23 results on '"Myopathies, Structural, Congenital genetics"'
Search Results
2. A case of congenital fiber-type disproportion syndrome presenting dilated cardiomyopathy with ACTA1 mutation.
- Author
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Matsumoto A, Tsuda H, Furui S, Kawada-Nagashima M, Anzai T, Seki M, Watanabe K, Muramatsu K, Osaka H, Iwamoto S, Nishino I, and Yamagata T
- Subjects
- Actins genetics, Actins metabolism, Humans, Mutation, Cardiomyopathy, Dilated complications, Cardiomyopathy, Dilated genetics, Myopathies, Nemaline genetics, Myopathies, Structural, Congenital genetics
- Abstract
Background: Actin, alpha, skeletal muscle 1 (ACTA1) is one of the causative genes of nemaline myopathy (NM) and congenital fiber-type disproportion (CFTD). CFTD is characterized by type 1 fiber atrophy and distinguished from NM in the absence of rods. Eight patients with CFTD, including one patient with dilated cardiomyopathy (DCM), have previously been reported. Herein, we report the case of a 10-year-old boy presenting with CFTD and DCM., Methods: We performed exome sequencing and analyzed the effect of Met327Lys mutations on cultured C2C12 muscle cells compared with that seen in the wild type (WT, ACTA1) and previously identified Asp294Val mutations associated with a severe phenotype of CFTD without cardiomyopathy., Results: Exome sequencing revealed a de novo mutation, c.980 T > A, p.(Met327Lys), in ACTA1 (NM_001100.4). C2C12 cells transfected with the WT plasmid expressed ACTA1 in the nucleus and cytoplasm. Cells with the Asp294Val mutant showed needle-like structures in the cytoplasm, whereas the expression of the Met327Lys mutant resulted in few aggregations but many apoptotic cells., Conclusion: Apoptosis induced in Met327Lys-transfected muscle cells supports the pathogenicity of the mutation and can be implicated as one of the histopathological features associated with CFTD, as in NM., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)
- Published
- 2022
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3. Hereditary myopathies associated with hematological abnormalities.
- Author
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Beecher G, Fleming MD, and Liewluck T
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- Child, Humans, Mutation, Anemia, Sideroblastic genetics, Anemia, Sideroblastic pathology, Lipid Metabolism, Inborn Errors, Mitochondrial Diseases, Mitochondrial Myopathies genetics, Myopathies, Structural, Congenital genetics
- Abstract
The diagnostic evaluation of a patient with suspected hereditary muscle disease can be challenging. Clinicians rely largely on clinical history and examination features, with additional serological, electrodiagnostic, radiologic, histopathologic, and genetic investigations assisting in definitive diagnosis. Hematological testing is inexpensive and widely available, but frequently overlooked in the hereditary myopathy evaluation. Hematological abnormalities are infrequently encountered in this setting; however, their presence provides a valuable clue, helps refine the differential diagnosis, tailors further investigation, and assists interpretation of variants of uncertain significance. A diverse spectrum of hematological abnormalities is associated with hereditary myopathies, including anemias, leukocyte abnormalities, and thrombocytopenia. Recurrent rhabdomyolysis in certain glycolytic enzymopathies co-occurs with hemolytic anemia, often chronic and mild in phosphofructokinase and phosphoglycerate kinase deficiencies, or acute and fever-associated in aldolase-A and triosephosphate isomerase deficiency. Sideroblastic anemia, commonly severe, accompanies congenital-to-childhood onset mitochondrial myopathies including Pearson marrow-pancreas syndrome and mitochondrial myopathy, lactic acidosis, and sideroblastic anemia phenotypes. Congenital megaloblastic macrocytic anemia and mitochondrial dysfunction characterize SFXN4-related myopathy. Neutropenia, chronic or cyclical, with recurrent infections, infantile-to-childhood onset skeletal myopathy and cardiomyopathy are typical of Barth syndrome, while chronic neutropenia without infection occurs rarely in DNM2-centronuclear myopathy. Peripheral eosinophilia may accompany eosinophilic inflammation in recessive calpainopathy. Lipid accumulation in leukocytes on peripheral blood smear (Jordans' anomaly) is pathognomonic for neutral lipid storage diseases. Mild thrombocytopenia occurs in autosomal dominant, childhood-onset STIM1 tubular aggregate myopathy, STIM1 and ORAI1 deficiency syndromes, and GNE myopathy. Herein, we review these hereditary myopathies in which hematological features play a prominent role., (© 2022 Wiley Periodicals LLC.)
