genetics, Tomography, X-Ray Computed, Ultrasonography, Muscular Dystrophies, Limb-Girdle diagnosis
- Abstract
Limb girdle muscular dystrophies are heterogeneous autosomal hereditary neuromuscular disorders. They produce dystrophic changes on muscle biopsy and they are associated with mutations in several genes involved in muscular structure and function. Detailed clinical, laboratorial, imaging, diagnostic flowchart, photographs, tables, and illustrated diagrams are presented for the differential diagnosis of common autosomal recessive limb girdle muscular dystrophy subtypes diagnosed nowadays at one reference center in Brazil. Preoperative image studies guide muscle biopsy site selection. Muscle involvement image pattern differs depending on the limb girdle muscular dystrophy subtype. Muscle involvement is conspicuous at the posterior thigh in calpainopathy and fukutin-related proteinopathy; anterior thigh in sarcoglycanopathy; whole thigh in dysferlinopathy, and telethoninopathy. The precise differential diagnosis of limb girdle muscular dystrophies is important for genetic counseling, prognostic orientation, cardiac and respiratory management. Besides that, it may probably, in the future, provide specific genetic therapies for each subtype. more...
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- 2014
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15. Muscle phenotypic variability in limb girdle muscular dystrophy 2 G.
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Paim JF, Cotta A, Vargas AP, Navarro MM, Valicek J, Carvalho E, da-Cunha AL Jr, Plentz E, Braz SV, Takata RI, Almeida CF, and Vainzof M
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- Child, Connectin genetics, Female, Humans, Mitochondria ultrastructure, Muscular Dystrophies, Limb-Girdle diagnosis, Polymorphism, Single Nucleotide, Sarcolemma ultrastructure, Muscle Fibers, Skeletal pathology, Muscular Dystrophies, Limb-Girdle genetics, Phenotype
- Abstract
Limb girdle muscular dystrophy type 2 G (LGMD2G) is caused by mutations in the telethonin gene. Only few families were described presenting this disease, and they are mainly Brazilians. Here, we identified one additional case carrying the same common c.157C > T mutation in the telethonin gene but with an atypical histopathological muscle pattern. In a female patient with a long duration of symptoms (46 years), muscle biopsy showed, in addition to telethonin deficiency, the presence of nemaline rods, type 1 fiber predominance, nuclear internalization, lobulated fibers, and mitochondrial paracrystalline inclusions. Her first clinical signs were identified at 8 years old, which include tiptoe walking, left lower limb deformity, and frequent falls. Ambulation loss occurred at 41 years old, and now, at 54 years old, she presented pelvic girdle atrophy, winging scapula, foot deformity with incapacity to perform ankle dorsiflexion, and absent tendon reflexes. The presence of nemaline bodies could be a secondary phenomenon, possibly associated with focal Z-line abnormalities of a long-standing disease. However, these new histopathological findings, characteristic of congenital myopathies, expand muscle phenotypic variability of telethoninopathy. more...
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- 2013
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16. Analysis of novel ARG1 mutations causing hyperargininemia and correlation with arginase I activity in erythrocytes.
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Carvalho DR, Brand GD, Brum JM, Takata RI, Speck-Martins CE, and Pratesi R
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- Adolescent, Adult, Amino Acid Sequence, Amino Acid Substitution, Arginase chemistry, Arginine blood, Brazil, Catalytic Domain genetics, Child, DNA Mutational Analysis, Enzyme Activation genetics, Erythrocytes enzymology, Female, Genetic Association Studies, Humans, Hyperargininemia blood, Male, Models, Molecular, Molecular Sequence Data, Mutant Proteins chemistry, Protein Conformation, Protein Folding, Protein Multimerization genetics, Protein Structure, Quaternary genetics, Sequence Homology, Amino Acid, Young Adult, Arginase blood, Arginase genetics, Hyperargininemia enzymology, Hyperargininemia genetics, Mutant Proteins blood, Mutant Proteins genetics, Mutation, Missense
- Abstract
Hyperargininemia (HA) is an autosomal recessive disease that typically has a clinical presentation that is distinct from other urea cycle disorders. It is caused by the deficient activity of the enzyme arginase I, encoded by the gene ARG1. We screened for ARG1 mutations and measured erythrocyte enzyme activity in a series of 16 Brazilian HA patients. Novel mutations, in addition to previously described missense mutations, were analysed for their effect on the structure, stability and/or function of arginase I (ARG1) using bioinformatics tools. Three previously reported mutations were found (p.R21X; p.I11T and p.W122X), and five novel mutations were identified (p.G27D; p.G74V; p.T134I; p.R308Q; p.I174fs179). The p.T134I mutation was the most frequent in the Brazilian population. Patients carrying the p.R308Q mutation had higher residual ARG1 decreased activity, but presented no distinguishable phenotype compared to the other patients. Bioinformatics analyses revealed that missense mutations (1) affect the ARG1 active site, (2) interfere with the stability of the ARG1 folded conformation or (3) alter the quaternary structure of the ARG1. Our study reinforced the role of Arg308 residue for assembly of the ARG1 homotrimer. The panel of heterogeneous ARG1 mutations that cause HA was expanded, nevertheless a clear genotype-phenotype correlation was not observed in our series., (Copyright © 2012 Elsevier B.V. All rights reserved.) more...
