Overview 

Centronuclear myopathy (CNM) is an inherited condition which affects the skeletal muscles. It is clinically characterised by muscle weakness and decreased muscle tone. Centronuclear myopathy is a broad term relating to myopathies (muscle weakness), which are histologically characterised by an abnormal placement of nuclei in the centre of muscle cells in a biopsy.^1,2

In some individuals with CNM, it is apparent from birth and very severe while for others, this condition may be present later during their infancy, or teens. The most severe and common form of CNM, is X-linked myotubular myopathy, which is widely known to cause respiratory failure as well.¹

In this article we will explore:

• The different gene mutations which lead to centronuclear myopathy
• Understand how different gene mutations can lead to the same condition 
• Understand the variety of this condition and how and why it affects people differently

CNM is a very serious condition and can be life threatening in infants. Deepening our understanding of this condition can help us discover new therapies, improve diagnostic techniques, and bring awareness to a condition which has a big effect on families and individuals. 

Introduction

What are myopathies?

Myopathy is a term used to cover the disease of skeletal muscles; a group of tissues that are crucial for maintaining posture, eating, walking and breathing. 

What is centronuclear myopathy?

Centronuclear myopathy is a rare inherited type of congenital myopathy, meaning it is present at birth.² 

CNM is defined by the incorrect placement of nuclei in skeletal muscle cells. Under normal circumstances, the nucleus is typically found in the edges of the cell. However, in individuals with CNM, the nuclei are instead found in the centre of the cell. This unusual placement leads to dysfunctioning of muscles, thus causing muscle weakness.³

Normal muscle development 

Figure 1: Skeletal muscle cell illustration, showing the peripheral placement of nuclei. Adapted from Medivizio by Ann, Shutterstock.⁴

Muscle cells are specialised cells which carry out distinct functions of contracting and relaxing, enabling one to consciously move. For this reason, they have a distinct structure and are highly organised, so that they can contract and relax effectively. The organisation of skeletal muscles allow muscle fibres to slide over each other to enable the muscle to strongly contract. Unfortunately, this process is hindered in people with myopathies, due to the abnormal muscle cell structures.⁵

Symptoms of centronuclear myopathy

In individuals with CNM, the integrity of muscle tissues is disrupted, which can lead to a range of symptoms. The most common symptoms are:¹

• Muscle weakness 
• Delayed motor development
• Hypotonia (reduced muscle tone)
• Muscle atrophy (muscle wasting)
• Stiffness
• Myalgia (muscle aches and pains)
• Muscle cramps
• Muscle spasms 
• Facial weakness, and difficulties speaking
• Dysphagia (difficulties swallowing)
• Respiratory failure

Roles of genes in centronuclear myopathy 

Centronuclear myopathy doesn’t have one distinct cause; it is often referred to as genetically heterogenous, which signifies that more than one faulty gene can be responsible for causing this condition. Certain genes have been identified for causing CNM when they are faulty. Examples include: MTM1, DNM2, BIN1, RYR1, TTN. Whilst these are the most commonly identified genetic causes of CNM, the SPEG1, MYF6 and MAP3K20 (ZAK) gene mutations were also found to contribute to CNM.¹

The MTM1, DNM2 and BIN1 genes encode for proteins involved in the development and maintenance of muscle cells. They are involved in processes such as managing the cell’s transport system.⁶

RYR1 and TTN genes play a crucial role in signalling muscle contraction. Not only do they contribute in stimulating muscle cells to receive electrical signals from the brain to elicit movement, but they also promote the formation of sarcomeres, which are the highly organised repeating units of muscle tissues, thus promoting contraction.¹

All of these genes encode proteins which are all involved in similar mechanisms and interact with each other. They work together to ensure the muscle cells can function properly. Therefore, the damage to one of these proteins, can affect the functioning and structural integrity of the muscle cells and the muscles themselves.

Why do different genetic mutations result in the same disease?

In centronuclear myopathies, mutations of different genes can lead to muscle cell dysfunction in similar ways, due to their interconnected signalling pathways. This explains why different gene mutations can sometimes lead to the same disease.⁶

Why does centronuclear myopathy present differently in different people?

Due to the variety of gene mutations known to cause CNM, we generally see the condition present itself differently in different people. We see a large variability in condition onset and degree of muscle impairment. In more severe cases, the condition is present at birth and can be referred to by doctors as ‘floppy infant syndrome’. In these cases, infants present severe muscle weakness at birth. In other milder cases, the condition can develop later on, where it only began to present itself as delayed motor functioning due to increased muscle weakness overtime.¹

Expanding the genotypic spectrum 

Why does the discovery of new gene mutations matter?

Recently, with the help of advanced genetic testing such as exome sequencing, research has begun to uncover new genes associated with CNM. Due to these advancements in technology, doctors have been able to attribute new specific mutations to CNM cases which previously had no identifiable genetic cause.⁷

The discovery of new gene mutations is important in improving the understanding of CNM. A deeper comprehension of these genetic mutations will allow us to understand why the severity of this condition presents itself differently in different people. It also highlights the different roles of the individual genes and their importance in the overall picture.⁶

Identifying new mutations is also important for diagnosis as it can allow doctors to accurately determine the underlying genetic cause and promote quicker diagnosis. When it comes to inherited conditions, this also has important implications for genetic counselling and family planning.

It also opens up possibilities for future targeted treatments where researchers can look into new ways to target the specific proteins and pathways which are affected in CNM.

Treatments

Unfortunately, there is currently no cure for centronuclear myopathies. However, there are still methods available that focus on management of the condition and supportive care. Myopathies as a whole is managed through physical and occupational therapy, specialised exercises and nutrition.²

Family support is an essential aspect of the management of CNM. Families should be well informed on how CNM will affect the child, the likely progression of the disease, which muscles are affected, and how it will impact the child's lifestyle. 

Muscle weakness typically affects movement and mobility. However, in more severe cases eating and chewing can be affected as well. Henceforth, it is absolutely crucial that adequate care is present to ensure the child receives sufficient nutrition.⁸ In other severe cases of CNM (particularly X-linked myopathy), breathing is also affected. Thus, respiratory support in the form of ventilation is required.³

Summary 

Centronuclear myopathy is a rare inherited condition and has a significant impact on individuals and families. Research into genetic causes of CNM is still ongoing, and the genotypic spectrum of this disease continues to expand. New discoveries improve our understanding of CNM and highlight why we see this condition present itself differently in each individual. 

The greater our understanding of these underlying causes, the closer we are to therapeutic intervention and improved genetic counselling. Increased awareness of rare genetic diseases is essential for a deeper understanding of such conditions, and affect individuals and how their lives are impacted.