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- 2022
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4. Expanding the clinical and genetic spectrum of pathogenic variants in STIM1.
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Ticci C, Cassandrini D, Rubegni A, Riva B, Vattemi G, Matà S, Ricci G, Baldacci J, Guglielmi V, Di Muzio A, Malandrini A, Tonin P, Siciliano G, Federico A, Genazzani AA, Santorelli FM, and Merlini L
- Subjects
- Calcium metabolism, Cross-Sectional Studies, Humans, Miosis genetics, Miosis metabolism, Miosis pathology, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Stromal Interaction Molecule 1 genetics, Stromal Interaction Molecule 1 metabolism, Blood Platelet Disorders genetics, Blood Platelet Disorders metabolism, Blood Platelet Disorders pathology, Myopathies, Structural, Congenital genetics
- Abstract
Introduction/aims: Stromal interaction molecule 1 (STIM1) is a reticular Ca
2+ sensor composed of a luminal and a cytosolic domain. Autosomal dominant mutations in STIM1 cause tubular aggregate myopathy and Stormorken syndrome or its variant York platelet syndrome. In this study we aimed to expand the features related to new variants in STIM1., Methods: We performed a cross-sectional study of individuals harboring monoallelic STIM1 variants recruited at five tertiary centers involved in a study of inherited myopathies analyzed with a multigene-targeted panel., Results: We identified seven individuals (age range, 26-57 years) harboring variants in STIM1, including five novel changes: three located in the EF-hand domain, one in the sterile α motif (SAM) domain, and one in the cytoplasmatic region of the protein. Functional evaluation of the pathogenic variants using a heterologous expression system and measuring store-operated calcium entry demonstrated their causative role and suggested a link of new variants with the clinical phenotype. Muscle contractures, found in three individuals, showed variability in body distribution and in the number of joints involved. Three patients showed cardiac and respiratory involvement. Short stature, hyposplenism, sensorineural hearing loss, hypothyroidism, and Gilbert syndrome were variably observed among the patients. Laboratory tests revealed hyperCKemia in six patients, thrombocytopenia in two patients, and hypocalcemia in one patient. Muscle biopsy showed the presence of tubular aggregates in three patients, type I fiber atrophy in one patient, and nonspecific myopathic changes in two patients., Discussion: Our clinical, histological, and molecular data expand the genetic and clinical spectrum of STIM1-related diseases., (© 2021 Wiley Periodicals LLC.)- Published
- 2021
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5. MYH2 myopathy, a new case expands the clinical and pathological spectrum of the recessive form.
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Telese R, Pagliarani S, Lerario A, Ciscato P, Fagiolari G, Cassandrini D, Grimoldi N, Conte G, Cinnante C, Santorelli FM, Comi GP, Sciacco M, and Peverelli L
- Subjects
- Adult, Genes, Recessive, Humans, Male, Muscle Fibers, Skeletal ultrastructure, Mutation, Myopathies, Structural, Congenital pathology, Myosin Heavy Chains metabolism, Vacuoles ultrastructure, Myopathies, Structural, Congenital genetics, Myosin Heavy Chains genetics, Phenotype
- Abstract
Background: Hereditary myosin myopathies are a group of rare muscle disorders, caused by mutations in genes encoding for skeletal myosin heavy chains (MyHCs). MyHCIIa is encoded by MYH2 and is expressed in fast type 2A and 2B muscle fibers. MYH2 mutations are responsible for an autosomal dominant (AD) progressive myopathy, characterized by the presence of rimmed vacuoles and by a reduction in the number and size of type 2A fibers, and a recessive early onset myopathy characterized by complete loss of type 2A fibers. Recently, a patient with a homozygous mutation but presenting a dominant phenotype has been reported., Methods: The patient was examined thoroughly and two muscle biopsies were performed through the years. NGS followed by confirmation in Sanger sequencing was used to identify the genetic cause., Results: We describe the second case presenting with late-onset ophthalmoparesis, ptosis, diffuse muscle weakness, and histopathological features typical for AD forms but with a recessive MYH2 genotype., Conclusion: This report contributes to expand the clinical and genetic spectrum of MYH2 myopathies and to increase the awareness of these very rare diseases., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)
- Published
- 2020
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6. Motor function performance in individuals with RYR1-related myopathies.