- Published
- 2012
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17. Mandibular hypoplasia in fibrodysplasia ossificans progressiva causing obstructive sleep apnoea with pulmonary hypertension.
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Carvalho DR, Pinnola GC, Ferreira DRA, Beraldo PSS, Coelho CVC, Farage L, Takata RI, and Speck-Martins CE
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- Adolescent, Child, Humans, Hypertension, Pulmonary physiopathology, Male, Mandible diagnostic imaging, Myositis Ossificans physiopathology, Polysomnography, Sleep Apnea, Obstructive physiopathology, Tomography, X-Ray Computed, Hypertension, Pulmonary etiology, Mandible abnormalities, Myositis Ossificans complications, Sleep Apnea, Obstructive etiology
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- 2010
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18. Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy.
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Kennerson ML, Nicholson GA, Kaler SG, Kowalski B, Mercer JF, Tang J, Llanos RM, Chu S, Takata RI, Speck-Martins CE, Baets J, Almeida-Souza L, Fischer D, Timmerman V, Taylor PE, Scherer SS, Ferguson TA, Bird TD, De Jonghe P, Feely SM, Shy ME, and Garbern JY more...
- Subjects
- Adenosine Triphosphatases chemistry, Adenosine Triphosphatases metabolism, Adolescent, Adult, Amino Acid Sequence, Base Sequence, Cation Transport Proteins chemistry, Cation Transport Proteins metabolism, Cells, Cultured, Child, Preschool, Copper metabolism, Copper-Transporting ATPases, DNA Primers genetics, Female, Genetic Association Studies, Genetic Complementation Test, Genetic Diseases, X-Linked metabolism, Humans, Immunohistochemistry, Male, Menkes Kinky Hair Syndrome genetics, Menkes Kinky Hair Syndrome metabolism, Middle Aged, Models, Molecular, Molecular Sequence Data, Motor Neuron Disease metabolism, Pedigree, RNA, Messenger genetics, RNA, Messenger metabolism, Sequence Homology, Amino Acid, Syndrome, Young Adult, Adenosine Triphosphatases genetics, Cation Transport Proteins genetics, Genetic Diseases, X-Linked genetics, Motor Neuron Disease genetics, Mutation, Missense
- Abstract
Distal hereditary motor neuropathies comprise a clinically and genetically heterogeneous group of disorders. We recently mapped an X-linked form of this condition to chromosome Xq13.1-q21 in two large unrelated families. The region of genetic linkage included ATP7A, which encodes a copper-transporting P-type ATPase mutated in patients with Menkes disease, a severe infantile-onset neurodegenerative condition. We identified two unique ATP7A missense mutations (p.P1386S and p.T994I) in males with distal motor neuropathy in two families. These molecular alterations impact highly conserved amino acids in the carboxyl half of ATP7A and do not directly involve the copper transporter's known critical functional domains. Studies of p.P1386S revealed normal ATP7A mRNA and protein levels, a defect in ATP7A trafficking, and partial rescue of a S. cerevisiae copper transport knockout. Although ATP7A mutations are typically associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome, we demonstrate here that certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency. This previously unrecognized genotype-phenotype correlation suggests an important role of the ATP7A copper transporter in motor-neuron maintenance and function., (Copyright 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2010
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19. Mutational screening of ACVR1 gene in Brazilian fibrodysplasia ossificans progressiva patients.
