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Andreia M Nunes, Ryan D Wuebbles, Apurva Sarathy, Tatiana M Fontelonga, Marianne Deries, Dean J Burkin, Sólveig Thorsteinsdóttir
Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a dramatic neuromuscular disease in which crippling muscle weakness is evident from birth. Here we use the dyW mouse model for human MDC1A to trace the onset of the disease during development in utero. We find that myotomal and primary myogenesis proceed normally in homozygous dyW-/-embryos. Fetal dyW-/-muscles display the same number of myofibers as wildtype muscles, but by E18.5 dyW-/-muscles are significantly smaller and muscle size is not recovered post-natally...
March 7, 2017: Human Molecular Genetics
Sarah J Smith, Jeffrey C Wang, Vandana A Gupta, James J Dowling
Merosin deficient congenital muscular dystrophy (MDC1A) is a severe neuromuscular disorder with onset in infancy that is associated with severe morbidities (particularly wheelchair dependence) and early mortality. It is caused by recessive mutations in the LAMA2 gene that encodes a subunit of the extracellular matrix protein laminin 211. At present, there are no treatments for this disabling disease. The zebrafish has emerged as a powerful model system for the identification of novel therapies. However, drug discovery in the zebrafish is largely dependent on the identification of phenotypes suitable for chemical screening...
2017: PloS One
Wen-Chen Liang, Xia Tian, Chung-Yee Yuo, Wan-Zi Chen, Tsu-Min Kan, Yi-Ning Su, Ichizo Nishino, Lee-Jun C Wong, Yuh-Jyh Jong
PURPOSE: Congenital muscular dystrophy (CMD) is a heterogeneous disease entity. The detailed clinical manifestation and causative gene for each subgroup of CMD are quite variable. This study aims to analyze the phenotypes and genotypes of Taiwanese patients with CMD as the epidemiology of CMD varies among populations and has been scantly described in Asia. METHODS: A total of 48 patients suspected to have CMD were screened and categorized by histochemistry and immunohistochemistry studies...
2017: PloS One
Aanchal Kakkar, Madhu Rajeshwari, Aasma Nalwa, Vaishali Suri, Chitra Sarkar, Biswaroop Chakrabarty, Sheffali Gulati, Mehar C Sharma
INTRODUCTION: Macrophagic myofasciitis (MMF) is a rare disorder, reported mainly in European adults, with occasional childhood cases. We report a series of 6 patients with pediatric MMF from the Indian subcontinent. METHODS: Clinical details, creatine kinase levels, and results of electromyography are described for patients diagnosed with MMF. Fresh-frozen and formalin-fixed muscle biopsies were evaluated by hematoxylin-eosin staining, histochemistry, immunohistochemistry, and electron microscopy...
November 11, 2016: Muscle & Nerve
Teuta Domi, Emanuela Porrello, Daniele Velardo, Alessia Capotondo, Alessandra Biffi, Rossana Tonlorenzi, Stefano Amadio, Alessandro Ambrosi, Yuko Miyagoe-Suzuki, Shin'ichi Takeda, Markus A Ruegg, Stefano Carlo Previtali
BACKGROUND: Merosin-deficient congenital muscular dystrophy type-1A (MDC1A) is characterized by progressive muscular dystrophy and dysmyelinating neuropathy caused by mutations of the α2 chain of laminin-211, the predominant laminin isoform of muscles and nerves. MDC1A has no available treatment so far, although preclinical studies showed amelioration of the disease by the overexpression of miniagrin (MAG). MAG reconnects orphan laminin-211 receptors to other laminin isoforms available in the extracellular matrix of MDC1A mice...
2015: Skeletal Muscle
Clinton Turner, Rachael Mein, Cynthia Sharpe, Donald R Love
Merosin deficient congenital muscular dystrophy (MDC1A) is an autosomal recessive disorder characterized by mutations in the LAMA2 gene at chromosome 6q22-23. This gene spans 65 exons and encodes the α2 chain subunit of laminin-2. A variety of deletions, missense, nonsense and splice site mutations have been described in the LAMA2 gene, with resultant MDC1A. We describe a novel LAMA2 homozygous sequence variant in a Samoan patient with MDC1A and confirm its pathogenic effect with merosin immunohistochemistry on skeletal muscle biopsy...
December 2015: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
Aneek Das Bhowmik, Ashwin B Dalal, Divya Matta, C Sundaram, Shagun Aggarwal
No abstract text is available yet for this article.