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Witherspoon JW, Vuillerot C, Vasavada RP, Waite MR, Shelton M, Chrismer IC, Jain MS, and Meilleur KG
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- Adolescent, Adult, Child, Disease Progression, Female, Humans, Male, Middle Aged, Myopathies, Structural, Congenital genetics, Myopathy, Central Core genetics, Myopathy, Central Core physiopathology, Ophthalmoplegia genetics, Ophthalmoplegia physiopathology, Ryanodine Receptor Calcium Release Channel deficiency, Young Adult, Movement physiology, Myopathies, Structural, Congenital physiopathology, Ryanodine Receptor Calcium Release Channel genetics
- Abstract
Introduction: The objective of this study was to obtain a 6-month natural history of motor function performance in individuals with RYR1- related myopathy (RYR1-RM) by using the Motor Function Measure-32 (MFM-32) and graded functional tests (GFT) while facilitating preparation for interventional trials., Methods: In total, 34 participants completed the MFM-32 and GFTs at baseline and 6-month visits., Results: Motor deficits according to MFM-32 were primarily observed in the standing and transfers domain (D1; mean 71%). Among the GFTs, participants required the most time to ascend/descend stairs (>7.5 s). Functional movement, determined by GFT grades, was strongly correlated with MFM-32 (D1; r ≥ 0.770, P < 0.001). Motor Function Measure-32 and GFT scores did not reflect any change in performance between baseline and 6-month visits., Discussion: The MFM-32 and GFTs detected motor impairment in RYR1-RM, which remained stable over 6 months. Thus, these measures may be suitable for assessing change in motor function in response to therapeutic intervention. Muscle Nerve 60: 80-87, 2019., (© 2019 The Authors. Muscle & Nerve published by Wiley Periodicals, Inc.)
- Published
- 2019
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7. Expanding the central nervous system disease spectrum associated with FLNC mutation.
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Previtali SC, Scarlato M, Vezzulli P, Ruggieri A, Velardo D, Benedetti S, Torini G, Colombo B, Maggi L, Di Bella D, Gellera C, D'Angelo G, and Mora M
- Subjects
- Adult, Ataxia, Atrophy, Cerebellar Ataxia diagnostic imaging, Cerebellar Ataxia physiopathology, Cerebellum diagnostic imaging, Cerebellum pathology, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Muscle, Skeletal ultrastructure, Myopathies, Structural, Congenital diagnostic imaging, Myopathies, Structural, Congenital pathology, Myopathies, Structural, Congenital physiopathology, Pedigree, Siblings, Spinal Cord diagnostic imaging, Spinal Cord pathology, Cerebellar Ataxia genetics, Filamins genetics, Muscle, Skeletal pathology, Myopathies, Structural, Congenital genetics
- Published
- 2019
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8. Three novel MTM1 pathogenic variants identified in Japanese patients with X-linked myotubular myopathy.
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Nishikawa A, Iida A, Hayashi S, Okubo M, Oya Y, Yamanaka G, Takahashi I, Nonaka I, Noguchi S, and Nishino I
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- Adolescent, Child, Hemizygote, Humans, Infant, Infant, Newborn, Male, Myopathies, Structural, Congenital pathology, Protein Tyrosine Phosphatases, Non-Receptor chemistry, Protein Tyrosine Phosphatases, Non-Receptor metabolism, Mutation, Missense, Myopathies, Structural, Congenital genetics, Protein Tyrosine Phosphatases, Non-Receptor genetics
- Abstract
Background: X-linked myotubular myopathy (XLMTM) is a form of the severest congenital muscle diseases characterized by marked muscle weakness, hypotonia, and feeding and breathing difficulties in male infants. It is caused by mutations in the myotubularin gene (MTM1)., Methods: Evaluation of clinical history and examination of muscle pathology of three patients and comprehensive genome analysis on our original targeted gene panel system for muscular diseases., Results: We report three patients, each of whom presents distinct muscle pathological features. The three patients have novel hemizygous MTM1 variants, including c.527A>G (p.Gln176Arg), c.595C>G (p.Pro199Ala), or c.688T>C (p.Trp230Arg)., Conclusions: All variants were assessed as "Class 4 (likely pathogenic)" on the basis of the guideline of American College of Medical Genetics and Genomics. These distinct pathological features among the patients with variants in the second cluster of PTP domain in MTM1 provides an insight into microheterogeneities in disease phenotypes in XLMTM., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)
- Published
- 2019
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9. Centronuclear myopathy with cardiomyopathy due to recessive titinopathy.