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Carvalho DR, Navarro MM, Martins BJ, Coelho KE, Mello WD, Takata RI, and Speck-Martins CE
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- Adolescent, Adult, Brazil, Child, Child, Preschool, Female, Genetic Testing, Humans, Male, Middle Aged, Activin Receptors, Type I genetics, Myositis Ossificans genetics
- Abstract
Fibrodysplasia ossificans progressiva (FOP) is a severe genetic disorder reported worldwide. A specific heterozygous mutation (c.617G> A; p.R206H) in the activin A type I receptor gene (ACVR1) is regarded as the genetic cause of FOP in all classically affected individuals worldwide. However, a few patients with FOP variants harbor distinct mutations in ACVR1. We screened a group of FOP Brazilian population for mutations in ACVR1. Of 16 patients with a classic FOP phenotype (10 males and 6 females, age range of 3-42 years), all had the classic mutation (p.R206H). One 21-year-old woman with a variant FOP phenotype had the previously reported c.983G> A mutation (p.G328E). Our study contributes to the understanding of the predominant FOP phenotype and genotype and suggests that variant FOP phenotypes are associated with specific mutations in ACVR1 gene. more...
- Published
- 2010
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20. A new locus for recessive distal spinal muscular atrophy at Xq13.1-q21.
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Takata RI, Speck Martins CE, Passosbueno MR, Abe KT, Nishimura AL, Da Silva MD, Monteiro A Jr, Lima MI, Kok F, and Zatz M
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- Brazil, Child, Child, Preschool, Female, Genetic Linkage genetics, Haplotypes genetics, Humans, Male, Microsatellite Repeats genetics, Muscular Atrophy, Spinal diagnosis, Muscular Atrophy, Spinal physiopathology, Pedigree, White People genetics, Chromosome Mapping, Chromosomes, Human, X genetics, Genes, Recessive genetics, Muscular Atrophy, Spinal genetics
- Published
- 2004
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21. Clinical diagnosis of heterozygous dystrophin gene deletions by fluorescence in situ hybridization.
- Author
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Rosenberg C, Navajas L, Vagenas DF, Bakker E, Vainzof M, Passos-Bueno MR, Takata RI, Van Ommen GJ, Zatz M, and Den Dunnen JT
- Subjects
- DNA Probes, Exons genetics, Gene Deletion, Heterozygote, Humans, In Situ Hybridization, Fluorescence, Muscular Dystrophies diagnosis, Dystrophin genetics, Genes genetics, Muscular Dystrophies genetics
- Abstract
Two-thirds of patients affected by Duchenne or Becker muscular dystrophy (DMD/BMD) carry large intra-genic deletions in the dystrophin gene. In males, the deletions can be efficiently detected using multiplex polymerase chain reaction (PCR) and Southern blotting. In contrast, deletion detection in carrier females is complicated by the presence of a normal gene copy on the second X-chromosome. We have analyzed the boundaries of 570 deletions and 34 duplications in the dystrophin gene identified in the São Paulo and Leiden diagnostic laboratories. The data were used to select an optimal set of cosmid probes for the detection of the most frequently deleted areas of the dystrophin gene. Six cosmids were evaluated in fluorescence in situ hybridization (FISH) experiments to assess deletions in 21 heterozygous deletion-carriers and nine controls. No discrepancy was found between the FISH analysis and the molecular data, demonstrating the accuracy of the technique for carrier detection in Duchenne and Becker muscular dystrophy. more...
- Published
- 1998
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22. Novel point mutations in the dystrophin gene.
- Author
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Sitnik R, Campiotto S, Vainzof M, Pavanello RC, Takata RI, Zatz M, and Passos-Bueno MR
- Subjects
- Dystrophin chemistry, Gene Deletion, Genetic Testing, Humans, Male, Muscular Dystrophies etiology, Muscular Dystrophies genetics, Polymorphism, Genetic, Polymorphism, Single-Stranded Conformational, Dystrophin genetics, Point Mutation
- Abstract
Duchenne (DMD) and Becker (BMD) type muscular dystrophies are allelic X-linked recessive disorders caused by mutations in the gene encoding dystrophin. About 65% of the cases are caused by deletions, while 5-10% are duplications. The remaining 30% of affected individuals may have smaller mutations (point mutations or small deletions/insertions) which cannot be identified by current diagnostic screening strategies. In order to look for pathogenic small mutations in the dystrophin gene, we have screened the 18 exons located in the hot spot region of this gene through two different single strand conformation polymorphism (SSCP) conditions. Five different pathogenic mutations were identified in 6 out of 192 DMD/BMD patients without detectable deletions: 2 nonsense, 1 bp insertion, 1 bp deletion and 1 intronic. Except for the intronic change, which alters a splice site, all the others cause a premature stop codon. In addition, 8 apparently neutral changes were identified. However, interestingly, one of them was not identified in 195 normal chromosomes, although it was previously described in a DMD patient from a different population. The possibility that this mutation may be pathogenic is discussed. Except for two neutral changes, all the others are apparently here described for the first time. more...