April 2016: Indian Journal of Pediatrics
Tuomas Komulainen, Milla-Riikka Hautakangas, Reetta Hinttala, Salla Pakanen, Vesa Vähäsarja, Petri Lehenkari, Päivi Olsen, Päivi Vieira, Outi Saarenpää-Heikkilä, Johanna Palmio, Hannu Tuominen, Pietari Kinnunen, Kari Majamaa, Heikki Rantala, Johanna Uusimaa
OBJECTIVE: To study the clinical manifestations and occurrence of mtDNA depletion and deletions in paediatric patients with neuromuscular diseases and to identify novel clinical phenotypes associated with mtDNA depletion or deletions. METHODS: Muscle DNA samples from patients presenting with undefined encephalomyopathies or myopathies were analysed for mtDNA content by quantitative real-time PCR and for deletions by long-range PCR. Direct sequencing of mtDNA maintenance genes and whole-exome sequencing were used to study the genetic aetiologies of the diseases...
2015: JIMD Reports
Yun Yang, Bing Mao, Lixia Wang, Liangwei Mao, Aifen Zhou, Jiangxia Cao, Jiasheng Hu, Yan Zhou, Yanhong Pan, Xiaoming Wei, Shuang Yang, Feng Mu, Zhisheng Liu
Mutations in the LAMA2 gene cause laminin α‑2 (merosin)‑deficient congenital muscular dystrophies, which are autosomal recessive muscle disorders. Laminin α‑2 is widely expressed in the basement membrane of skeletal muscle, the myotendinous junctions and extra‑synaptically at neuromuscular synapses. In the present study, target next‑generation sequencing was used for mutation detection, and polymerase chain reaction (PCR) analysis and Sanger sequencing were used in the identification of small deletions...
May 2015: Molecular Medicine Reports
Raissa Coelho Andrade, Julián Nevado, Maria Angélica de Faria Domingues de Lima, Tânia Saad, Lucia Moraes, Leila Chimelli, Pablo Lapunzina, Fernando Regla Vargas
Segmental uniparental isodisomy (iUPD) is a rare genetic event that may cause aberrant expression of imprinted genes, and reduction to homozygosity of a recessive mutation. Transient neonatal diabetes mellitus (TNDM) is typically caused by imprinting aberrations in chromosome 6q24 TNDM differentially-methylated region (DMR). Approximately, 15.12 Mb upstream in 6q22-q23 is located LAMA2, the gene responsible of merosin-deficient congenital muscular dystrophy type 1A (MDC1A). We investigated a patient diagnosed both with TNDM and MDC1A, born from a twin dichorionic discordant pregnancy...
November 2014: American Journal of Medical Genetics. Part A
Heather R Gilbreath, Diana Castro, Susan T Iannaccone
The congenital muscular dystrophies (CMD) and myopathies (CM) are a diverse group of diseases that share features such as early onset of symptoms (in the first year of life), genetic causes, and high risks for restrictive lung disease and orthopedic deformities. Understanding for disease mechanism is available and a fairly well-structured genotype-phenotype correlation for all the CMDs and CMs is now available. To best illustrate the clinical spectrum and diagnostic algorithm for these diseases, this article presents 5 cases, including Ullrich congenital muscular dystrophy, nemaline myopathy, centronuclear myopathy, merosin deficiency congenital muscular dystrophy, and core myopathy...
August 2014: Neurologic Clinics
Sophelia H S Chan, A Reghan Foley, Rahul Phadke, Ann Agnes Mathew, Matthew Pitt, Caroline Sewry, Francesco Muntoni
We report an eleven year old girl with early motor difficulties initially diagnosed with a peripheral neuropathy in another hospital based on abnormal electrophysiological findings. Our clinical assessment did not highlight obvious clinical features supporting a peripheral neuropathy but evidence of mild proximal weakness. Electrophysiological studies performed at our hospital revealed evidence of a sensorimotor demyelinating polyneuropathy with possible axonal involvement. Brain magnetic resonance imaging (MRI) revealed subtle white matter signal abnormalities, interpreted as nonspecific...
August 2014: Neuromuscular Disorders: NMD
Hyo Jeong Kim, Young-Chul Choi, Hyung Jun Park, Young-Mock Lee, Heung Dong Kim, Joon Soo Lee, Hoon-Chul Kang
Congenital muscular dystrophy type 1A (MDC1A) is an autosomal recessive disorder characterized by hypotonia, elevated serum creatine kinase level, delayed motor milestones, white matter changes observed by brain magnetic resonance imaging, and normal intelligence. A mutation in the laminin α2 (LAMA2) gene, located at 6q22-23, is a genetic cause of MDC1A. Patients have merosin (laminin α2)-deficient skeletal muscles. However, the degree of merosin expression ranges from total absence to partial reduction. Patients with residual merosin expression have more variable and milder phenotypes than those with absolute merosin deficiency...
