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Cardiac effects of the c.1583 C→G LMNA mutation in two families with Emery-Dreifuss muscular dystrophy.

Zhang L, Shen H, Zhao Z, Bing Q, Hu J - Mol Med Rep (2015)

Bottom Line: The three affected individuals exhibited a heterozygous missense mutation in the LMNA gene (c.1583 C→G), which caused a T528R amino acid change in the LMNA protein.In conclusion, the present study identified three patients with EDMD, exhibiting the same dominant LMNA mutation and presenting with a spectrum of severe cardiac abnormalities, including cardiac conduction system defects, cardiomyopathy and heart failure.As LMNA mutations have been associated with at least six clinical disorders, including EDMD, the results of the present study provide additional mutational and functional data, which may assist in further establishing LMNA mutational variation and disease pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Disorders, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China.

ABSTRACT
The present study aimed to examine and analyze cardiac involvement in two Emery‑Dreifuss muscular dystrophy (EDMD) pedigrees caused by the c.1583 C→G mutation of the lamin A/C gene (LMNA). The clinical and genetic characteristics of members of two families with EDMD were evaluated by performing neurological examinations, skeletal muscle biopsies, cardiac evaluations, including electrocardiography, 24 h Holter, ultrasound cardiography and 99TcM‑MIBI‑gated myocardiac perfusion imaging, and genomic DNA sequencing. Family history investigations revealed an autosomal dominant transmission pattern of the disease in Family 1 and a sporadic case in Family 2. The three affected patients exhibited typical clinical features of EDMD, including joint contractures, muscle weakness and cardiac involvement. Muscle histopathological investigation revealed dystrophic features. In addition, each affected individual exhibited either cardiac arrhythmia, which was evident as sinus tachycardia, atrial flutter or complete atrioventricular inhibition. Cardiac imaging revealed dilated cardiomyopathy in two of the individuals, one of whom was presented with heart failure. The second patient presented with no significant abnormalities in cardiac structure or function. The three affected individuals exhibited a heterozygous missense mutation in the LMNA gene (c.1583 C→G), which caused a T528R amino acid change in the LMNA protein. In conclusion, the present study identified three patients with EDMD, exhibiting the same dominant LMNA mutation and presenting with a spectrum of severe cardiac abnormalities, including cardiac conduction system defects, cardiomyopathy and heart failure. As LMNA mutations have been associated with at least six clinical disorders, including EDMD, the results of the present study provide additional mutational and functional data, which may assist in further establishing LMNA mutational variation and disease pathogenesis.

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Representative histopathological analysis of muscle biopsies from Patient 1 with Emery Dreifuss muscular dystrophy. (A) Hematoxylin and eosin staining revealed scattered muscle fiber degeneration, necrosis, regeneration and connective tissue proliferation. (B) Cytochrome c staining revealed decreased enzyme activity. (C) Staining of the ATP enzyme revealed type I fiber predominance. (D) Immunofluorescence staining using a monoclonal antibody against emerin demonstrated a normal muscle fiber nuclear membrane. (E) Immunofluorescence staining using a monoclonal antibody against lamin A/C revealed a normal muscle fiber nuclear membrane. (F) Merged immunofluorescence staining using monoclonal antibodies against emerin and lamin A/C demonstrated normal labeling along the muscle fiber nuclear membrane. Magnification, ×40.
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f3-mmr-12-04-5065: Representative histopathological analysis of muscle biopsies from Patient 1 with Emery Dreifuss muscular dystrophy. (A) Hematoxylin and eosin staining revealed scattered muscle fiber degeneration, necrosis, regeneration and connective tissue proliferation. (B) Cytochrome c staining revealed decreased enzyme activity. (C) Staining of the ATP enzyme revealed type I fiber predominance. (D) Immunofluorescence staining using a monoclonal antibody against emerin demonstrated a normal muscle fiber nuclear membrane. (E) Immunofluorescence staining using a monoclonal antibody against lamin A/C revealed a normal muscle fiber nuclear membrane. (F) Merged immunofluorescence staining using monoclonal antibodies against emerin and lamin A/C demonstrated normal labeling along the muscle fiber nuclear membrane. Magnification, ×40.

Mentions: Routine histological analysis revealed dystrophic features in the muscle tissues, with degeneration, polyfocal necrosis, fiber splitting and moderate to marked fibrosis. Adipose tissue infiltration was also observed. In addition, atrophic and scattered regenerating fibers were noted. The ATP enzyme staining revealed a predominance of type I fibers. Immunofluorescence staining for emerin and lamin A/C revealed normal labeling along the membrane in all three cases (Fig. 3).


