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Phenotype-Genotype Analysis of Chinese Patients with Early-Onset LMNA-Related Muscular Dystrophy.

Tan D, Yang H, Yuan Y, Bonnemann C, Chang X, Wang S, Wu Y, Wu X, Xiong H - PLoS ONE (2015)

Bottom Line: Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD).Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD.Phenotype-genotype analysis determines that some mutations are well correlated with LMNA-related MD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric, Peking University First Hospital, Beijing, China; Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, China.

ABSTRACT
This study aimed to analyze the correlation between the phenotype and genotype of Chinese patients with early-onset lamin A (LMNA)-related muscular dystrophy (MD). The clinical and myopathological data of 21 Chinese pediatric patients with early-onset LMNA-related MD were collected and analyzed. LMNA gene mutation analysis was performed by direct sequencing of genomic DNA. Sublocalization of wild-type and mutant proteins were observed by immunofluorescence using cultured fibroblasts and human embryonic kidney 293 (HEK 293) cell. Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD). Four biopsy specimens from the L-CMD cases exhibited inflammatory changes. Abnormal nuclear morphology was observed with both transmission electron microscopy and lamin A/C staining. We identified 10 novel and nine known LMNA gene mutations in the 21 patients. Some mutations (c.91G>A, c.94_96delAAG, c.116A>G, c.745C>T, c.746G>A, and c.1580G>C) were well correlated with EDMD or L-CMD. LMNA-related MD has a common symptom triad of muscle weakness, joint contractures, and cardiac involvement, but the severity of symptoms and disease progression differ greatly. Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD. Phenotype-genotype analysis determines that some mutations are well correlated with LMNA-related MD.

No MeSH data available.


Related in: MedlinePlus

Muscle biopsy specimens stained with hematoxylin and eosin.(A) Normal control (×200). (B) Specimen from patient 11 exhibiting inflammatory cellular infiltration with necrotic and regenerative fibers (×200). (C) Specimen from patient 15 exhibiting mild nuclear transfer and regenerative fibers (×400).
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pone.0129699.g001: Muscle biopsy specimens stained with hematoxylin and eosin.(A) Normal control (×200). (B) Specimen from patient 11 exhibiting inflammatory cellular infiltration with necrotic and regenerative fibers (×200). (C) Specimen from patient 15 exhibiting mild nuclear transfer and regenerative fibers (×400).

Mentions: We performed muscle biopsy on 13 patients. In the L-CMD group, the muscle biopsies of patients 7, 9, 11, and 13 revealed inflammatory cell infiltration. Two biopsy specimens had dystrophic changes accompanied by inflammation. Two biopsy samples had inflammatory myopathy (Fig 1B), and two had mild myopathic changes (Fig 1C). The EDMD group had only dystrophic changes, observed as increased variation in fiber size and proliferation of connective tissue. We examined the muscle cell ultrastructure of 11 patients, finding focal or extended filament disruption, indistinct sarcomeres, many vacuoles in the muscle fibers, increased adipose and connective tissue, abnormal nuclear morphology with heterochromatin condensation, focal loss of nuclear membrane, accumulation of mitochondria around the nucleus, nuclear bands, and nucleolar holes (Fig 2). There was abnormal nuclear morphology in 10 patients.


Phenotype-Genotype Analysis of Chinese Patients with Early-Onset LMNA-Related Muscular Dystrophy.

Tan D, Yang H, Yuan Y, Bonnemann C, Chang X, Wang S, Wu Y, Wu X, Xiong H - PLoS ONE (2015)

Muscle biopsy specimens stained with hematoxylin and eosin.(A) Normal control (×200). (B) Specimen from patient 11 exhibiting inflammatory cellular infiltration with necrotic and regenerative fibers (×200). (C) Specimen from patient 15 exhibiting mild nuclear transfer and regenerative fibers (×400).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476780&req=5

pone.0129699.g001: Muscle biopsy specimens stained with hematoxylin and eosin.(A) Normal control (×200). (B) Specimen from patient 11 exhibiting inflammatory cellular infiltration with necrotic and regenerative fibers (×200). (C) Specimen from patient 15 exhibiting mild nuclear transfer and regenerative fibers (×400).
Mentions: We performed muscle biopsy on 13 patients. In the L-CMD group, the muscle biopsies of patients 7, 9, 11, and 13 revealed inflammatory cell infiltration. Two biopsy specimens had dystrophic changes accompanied by inflammation. Two biopsy samples had inflammatory myopathy (Fig 1B), and two had mild myopathic changes (Fig 1C). The EDMD group had only dystrophic changes, observed as increased variation in fiber size and proliferation of connective tissue. We examined the muscle cell ultrastructure of 11 patients, finding focal or extended filament disruption, indistinct sarcomeres, many vacuoles in the muscle fibers, increased adipose and connective tissue, abnormal nuclear morphology with heterochromatin condensation, focal loss of nuclear membrane, accumulation of mitochondria around the nucleus, nuclear bands, and nucleolar holes (Fig 2). There was abnormal nuclear morphology in 10 patients.

Bottom Line: Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD).Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD.Phenotype-genotype analysis determines that some mutations are well correlated with LMNA-related MD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric, Peking University First Hospital, Beijing, China; Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, China.

ABSTRACT
This study aimed to analyze the correlation between the phenotype and genotype of Chinese patients with early-onset lamin A (LMNA)-related muscular dystrophy (MD). The clinical and myopathological data of 21 Chinese pediatric patients with early-onset LMNA-related MD were collected and analyzed. LMNA gene mutation analysis was performed by direct sequencing of genomic DNA. Sublocalization of wild-type and mutant proteins were observed by immunofluorescence using cultured fibroblasts and human embryonic kidney 293 (HEK 293) cell. Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD). Four biopsy specimens from the L-CMD cases exhibited inflammatory changes. Abnormal nuclear morphology was observed with both transmission electron microscopy and lamin A/C staining. We identified 10 novel and nine known LMNA gene mutations in the 21 patients. Some mutations (c.91G>A, c.94_96delAAG, c.116A>G, c.745C>T, c.746G>A, and c.1580G>C) were well correlated with EDMD or L-CMD. LMNA-related MD has a common symptom triad of muscle weakness, joint contractures, and cardiac involvement, but the severity of symptoms and disease progression differ greatly. Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD. Phenotype-genotype analysis determines that some mutations are well correlated with LMNA-related MD.

No MeSH data available.


Related in: MedlinePlus