Introduction

Centronuclear myopathy (CNM) comprises a rare group of inherited myopathies characterised by an abnormal histological finding: the presence of centrally positioned nuclei within skeletal muscle fibers. In healthy muscle tissue, nuclei are typically located at the periphery of the fiber, allowing the contractile machinery to occupy the central space. The mislocalization of nuclei in CNM reflects deeper disturbances in muscle cell architecture and function.^1,2

One disorder that reflects this is autosomal dominant centronuclear myopathy (AD-CNM). It is caused predominantly by pathogenic variants in the DNM2 gene, which encodes dynamin 2, a large protein involved in membrane remodeling.² The autosomal dominant pattern of inheritance means that a single copy of the mutated gene, inherited from either parent, is sufficient to produce the disease phenotype. Each child of an affected individual has a 50% risk of inheriting the pathogenic variant.^1,2

Recent research into DNM2 and its role in CNM has allowed scientists to understand key aspects of the molecular mechanisms driving this disorder. Such knowledge is vital for accurate diagnosis, prognosis, and the development of targeted therapies.

Understanding dynamin 2

What is dynamin 2?

Dynamin 2 belongs to the dynamin superfamily, a group of protein enzymes that play a role in remodeling the membranes of cells, via a process called GTP hydrolysis. While it is widely expressed, dynamin 2 is particularly important in tissues requiring dynamic membrane trafficking, to initiate fast responses, such as in skeletal muscle.³

Dynamin proteins are primarily involved in endocytosis, the process by which cells internalize molecules from outside the cell to use for other processes. Dynamin 2 assembles around the neck of vesicles, which are carriers for molecules budding from the plasma membrane. Upon hydrolysis, or breakdown, of GTP,  it undergoes a conformational change that constricts and severs the vesicle from the membrane, allowing for endocytosis to occur.^2,3

In skeletal muscle fibers, dynamin 2 also contributes to the formation and maintenance of transverse tubules (T-tubules). These are deep invaginations of the muscle cell membrane that allow for rapid propagation of electrical signals from the cell surface to the interior, triggering coordinated contraction. Proper T-tubule architecture is essential for effective excitation–contraction coupling, allowing our muscles to function as intended.³

Pathogenic variants and molecular mechanisms

Most pathogenic DNM2 variants associated with AD-CNM are missense mutations, which means that a single part of the gene protein (an amino acid) is substituted with another, rendering the protein non-functional. These mutations play crucial roles in protein oligomerization (the formation of complex proteins from its monomers), membrane binding, and regulation of GTPase activity.²

Experimental evidence suggests that many of these mutations lead to a gain-of-function effect. This means that the mutant protein may have enhanced self-assembly or excessive membrane-constricting activity. In skeletal muscle, this aberrant activity can destabilize membrane organization and disrupt T-tubule formation.²

The resulting defects impair the uniform spread of depolarization signals(electrical signals that trigger muscle contraction) within the muscle fiber, compromising the synchronous activation of the contractile apparatus. Furthermore, altered membrane trafficking may hinder the repair of microtears and other structural damage sustained during muscle use, gradually leading to fiber degeneration.²

From molecular defect to clinical phenotype

The dysfunction cascade

The pathogenesis of AD-CNM can be conceptualised as a cascade:

• Mutation: A pathogenic variant occurs in one allele of DNM2
• Protein dysfunction:  Altered GTPase activity and abnormal membrane remodeling by dynamin 2
• Cellular disruption: Defective T-tubule network and impaired endocytic trafficking
• Cell abnormalities: Centrally located nuclei, disorganised sarcomeres(the basic contractile unit of a muscle fiber), and compromised fiber repair capacity
• Clinical manifestations, such as muscle weakness and dysfunction