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Martinez-Thompson JM, Winder TL, and Liewluck T
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- Cardiomyopathies pathology, Female, Genes, Recessive genetics, Humans, Middle Aged, Muscle Weakness etiology, Muscle, Skeletal pathology, Myopathies, Structural, Congenital pathology, Pedigree, Cardiomyopathies genetics, Connectin genetics, Myopathies, Structural, Congenital genetics
- Published
- 2019
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10. Novel SPEG mutations in congenital myopathies: Genotype-phenotype correlations.
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Qualls AE, Donkervoort S, Herkert JC, D'gama AM, Bharucha-Goebel D, Collins J, Chao KR, Foley AR, Schoots MH, Jongbloed JDH, Bönnemann CG, and Agrawal PB
- Subjects
- Biopsy, Child, Child, Preschool, Consanguinity, Exome genetics, Female, Genetic Association Studies, Humans, Infant, Male, Muscle Weakness etiology, Muscle Weakness genetics, Muscle, Skeletal pathology, Mutation genetics, Sequence Analysis, Muscle Proteins genetics, Myopathies, Structural, Congenital congenital, Myopathies, Structural, Congenital genetics, Protein Serine-Threonine Kinases genetics
- Abstract
Introduction: Centronuclear myopathies (CNMs) are a subtype of congenital myopathies (CMs) characterized by muscle weakness, predominant type 1 fibers, and increased central nuclei. SPEG (striated preferentially expressed protein kinase) mutations have recently been identified in 7 CM patients (6 with CNMs). We report 2 additional patients with SPEG mutations expanding the phenotype and evaluate genotype-phenotype correlations associated with SPEG mutations., Methods: Using whole exome/genome sequencing in CM families, we identified novel recessive SPEG mutations in 2 patients., Results: Patient 1, with severe muscle weakness requiring respiratory support, dilated cardiomyopathy, ophthalmoplegia, and findings of nonspecific CM on muscle biopsy carried a homozygous SPEG mutation (p.Val3062del). Patient 2, with milder muscle weakness, ophthalmoplegia, and CNM carried compound heterozygous mutations (p.Leu728Argfs*82) and (p.Val2997Glyfs*52)., Conclusions: The 2 patients add insight into genotype-phenotype correlations of SPEG-associated CMs. Clinicians should consider evaluating a CM patient for SPEG mutations even in the absence of CNM features. Muscle Nerve 59:357-362, 2019., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2019
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11. Using exome sequencing to decipher family history in a healthy individual: Comparison of pathogenic and population MTM1 variants.
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Penon M, Zahed H, Berger V, Su I, and Shieh JT
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- Adult, Female, Humans, Male, Exome, High-Throughput Nucleotide Sequencing, Mutation, Missense, Myopathies, Structural, Congenital genetics, Pedigree, Protein Tyrosine Phosphatases, Non-Receptor genetics
- Abstract
Background: When a family encounters the loss of a child early in life, extensive genetic testing of the affected neonate is sometimes not performed or not possible. However, the increasing availability of genomic sequencing may allow for direct application to families in cases where there is a condition inherited from parental gene(s). When neonatal testing is not possible, it is feasible to perform family testing as long as there is optimal interpretation of the genomic information. Here, we present an example of a healthy adult woman with a history of recurrent male neonatal losses due to severe respiratory distress who presented to Medical Genetics for evaluation. A family history of additional male neonatal loss was present, suggesting a potential inherited genetic etiology., Methods: Although there was no DNA available from the neonates, by performing exome sequencing on the healthy adult woman, we found a missense variant in MTM1 as a potential candidate, which was deemed pathogenic based on multiple criteria including past report., Results: By performing an analysis of all known MTM1-disease associated mutations and control population variation, we can also better infer the effects of missense variations on MTM1, as not all variants are truncating. MTM1-X-linked myotubular myopathy is a condition that leads to male perinatal respiratory failure and a high risk for early mortality., Conclusions: The application of genetic testing in the healthy population here highlights the broader utility of genomic sequencing in evaluating unexplained recurrent neonatal loss, especially when genetic testing is not available on the affected neonates., (© 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)
- Published
- 2018
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12. Characterization of congenital myopathies at a Korean neuromuscular center.
