What is Centronuclear Myopathy?

Myopathy is a general medical term used to describe a group of disorders that affect skeletal muscle fibers, leading to muscle weakness. Centronuclear myopathies (CNM) are a group of rare and congenital myopathies that are characterized by abnormally located cell nuclei in skeletal muscle cells.

muscle tissueImage Credit: nobeastsofierce / Shutterstock.com

In healthy muscle tissue, nuclei are located on the periphery of muscle fibers, whereas in CNM nuclei are found in the center. As with other forms of myopathy, clinical features of CNM include muscle weakness, stiffness and cramps, but can vary significantly in terms of severity across individuals. Some individuals experience only mild disturbance whilst others can develop life-limiting symptoms.

Symptom onset can range from birth to early adulthood, with progressive muscle weakness resulting in developmental delays to motor skills, or later difficulties walking. Although some patients will remain mobile throughout their lives, others will require wheelchair assistance as muscle weakness progresses.

What are the different forms of centronuclear myopathy?

Three distinct forms of centronuclear myopathy have been described, and are identified via their pattern of inheritance and genetic mutation:

X-linked centronuclear myopathy

Also referred to as myotubular myopathy, X-linked CNM (XLMTM) is the most comment and most severe form of CNM. It is caused by mutations to the MTM1 gene which leads to faulty or insufficient production of the protein myotubularin, thought to be critical in the development and maintenance of healthy muscle tissue.

Approximately 80% of cases present with severe XLMTM, where muscle weakness is profound. Most patients fail to ever become ambulatory. A common feature is respiratory distress, with some affected patients requiring 24-hour ventilation. Approximately 25% of people with severe XLMTM die within the first year of life, and survival into adulthood is rare. Usually evident from birth or during pregnancy, infants with XLMTM present with severe hypotonia and difficulties feeding and swallowing.

Males with moderate XLMTM will have similar symptomology to those with the severe type but require fewer periods of ventilation, may achieve the ability to walk and may survive into adulthood. Those with mild XLMTM may only develop symptoms in adulthood.

XLMTM is caused by a mutation on the X chromosome, meaning that females with the gene change on one X-chromosome carry the disorder with a 50% risk of it passing to offspring, with female offspring becoming carriers and male offspring developing the disorder.

Autosomal dominant centronuclear myopathy

Autosomal dominance is a term used to describe a pattern of inheritance that is characteristic of certain genetic disorders. If a disease mutation is ‘dominant’ then only a single copy (i.e. from one parent only) is needed to develop the disorder. This contrasts with a recessive mutation whereby two copies are required to develop the disease. ‘Autosomal’ denotes that the mutation exists on a numbered, rather than sex chromosome.

Generally accepted as less severe than XLMTM, the onset of autosomal dominant CNM is varied and can be evident from birth or become apparent during adolescence or early adulthood. Mutations are observed in the dynamin 2 producing DNMN2 gene.

DNM2 mutations enhance the activity of dynamin 2, affecting the formation of cell vesicles during endocytosis and leading to disorganization of structures within muscle fibers. These structures are known as transverse tubules and are responsible for the contraction and relaxation of muscles. Abnormalities of the tubules lead to the muscle weakness characteristic of CNM.

Autosomal recessive centronuclear myopathy

Autosomal recessive CNM varies widely in severity, with onset during infancy or very early childhood. Weakness in facial and eye muscles are common, as are weaknesses in the axial and proximal muscles.

Prevalence is unknown but exceedingly rare as it requires both sets of parents to pass copies of the implicated mutated genes to their offspring. Autosomal recessive CNM has been associated with mutations in the BIN1 and RYR1 genes.

The BIN1 gene encodes several isoforms of myc box-dependent interacting protein 1 (also referred to as amphiphysin 2 and bridging integer 1). BIN1 isoforms which are expressed in muscular tissue locate on transverse tubules, with mutations leading to disorganization of tubules with resultant muscle weakness.

The RYR1 gene encodes the production of RYR1 receptors, which are found within the sarcoplasmic reticulum, a specific type of transverse tubule. The main function of RYR1 receptors is to regulate the flow of calcium in skeletal muscle cells, with a reduction or dysfunction of receptors causing abnormalities in muscle contractions.

physiotherapyImage Credit: By Dmytro Zinkevych / Shutterstock.com

Standard therapies for centronuclear myopathy

Currently, as there is no cure or specific treatment for centronuclear myopathy, therapies are aimed at the active management of symptoms. Guidelines for effective management have been developed and include:

  • Regular monitoring of respiration at all severity levels, with bi-pap or invasive ventilation support as required,
  • Support for feeding and swallowing by insertion of a gastronomy,
  • Physiotherapy to prevent contractures and maintain breathing capacity, with respiratory physiotherapy in the form of airway clearance.
  • Treatment of chest infections with antibiotics as required.


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Last Updated: Jan 11, 2021

Clare Knight

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Clare Knight

Since graduating from the University of Cardiff, Wales with first-class honors in Applied Psychology (BSc) in 2004, Clare has gained more than 15 years of experience in conducting and disseminating social justice and applied healthcare research.


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