Clinical features of AD-CNM

The clinical spectrum of AD-CNM is broad, with onset ranging from infancy to late adulthood.¹ Early-onset cases tend to be more severe, with delayed motor milestones, generalized hypotonia, and, in some cases, respiratory insufficiency. Later-onset forms may present with subtle weakness and progress slowly over decades.¹

Common symptoms

• Proximal and distal limb muscle weakness, often beginning in the lower limbs¹
• Facial weakness, sometimes leading to drooping eyelids¹
• Axial muscle involvement, which may cause head drop or difficulty maintaining posture¹
• In severe cases, dysphagia (difficulty swallowing) and restrictive respiratory impairment¹

Diagnostic evaluation typically involves:

• Muscle biopsy, allowing for examination of tissue to look for clues such as centrally located nuclei, fiber size variability, and disruption of the cell architecture
• Genetic testing, to confirm the presence of a pathogenic DNM2 variant

Treatment options

Current management approaches

At present, there is no cure for AD-CNM, however therapeutic options to manage symptoms and disease progression are often recommended. Management is primarily supportive and tailored to individual needs. 

Physiotherapy

Regular physiotherapy can help to preserve muscle strength, flexibility, and mobility and has proven useful for a range of movement disorders. Stretching exercises and range-of-motion activities prevent or delay joint defects, and use of supportive devices such as splints or braces can further provide support and improve posture.

Respiratory support 

This can include non-invasive ventilation support in more severe cases of AD-CNM where respiratory muscle weakness is present.

Other strategies

• Orthopedic interventions for skeletal deformities that arise from AD-CNM, such as scoliosis
• Nutritional support in individuals with swallowing difficulties

Because AD-CNM is a progressive disorder, ongoing clinical monitoring is essential to adjust interventions as the disease changes with time.

Emerging therapeutic strategies

Advances in molecular medicine have opened promising avenues for targeted therapies.

• Antisense oligonucleotides (ASOs): These short synthetic strands of nucleic acids can be designed to selectively reduce the expression of mutant DNM2 mRNA, thereby lowering the levels of toxic gain-off-function protein⁴
• Small molecule modulators: Compounds that influence membrane remodeling or DNM2 oligomerization are being investigated in cellular systems, though translation to clinical use remains in early stages¹
• Gene editing technologies: CRISPR/Cas9 and related tools offer the potential to correct or silence the mutant allele directly at the genomic level. While proof-of-concept work is encouraging, challenges in delivery and long-term safety must be addressed⁵

These strategies aim, not just to alleviate symptoms, but to modify the underlying disease process.

Living with AD-CNM

For individuals and families affected by AD-CNM, daily life and quality of life in general can be significantly impacted. Adaptive strategies often include the use of mobility aids, tailored exercise programs to preserve strength without overexertion, and environmental modifications to help people with CNM live independently. 

Genetic counseling plays a crucial role in helping families understand inheritance risks, implications for family planning, and the value of early diagnosis in at-risk individuals. Patient advocacy organizations can also provide resources, connect affected individuals to research studies, and foster community support.

Future directions

Several key questions remain unanswered. Not all DNM2 mutations produce the same severity of symptoms, suggesting that genetic or environmental modifiers influence disease expression. Identifying such modifiers could inform personalised management and therapy selection.

Furthermore, a deeper understanding of dynamin 2’s interactions with other muscle proteins may reveal additional therapeutic targets. Advances in medicine tailoring interventions to an individual’s specific mutation and disease profile, hold particular promise for rare disorders such as AD-CNM^.

Conclusion

Autosomal dominant centronuclear myopathy, caused by mutations in the DNM2 allele, is a compelling example of how a single molecular defect can disrupt highly specialised cellular architecture, leading to complex clinical disorders. Research over the last two decades has exponentially built on our understanding of dynamin 2’s functions in muscle membrane dynamics, the pathogenic consequences of its mutations, and potential therapeutic strategies. Although no cure or treatment is yet available, advances in gene-targeted therapies as well as further research offer hope for those living with AD-CNM.