- Published
- 1997
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23. Why is the reproductive performance lower in Becker (BMD) as compared to limb girdle (LGMD) muscular dystrophy male patients?
- Author
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Eggers S, Lauriano V, Melo M, Takata RI, Akiyama J, Passos-Bueno MR, Gentil V, Frota-Pessoa O, and Zatz M
- Subjects
- Adult, Child, Female, Genes, Recessive, Genetic Linkage, Humans, Male, Middle Aged, Muscular Dystrophies classification, Pregnancy, X Chromosome, Muscular Dystrophies genetics, Muscular Dystrophies physiopathology, Reproduction genetics
- Abstract
We had previously reported that patients affected with BMD have a significantly reduced reproductive performance (f = 0.12) as compared to male LGMD patients of similar age and physical impairment (f = 0.98). In the present study parameters such as the socio-economic level, as well as psychosocial, intellectual, and psychiatric functionings could not explain the low fitness of BMD patients. The effect of genetic counseling, a greater difficulty in coping with the disease, and relating to women and/or a potential malfunction of reproductive physiology are discussed as possible causes. more...
- Published
- 1995
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24. Intrafamilial variability in dystrophin abundance correlated with difference in the severity of the phenotype.
- Author
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Vainzof M, Passos-Bueno MR, Takata RI, Pavanello Rde C, and Zatz M
- Subjects
- Adolescent, Adult, Blotting, Western, Creatine Kinase metabolism, Cytoskeletal Proteins chemistry, Cytoskeletal Proteins metabolism, DNA analysis, Dystrophin chemistry, Dystrophin genetics, Family, Female, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Male, Muscles chemistry, Muscles pathology, Muscular Dystrophies genetics, Phenotype, Polymerase Chain Reaction, Utrophin, Dystrophin metabolism, Membrane Proteins, Muscular Dystrophies metabolism
- Abstract
In Duchenne muscular dystrophy, the progression of the disease is always severe and predictable, while in Becker dystrophy there is a wide variability (intra and inter familial) in the severity of the phenotype. We report here a family in which the proband, who is currently 15 years old, is showing a severe DMD progression, while his affected maternal uncle, aged 29, has a more benign course, compatible with BMD. No DNA deletion was detected in both patients. Dystrophin analysis through immunofluorescence and western blotting showed a negative pattern in the youngest patient and a positive one in the oldest. Apparently, this is the first report on intrafamilial variability in dystrophin abundance correlated with a difference in the severity of the phenotype. more...
- Published
- 1993
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25. Severe nonspecific X-linked mental retardation caused by a proximally Xp located gene: intragenic heterogeneity or a new form of X-linked mental retardation?
- Author
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Passos-Bueno MR, Byth BC, Rosenberg S, Takata RI, Bakker E, Beggs AH, Pavanello RC, Vainzof M, Davies KE, and Zatz M
- Subjects
- Adolescent, Adult, Child, Chromosome Mapping, Female, Genes, Recessive, Genetic Markers, Humans, Lod Score, Male, Middle Aged, Pedigree, Phenotype, Genetic Linkage, Intellectual Disability genetics, X Chromosome
- Abstract
X-linked mental retardation (XLMR) can be subdivided into syndromic and nonsyndromic or nonspecific. Patients with non-syndromal XLMR show no characteristic manifestations, biochemical defects, or distinct fragile sites. Nevertheless, nonspecific XLMR seems to be heterogeneous. To determine the number and location of the genes responsible for XLMR, linkage studies in large pedigrees have to be performed. Here we report the data of linkage analysis in a large Brazilian family with 7 patients affected by a severe form of XLMR, with no other associated malformations. All the obligate carriers are normal. A close linkage without recombination (lod scores 1.95 and 3.25) was found between the disease locus and polymorphic DNA loci DXS255 (Xp11.22), DXS14 (Xp11.21). These results suggest that the gene responsible for the disease in this family maps in the Xp11-cent of the X chromosome. Positive lod scores in this region have also been reported for other XLMR genealogies, but with a much milder phenotype. The possibility of intragenic or locus heterogeneity is discussed. more...
- Published
- 1993
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26. Is the maintainance of the C-terminus domain of dystrophin enough to ensure a milder Becker muscular dystrophy phenotype?
