Clinical features and therapeutic strategies for managing the striated muscle laminopathies

ABSTRACT

Introduction: Laminopathies are a diverse and complex group of rare genetic conditions due to mutations in A-type lamins gene (LMNA). Striated muscle laminopathies (SML) are the most frequent type of laminopathies that affect skeletal and/or cardiac muscle, with cardiac disease being the major cause of death of SML patients. There is currently no specific treatment to prevent or slow down the disease progression of SML.

Areas covered: Remarkable progress has been made in the description of the clinical and genetic spectrum of SML since the first described LMNA mutation seventeen years ago, that had allowed first deciphering of the cardiac disease mechanisms and identification of therapeutic targets. This review will provide the current status of the clinical features and standards of care of SML as well as the therapeutic strategies under development for a better and specific management of the cardiac involvement of SML.

Expert opinion: Current treatment of SML is not targeted and relies on approaches considered standard for any form of dilated cardiomyopathy. Research on pathophysiology with mouse models has been extremely helpful in deciphering critical mechanisms and for proposing potential innovative pharmacological therapies. Still, it appears necessary to have a better grasp on the pathogenesis to develop and propose the first targeted treatment for SML patients and to successfully move from bench to bed.

KEYWORDS:

• LMNA gene
• lamin A/C
• cardiomyopathy
• laminopathy
• Emery-Dreifuss muscular dystrophy
• limb-girdle muscular dystrophy type 1B
• LMNA-related congenital muscular dystrophy
• dilated cardiomyopathy with conduction system disease

Article highlights

• Striated muscle laminopathies (SML) are due to mutations in the LMNA gene encoding A-type lamins.

• SML encompass a wide range of skeletal and cardiac diseases.

• Skeletal muscle involvement of SML may be highly disabling.

• The main concerns for SML are cardiac and respiratory involvements.

• Stress activated signaling is a potential therapeutic target for SML.

This box summarizes key points contained in the article.

Declaration of interest

This work was financially supported by the Institut National de la Santé et de la Recherche Médicale; the Université Pierre et Marie Curie Paris 06, the Centre National de la Recherche Scientifique, the Association Française contre les Myopathies, the Deutsche Forschungsgemeinschaft and the Université Franco-Allemande (as part of the MyoGrad International Graduate School for Myology GK 1631/1 and CDFA-06-11). C Macquart received an UPMC-sponsored MyoGrad PhD fellowship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.