March 2014: Korean Journal of Pediatrics
María Fernanda Montenegro, María Teresa Moral-Naranjo, Francisco J Campoy, Encarnación Muñoz-Delgado, Cecilio J Vidal
Alkaline phosphatase (AP) and other proteins add glycosylphosphatidylinositol (GPI) before addressing to raft domains of the cell membrane. Our previous report showing an increased density of lipid rafts in muscle of dystrophic Lama2dy mice prompted us to compare livers of normal (NL) and dystrophic mice (DL) for their levels of rafts. With this aim, hepatic rafts were isolated as Triton X-100 resistant membranes, and identified by their abundance of flotillin-2, alkaline phosphatase (AP) and other raft markers...
June 5, 2014: Chemico-biological Interactions
Yalda Nilipor, Fakhredin Shariatmadari, Fatemeh Abdollah Gorji, Mohsen Rouzrokh, Mohamad Ghofrani, Parvaneh Karimzadeh, Moahammad Mehdi Taghdiri, Hosein Delavarkasmaei, Farzad Ahmadabadi, Mohammad Kazem Bakhshandeh Bali, Hamid Nemati, Sasan Saket, Narges Jafari, Omid Yaghini, Seyed Hasan Tonekaboni
OBJECTIVE: Muscle biopsy is a very important diagnostic test in the investigation of a child with suspected neuromuscular disorder. The goal of this study was to review and evaluate pediatric muscle biopsies during a 2-year period with focus on histopathology diagnosis and correlations with other paraclinic studies. MATERIALS & METHODS: We investigated 100 muscle biopsies belonging to patients with clinical impression of neuromuscular disorder. These patients have been visited consecutively by pediatric neurologists during 2010 to 2012...
2013: Iranian Journal of Child Neurology
Sandeep Kumar, Shrikiran Aroor, Suneel Mundkur, Maneesh Kumar
A 6-year-old boy born by a third-degree consanguineous marriage presented with progressive muscle weakness and delayed motor milestones noticed in early infancy with preserved language and social milestones. Examination revealed generalised hypotonia and hyporeflexia. Baseline haematological and biochemical investigations were normal except for mildly elevated creatine kinase. Provisional diagnosis of congenital myopathy was entertained. We performed brain imaging to look for abnormalities associated with congenital muscular dystrophy even though there were only features of myopathy with normal mentation...
2014: BMJ Case Reports
Anja von Renesse, Mina V Petkova, Susanne Lützkendorf, Jan Heinemeyer, Esther Gill, Christoph Hübner, Arpad von Moers, Werner Stenzel, Markus Schuelke
BACKGROUND: Congenital muscular dystrophies (CMD) with hypoglycosylation of α-dystroglycan are clinically and genetically heterogeneous disorders that are often associated with brain malformations and eye defects. Presently, 16 proteins are known whose dysfunction impedes glycosylation of α-dystroglycan and leads to secondary dystroglycanopathy. OBJECTIVE: To identify the cause of CMD with secondary merosin deficiency, hypomyelination and intellectual disability in two siblings from a consanguineous family...
April 2014: Journal of Medical Genetics
Madhu Nagappa, Nalini Atchayaram, Gayathri Narayanappa
BACKGROUND: Although congenital muscular dystrophies (CMD) is a common condition among primary muscle disorders, there are only a few small series reported from India. AIMS, SETTINGS, AND DESIGN: Retrospective analysis to characterize histopathologically and/or immunohistochemically confirmed cases of CMD. MATERIALS AND METHODS: Patients were identified retrospectively from the archived muscle biopsy reports between 1997 and 2007 at the Department of Neuropathology of the institute...
September 2013: Neurology India
Zhanwen He, Xiangyang Luo, Liyang Liang, Pinggan Li, Dongfang Li, Meng Zhe
The aim of this study was to characterize the clinical and genetic features of a 4-year-old female with merosin-deficient congenital muscular dystrophy type 1A (MDC1A). MDC1A is the most common form of congenital muscular dystrophy. MDC1A is caused by mutation of the laminin α-2 gene (LAMA2), localized to chromosome 6q22-23. Clinical presentation, as well as the results of neuro-imaging, electrophysiology and molecular genetic tests were used to evaluate a patient with MDC1A. The patient exhibited severe hypotonia and marked proximal weakness at 6 months of age, as well as delayed developmental milestones...
November 2013: Experimental and Therapeutic Medicine
Pam M Van Ry, Priscilla Minogue, Bradley L Hodges, Dean J Burkin
Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a severe and fatal muscle-wasting disease with no cure. MDC1A patients and the dy(W-/-) mouse model exhibit severe muscle weakness, demyelinating neuropathy, failed muscle regeneration and premature death. We have recently shown that laminin-111, a form of laminin found in embryonic skeletal muscle, can substitute for the loss of laminin-211/221 and prevent muscle disease progression in the dy(W-/-) mouse model. What is unclear from these studies is whether laminin-111 can restore failed regeneration to laminin-α2-deficient muscle...
January 15, 2014: Human Molecular Genetics
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