- Author
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Vainzof M, Takata RI, Passos-Bueno MR, Pavanello RC, and Zatz M
- Subjects
- Adolescent, Alleles, Blotting, Western, Child, Preschool, DNA genetics, Dystrophin analysis, Fluorescent Antibody Technique, Humans, Male, Muscles pathology, Muscular Dystrophies pathology, Phenotype, Polymerase Chain Reaction, Prognosis, Dystrophin genetics, Muscular Dystrophies genetics, Muscular Dystrophies physiopathology, Sequence Deletion, X Chromosome
- Abstract
The severe Duchenne muscular dystrophy (DMD) and the more benign Becker type (BMD) are allelic conditions, controlled by a defective gene at Xp21, caused by the absence (DMD) or a defect in quantity or quality (BMD) of the protein dystrophin. It has been suggested that the C-terminus domain of dystrophin is fundamental to ensure the proper protein sub-cellular localization and function. We wish to report our dystrophin findings in 4 among 142 DMD patients studied for DNA deletions and dystrophin analysis. Although they have a severe clinical course, a positive dystrophin immunofluorescence pattern was seen using C-terminal antibody, and a dystrophin band of reduced molecular weight (corresponding to their DNA deletions), but which maintained the C-terminus was seen through Western blot (WB). Based on these findings, we suggest that in order to partially maintain its function, resulting in a milder phenotype, dystrophin may carry large internal deletions but in addition to the C-terminus, the region encompassing both the N-terminus and the proximal region of the rod domain cannot be absent. Therefore, the prognosis of a Becker phenotype in a young patient should be done with caution if based only on the presence or not of dystrophin. more...
- Published
- 1993
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27. Different mosaicism frequencies for proximal and distal Duchenne muscular dystrophy (DMD) mutations indicate difference in etiology and recurrence risk.
- Author
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Passos-Bueno MR, Bakker E, Kneppers AL, Takata RI, Rapaport D, den Dunnen JT, Zatz M, and van Ommen GJ
- Subjects
- Blotting, Southern, Humans, Mosaicism, Muscular Dystrophies etiology, Polymerase Chain Reaction, Risk, Dystrophin genetics, Muscular Dystrophies genetics, Mutation genetics, Polymorphism, Genetic genetics
- Abstract
In about 65% of the cases of Duchenne muscular dystrophy (DMD) a partial gene deletion or duplication in the dystrophin gene can be detected. These mutations are clustered at two hot spots: 30% at the hot spot in the proximal part of the gene and about 70% at a more distal hot spot. Unexpectedly we observed a higher frequency of proximal gene rearrangements among proved "germ line" mosaic cases. Of the 24 mosaic cases we are aware of, 19 (79%) have a proximal mutation, while only 5 (21%) have a distal mutation. This finding indicates that the mutations at the two hot spots in the dystrophin gene differ in origin. Independent support for the different mosaicism frequency was found by comparing the mutation spectra observed in isolated cases of DMD and familial cases of DMD. In a large two-center study of 473 patients from Brazil and the Netherlands, we detected a significant difference in the deletion distribution of isolated (proximal:distal ratio 1:3) and familial cases (ratio 1:1). We conclude from these data that proximal deletions most likely occur early in embryonic development, causing them to have a higher chance of becoming familial, while distal deletions occur later and have a higher chance of causing only isolated cases. Finally, our findings have important consequences for the calculation of recurrence-risk estimates according to the site of the deletion: a "proximal" new mutant has an increased recurrence risk of approximately 30%, and a "distal" new mutant has a decreased recurrence risk of approximately 4%. more...
- Published
- 1992
28. A deletion including the brain promoter of the Duchenne muscular dystrophy gene is not associated with mental retardation.
- Author
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Rapaport D, Passos-Bueno MR, Takata RI, Campiotto S, Eggers S, Vainzof M, Makover A, Nudel U, Yaffe D, and Zatz M
- Subjects
- Adult, Dystrophin genetics, Genetic Testing, Humans, Male, Pedigree, Brain metabolism, Gene Deletion, Intellectual Disability genetics, Muscular Dystrophies genetics, Promoter Regions, Genetic genetics
- Abstract
A total of 161 unrelated Duchenne (DMD) and Becker muscular dystrophy (BMD) patients were screened for deletions in the brain promoter region of the dystrophin gene. Southern blot analysis using a probe for the brain promoter detected a deletion in this region in only one of the DMD families, in a patient with normal intelligence. This deletion also included the promoter of the muscle-type dystrophin and the exons encoding the actin-binding and part of the spectrin-like domains. Our data suggest that deletions in the brain promoter region are rare in DMD and are compatible with normal intelligence. more...
- Published
- 1992
- Full Text
- View/download PDF
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