Cardiac effects of the c.1583 C→G LMNA mutation in two families with Emery-Dreifuss muscular dystrophy.

Zhang L, Shen H, Zhao Z, Bing Q, Hu J - Mol Med Rep (2015)

Representative histopathological analysis of muscle biopsies from Patient 1 with Emery Dreifuss muscular dystrophy. (A) Hematoxylin and eosin staining revealed scattered muscle fiber degeneration, necrosis, regeneration and connective tissue proliferation. (B) Cytochrome c staining revealed decreased enzyme activity. (C) Staining of the ATP enzyme revealed type I fiber predominance. (D) Immunofluorescence staining using a monoclonal antibody against emerin demonstrated a normal muscle fiber nuclear membrane. (E) Immunofluorescence staining using a monoclonal antibody against lamin A/C revealed a normal muscle fiber nuclear membrane. (F) Merged immunofluorescence staining using monoclonal antibodies against emerin and lamin A/C demonstrated normal labeling along the muscle fiber nuclear membrane. Magnification, ×40.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581790&req=5

f3-mmr-12-04-5065: Representative histopathological analysis of muscle biopsies from Patient 1 with Emery Dreifuss muscular dystrophy. (A) Hematoxylin and eosin staining revealed scattered muscle fiber degeneration, necrosis, regeneration and connective tissue proliferation. (B) Cytochrome c staining revealed decreased enzyme activity. (C) Staining of the ATP enzyme revealed type I fiber predominance. (D) Immunofluorescence staining using a monoclonal antibody against emerin demonstrated a normal muscle fiber nuclear membrane. (E) Immunofluorescence staining using a monoclonal antibody against lamin A/C revealed a normal muscle fiber nuclear membrane. (F) Merged immunofluorescence staining using monoclonal antibodies against emerin and lamin A/C demonstrated normal labeling along the muscle fiber nuclear membrane. Magnification, ×40.
Mentions: Routine histological analysis revealed dystrophic features in the muscle tissues, with degeneration, polyfocal necrosis, fiber splitting and moderate to marked fibrosis. Adipose tissue infiltration was also observed. In addition, atrophic and scattered regenerating fibers were noted. The ATP enzyme staining revealed a predominance of type I fibers. Immunofluorescence staining for emerin and lamin A/C revealed normal labeling along the membrane in all three cases (Fig. 3).

Bottom Line: The three affected individuals exhibited a heterozygous missense mutation in the LMNA gene (c.1583 C→G), which caused a T528R amino acid change in the LMNA protein.In conclusion, the present study identified three patients with EDMD, exhibiting the same dominant LMNA mutation and presenting with a spectrum of severe cardiac abnormalities, including cardiac conduction system defects, cardiomyopathy and heart failure.As LMNA mutations have been associated with at least six clinical disorders, including EDMD, the results of the present study provide additional mutational and functional data, which may assist in further establishing LMNA mutational variation and disease pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Disorders, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China.

ABSTRACT
The present study aimed to examine and analyze cardiac involvement in two Emery‑Dreifuss muscular dystrophy (EDMD) pedigrees caused by the c.1583 C→G mutation of the lamin A/C gene (LMNA). The clinical and genetic characteristics of members of two families with EDMD were evaluated by performing neurological examinations, skeletal muscle biopsies, cardiac evaluations, including electrocardiography, 24 h Holter, ultrasound cardiography and 99TcM‑MIBI‑gated myocardiac perfusion imaging, and genomic DNA sequencing. Family history investigations revealed an autosomal dominant transmission pattern of the disease in Family 1 and a sporadic case in Family 2. The three affected patients exhibited typical clinical features of EDMD, including joint contractures, muscle weakness and cardiac involvement. Muscle histopathological investigation revealed dystrophic features. In addition, each affected individual exhibited either cardiac arrhythmia, which was evident as sinus tachycardia, atrial flutter or complete atrioventricular inhibition. Cardiac imaging revealed dilated cardiomyopathy in two of the individuals, one of whom was presented with heart failure. The second patient presented with no significant abnormalities in cardiac structure or function. The three affected individuals exhibited a heterozygous missense mutation in the LMNA gene (c.1583 C→G), which caused a T528R amino acid change in the LMNA protein. In conclusion, the present study identified three patients with EDMD, exhibiting the same dominant LMNA mutation and presenting with a spectrum of severe cardiac abnormalities, including cardiac conduction system defects, cardiomyopathy and heart failure. As LMNA mutations have been associated with at least six clinical disorders, including EDMD, the results of the present study provide additional mutational and functional data, which may assist in further establishing LMNA mutational variation and disease pathogenesis.

Show MeSH
Related in: MedlinePlus