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Park YE, Shin JH, Kim HS, Lee CH, and Kim DS
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- Adolescent, Adult, Age of Onset, Child, Child, Preschool, Dynamin II, Dynamins genetics, Female, Humans, Infant, Male, Muscle Fibers, Skeletal pathology, Muscle Proteins genetics, Mutation, Myopathies, Nemaline genetics, Myopathies, Nemaline pathology, Myopathies, Structural, Congenital congenital, Myopathies, Structural, Congenital genetics, Myopathies, Structural, Congenital pathology, Myopathy, Central Core congenital, Myopathy, Central Core genetics, Myopathy, Central Core pathology, Myotonia Congenita genetics, Republic of Korea, Retrospective Studies, Ryanodine Receptor Calcium Release Channel genetics, Treatment Outcome, Young Adult, Myotonia Congenita pathology
- Abstract
Introduction: Congenital myopathies are muscle diseases characterized by specific histopathologic features, generalized hypotonia from birth, and perinatal complications, although some cases develop during childhood or, rarely, in adulthood. We undertook this study to characterize congenital myopathies among patients registered at our institution., Methods: Clinical, histopathologic, and genetic features were evaluated in 34 patients recruited for this study., Results: The majority of patients experienced a childhood onset, and no disease-related mortality was recorded during follow-up. Functional outcomes were no better for those with late-onset disease, indicating later disease progression can be significant. Nemaline myopathy was the most frequent pathology, followed by central core disease and centronuclear myopathy. Among the 18 (54.5%) genetically confirmed patients, NEB and RYR1 mutations were the most common, followed by DNM2 mutations., Discussion: This study shows features not previously reported and suggests that congenital myopathy should be considered an important issue among adult patients. Muscle Nerve 58: 235-244, 2018., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
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13. Myofibrillar myopathy due to dominant LMNA mutations: A report of 2 cases.
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Dhawan PS, Liewluck T, Knapik J, and Milone M
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- Adult, Female, Humans, Male, Middle Aged, Muscle, Skeletal diagnostic imaging, Myopathies, Structural, Congenital diagnostic imaging, Tomography Scanners, X-Ray Computed, Lamin Type A genetics, Mutation genetics, Myopathies, Structural, Congenital genetics
- Published
- 2018
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14. An adult with a rare form of congenital fiber type disproportion.
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Anandan C and Milone M
- Subjects
- Female, Humans, Middle Aged, Muscle, Skeletal physiopathology, Mutation genetics, Myopathies, Structural, Congenital genetics, Myopathies, Structural, Congenital physiopathology, Tropomyosin genetics, Muscle, Skeletal pathology, Myopathies, Structural, Congenital pathology
- Published
- 2018
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15. Long-term effects of systemic gene therapy in a canine model of myotubular myopathy.
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Elverman M, Goddard MA, Mack D, Snyder JM, Lawlor MW, Meng H, Beggs AH, Buj-Bello A, Poulard K, Marsh AP, Grange RW, Kelly VE, and Childers MK
- Subjects
- Adenosine Triphosphatases metabolism, Animals, Dependovirus genetics, Disease Models, Animal, Dogs, Female, Gait Disorders, Neurologic etiology, Glucuronidase genetics, Glucuronidase metabolism, Humans, Longitudinal Studies, Microscopy, Electron, Muscle, Skeletal pathology, Muscle, Skeletal ultrastructure, Mutation genetics, Myopathies, Structural, Congenital complications, Myopathies, Structural, Congenital genetics, Myopathies, Structural, Congenital veterinary, NAD metabolism, Neurologic Examination, Protein Tyrosine Phosphatases, Non-Receptor genetics, Respiration Disorders etiology, Transduction, Genetic, Genetic Therapy, Myopathies, Structural, Congenital therapy, Protein Tyrosine Phosphatases, Non-Receptor therapeutic use
- Abstract
Introduction: X-linked myotubular myopathy (XLMTM), a devastating pediatric disease caused by the absence of the protein myotubularin, results from mutations in the MTM1 gene. While there is no cure for XLMTM, we previously reported effects of MTM1 gene therapy using adeno-associated virus (AAV) vector on muscle weakness and pathology in MTM1-mutant dogs. Here, we followed 2 AAV-infused dogs over 4 years., Methods: We evaluated gait, strength, respiration, neurological function, muscle pathology, AAV vector copy number (VCN), and transgene expression., Results: Four years following AAV-mediated gene therapy, gait, respiratory performance, neurological function and pathology in AAV-infused XLMTM dogs remained comparable to their healthy littermate controls despite a decline in VCN and muscle strength., Conclusions: AAV-mediated gene transfer of MTM1 in young XLMTM dogs results in long-term expression of myotubularin transgene with normal muscular performance and neurological function in the absence of muscle pathology. These findings support a clinical trial in patients. Muscle Nerve 56: 943-953, 2017., (© 2017 Wiley Periodicals, Inc.)
- Published
- 2017
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16. Adult-onset respiratory insufficiency, scoliosis, and distal joint hyperlaxity in patients with multiminicore disease due to novel Megf10 mutations.
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Liewluck T, Milone M, Tian X, Engel AG, Staff NP, and Wong LJ
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- Adult, Family Health, Female, Humans, Joint Instability complications, Myopathies, Structural, Congenital complications, Ophthalmoplegia complications, Respiratory Insufficiency complications, Ryanodine Receptor Calcium Release Channel genetics, Scoliosis complications, Joint Instability genetics, Membrane Proteins genetics, Mutation genetics, Myopathies, Structural, Congenital genetics, Ophthalmoplegia genetics, Respiratory Insufficiency genetics, Ryanodine Receptor Calcium Release Channel deficiency, Scoliosis genetics
- Abstract
Introduction: Multiminicore disease is a congenital myopathy characterized pathologically by the presence of multiple minicore structures in the sarcoplasm. Mutations in the selenoprotein N1-encoding gene (SEPN1) and ryanodine receptor 1-encoding gene (RYR1) are responsible for half of the reported cases. Mutations in multiple epidermal growth factor-like domains 10-encoding gene (MEGF10) have been identified only recently in a few patients with antenatal to infantile-onset myopathy, with and without minicore pathology., Methods: We report 2 sisters with adult-onset respiratory insufficiency followed by development of limb weakness. Both had scoliosis, distal joint hyperlaxity, and high-arched feet., Results: A biopsy of the right triceps muscle in 1 sister showed multiple minicore structures. She had electromyographic changes of myopathy with fibrillation potentials and myotonic discharges. Next generation sequencing identified novel compound heterozygous missense variants in MEGF10 c.230G>A (p.Arg77Gln) and c.1833T>G (p.Cys611Trp) in both sisters., Conclusions: MEGF10 mutations can cause myopathy with adult-onset respiratory insufficiency. Muscle Nerve, 2016 Muscle Nerve 53: 984-988, 2016., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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17. Muscle magnetic resonance imaging abnormalities in X-linked myopathy with excessive autophagy.
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Mercier S, Magot A, Caillon F, Isidor B, David A, Ferrer X, Vital A, Coquet M, Penttilä S, Udd B, Mussini JM, and Pereon Y
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- Adolescent, Adult, Biopsy, Humans, Magnetic Resonance Imaging, Male, Muscle, Skeletal ultrastructure, Mutation genetics, Myopathies, Structural, Congenital genetics, Vacuolar Proton-Translocating ATPases genetics, Autophagy, Muscle, Skeletal pathology, Myopathies, Structural, Congenital pathology
- Abstract
Introduction: X-linked myopathy with excessive autophagy (XMEA) is an X-linked recessive myopathy due to recently reported mutations in the VMA21 gene., Methods: Four men from 2 separate families were studied. The clinical presentation, genetic data, muscle biopsy, and muscle MRI were analyzed., Results: A known VMA21 mutation, c.163+4A>G, and a new mutation, c.163+3A>G, respectively, were found in the 2 families. The clinical course was characterized by onset in childhood and progressive muscle weakness with a limb-girdle pattern. Muscle biopsy revealed a mild myopathy with an increased number of giant autophagic vacuoles. Whole-body muscle MRI showed that pelvic girdle and proximal thighs were the most and earliest affected territories, with sparing of rectus femoris muscles. Muscle changes essentially consisted of degenerative fatty replacement., Conclusions: This study highlights a distinctive MRI pattern of muscle involvement, which can be helpful for diagnosis of XMEA, even before muscle biopsy or genetic analysis., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2015
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18. Muscle fiber type disproportion (FTD) in a family with mutations in the LMNA gene.
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Ruggiero L, Fiorillo C, Tessa A, Manganelli F, Iodice R, Dubbioso R, Vitale F, Storti E, Soscia E, Santorelli F, and Santoro L
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- Adult, Female, Humans, Male, Middle Aged, Myopathies, Structural, Congenital diagnosis, Pedigree, Phenotype, Genetic Predisposition to Disease genetics, Lamin Type A genetics, Muscle Fibers, Skeletal, Mutation genetics, Myopathies, Structural, Congenital genetics
- Abstract
Introduction: Mutations in the lamin A/C protein cause laminopathies, a heterogeneous group of disorders that include recessive axonal neuropathy (CMT2B1), Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), dilated cardiomyopathy with conduction defect, and different forms of lipodystrophy and progeria., Methods: We provide clinical, histopathological, muscle imaging, and cardiac features of a family with heterozygous mutation in the LMNA gene., Results: We identified heterozygous mutations (c.80C> T; pT27I) in the LMNA gene in 3 family members who had the LGMD phenotype with onset in their early thirties and cardiac conduction defects or dilated cardiomyopathy. Interestingly, muscle biopsies showed changes consistent with fiber type disproportion (FTD)., Conclusions: Fiber type disproportion has been reported only anecdotally in muscle biopsies of patients with LMNA mutations. Our report further supports this association and suggests inclusion of molecular testing for LMNA in the differential diagnosis of myopathies with FTD due to the risk for life threatening events., (© 2014 Wiley Periodicals, Inc.)
- Published
- 2015
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19. Respiratory assessment in centronuclear myopathies.
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Smith BK, Goddard M, and Childers MK
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- Animals, Disease Models, Animal, Humans, Muscle Weakness pathology, Muscle, Skeletal physiopathology, Myopathies, Structural, Congenital genetics, Respiration Disorders etiology, Respiration, Artificial, Myopathies, Structural, Congenital diagnosis, Myopathies, Structural, Congenital physiopathology, Respiratory Function Tests methods
- Abstract
The centronuclear myopathies (CNMs) are a group of inherited neuromuscular disorders classified as congenital myopathies. While several causative genes have been identified, some patients do not harbor any of the currently known mutations. These diverse disorders have common histological features, which include a high proportion of centrally nucleated muscle fibers, and clinical attributes of muscle weakness and respiratory insufficiency. Respiratory problems in CNMs may manifest initially during sleep, but daytime symptoms, ineffective airway clearance, and hypoventilation predominate as more severe respiratory muscle dysfunction evolves. Respiratory muscle capacity can be evaluated using a variety of clinical tests selected with consideration for the age and baseline motor function of the patient. Similar clinical tests of respiratory function can also be incorporated into preclinical CNM canine models to offer insight for clinical trials. Because respiratory problems account for significant morbidity in patients, routine assessments of respiratory muscle function are discussed., (© 2014 Wiley Periodicals, Inc.)
- Published
- 2014
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20. Congenital myasthenic syndrome and minicore-like myopathy with DOK7 mutation.
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Lorenzoni PJ, Scola RH, Kay CS, Lochmüller H, and Werneck LC
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- Child, Female, Humans, Myasthenic Syndromes, Congenital diagnosis, Myopathies, Structural, Congenital diagnosis, Ophthalmoplegia diagnosis, Ryanodine Receptor Calcium Release Channel deficiency, Ryanodine Receptor Calcium Release Channel genetics, Muscle Proteins genetics, Mutation genetics, Myasthenic Syndromes, Congenital genetics, Myopathies, Structural, Congenital genetics, Ophthalmoplegia genetics
- Published
- 2013
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21. Muscle function in a canine model of X-linked myotubular myopathy.
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Grange RW, Doering J, Mitchell E, Holder MN, Guan X, Goddard M, Tegeler C, Beggs AH, and Childers MK
- Subjects
- Animals, Disease Models, Animal, Dogs, Male, Mutation, Missense, Protein Tyrosine Phosphatases, Non-Receptor genetics, Muscle, Skeletal physiopathology, Myopathies, Structural, Congenital genetics, Myopathies, Structural, Congenital physiopathology, X Chromosome genetics
- Abstract
Introduction: We established a colony of dogs that harbor an X-linked MTM1 missense mutation.Muscle from affected male dogs exhibits reduction and altered localization of the MTM1 gene product, myotubularin, and provides a model analogous to X-linked myotubular myopathy (XLMTM)., Methods: We studied hindlimb muscle function in age-matched canine XLMTM genotypes between ages 9 and 18 weeks., Results: By the end of the study, affected dogs produce only ∼15% of the torque generated by normals or carriers (0.023 ± 0.005 vs. 0.152 ± 0.007 and 0.154 ± 0.003 N-m/kg body mass, respectively, P < 0.05) and are too weak to stand unassisted. At this age, XLMTM dogs also demonstrate an abnormally low twitch:tetanus ratio, a right-shifted torque-frequency relationship and an increase in torque during repetitive stimulation (P < 0.05)., Conclusions: We hypothesize that muscle weakness results from impaired excitation-contraction (E-C) coupling. Interventions that improve E-C coupling might be translated from the XLMTM dog model to patients., (Copyright © 2012 Wiley Periodicals, Inc.)
- Published
- 2012
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22. Desminopathies: good stuff lost, garbage gained, or the trashman misdirected?
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Hoffman EP
- Subjects
- Amino Acid Sequence genetics, Animals, Desmin genetics, Humans, Macromolecular Substances, Mice, Mice, Knockout abnormalities, Mice, Knockout genetics, Muscle Fibers, Skeletal pathology, Myopathies, Structural, Congenital metabolism, Myopathies, Structural, Congenital physiopathology, alpha-Crystallin B Chain genetics, alpha-Crystallin B Chain metabolism, Desmin deficiency, Muscle Fibers, Skeletal metabolism, Myopathies, Structural, Congenital genetics, Point Mutation genetics
- Published
- 2003
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23. Familial neuromuscular disease with tubular aggregates.
- Author
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Pierobon-Bormioli S, Armani M, Ringel SP, Angelini C, Vergani L, Betto R, and Salviati G
- Subjects
- Adolescent, Adult, Child, Electrophoresis, Polyacrylamide Gel methods, Female, Humans, Immunohistochemistry methods, Male, Microscopy, Electron, Transmission methods, Middle Aged, Muscle Proteins metabolism, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Muscle, Skeletal ultrastructure, Myopathies, Structural, Congenital genetics, Myopathies, Structural, Congenital metabolism, Myopathies, Structural, Congenital pathology, Myosins metabolism, Neuromuscular Diseases genetics, Neuromuscular Diseases metabolism, Neuromuscular Diseases pathology, Family Health, Myopathies, Structural, Congenital etiology, Neuromuscular Diseases complications
- Abstract
We have studied four members of a family in which five individuals of both sexes in three generations have mild weakness and muscle aching. Serum creatine kinase (CK) and/or aldolase were mildly to moderately elevated. Tubular aggregates were present in all patients in all fiber types. Type 1 fiber predominance and type 2 hypotrophy or atrophy was noted in three biopsies. Fiber splitting was prominent in two cases. Electron microscopic studies confirm that the tubular aggregates originate from muscle sarcoplasmic reticulum (SR). The presence of T tubules making contacts with some tubules inside the collection of tubular aggregates is suggestive of their derivation from terminal cisternae.
- Published
- 1985
- Full Text
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