What is centronuclear myopathy (CNM)?

Centronuclear myopathy (CNM) is a term used to describe a group of rare genetic muscle disorders that all cause muscle weakness, ranging from mild to severe, that are evident at around the time of birth/infancy.¹

What are the symptoms of CNM?

The severity and symptoms of centronuclear myopathies (CNMs) range from person to person, with some developing mild symptoms while others develop serious, life-threatening conditions.¹

This can all vary depending on the genetic subtypes that cause the CNM.¹

What causes CNM?

CNMs are genetically inherited disorders caused by mutations in specific genes that affect muscle structure, development, and function.¹ The main feature of this condition is the positioning of the nuclei in the centre of skeletal muscle fibres, an abnormal feature as the nuclei are normally located at the ‘sides’ of these muscle cells.^1,2

There are 4 types of genetic mutations related to CNM, which result in distinct differences in the CNMs:

• DNM2
• BIN1
• RYR1
• MTM1

Inheritance patterns

These mutations cause different inheritance patterns, which are typically how CNMs are passed down through genetics:

Autosomal dominant – A change in one copy of a gene is enough to cause CNM in an individual.³ This means a child needs to inherit one mutated gene from one parent to have the condition.

Autosomal recessive – A person must inherit two changed copies of a gene rather than one to inherit this condition.³ This means a child needs to inherit one mutated gene from each parent to have the condition.

X-linked recessive pattern – X-linked recessive inheritance means that the gene mutation that causes CNM is located on the X chromosome, one of the two sex chromosomes.

Males have one X chromosome; they are more likely to be affected because one faulty copy can cause the condition.⁷

Females have two X chromosomes, so they’re usually carriers if only one is mutated. Carriers can pass the mutation to their children.⁷

DNM2-related CNM

This type of CNM is caused by an autosomal dominant change (mutation) in the DNM2 gene. ¹ It affects how muscles work and can vary a lot from person to person. Some people show symptoms from birth, while others may not notice problems until later in life.^1,2,4

The DNM2 gene gives instructions to make a protein called dynamin 2. This protein helps your muscle cells stay healthy by controlling how they move, and helps keep muscle cells organised so the muscles can move properly.^1,2,4

Mutations in the DNM2 gene can cause the dynamin 2 protein to work too much or not properly. This can disrupt how muscle cells function and how their internal structures (T-tubules) are built.^1,2,4 When these structures are damaged, muscles become weak and might not work the way they should. ^2,4

Common signs and symptoms

In Infants and Children:¹

• Low muscle tone (floppy muscles)
• Weakness, especially in the arms, legs, and face
• Delayed milestones, like sitting and walking
• Eye movement problems such as droopy eyelids (ptosis)
• Eating problems (due to weak sucking and swallowing muscles)
• Breathing problems may develop as the child grows

In Teenagers and Adults:¹

• Muscle fatigue and cramps, especially during exercise
• Gradual muscle weakness that can worsen over time, usually starting in the upper legs or arms
• Trouble with walking, climbing stairs, or running
• Walking ability may be lost later in life (usually not before age 60) - Rare

Other Possible symptoms:¹

• Cataracts (cloudy eye lenses)
• Enlarged muscles (especially in the legs)
• Limited jaw opening
• High-arched feet (pes cavus)
• Spine curvature (scoliosis)
• Tight heel cords (Achilles tendon contractures)

BIN1-related CNM

This type of CNM is caused by an autosomal recessive mutation in the BIN1 gene.¹

This condition affects muscle strength and function, and symptoms can appear at birth or early childhood. How it affects each person can vary.¹ While some people have mild symptoms, others experience more serious muscle problems.¹

The BIN1 gene helps make amphiphysin 2, a protein that is important for building and organising T-tubules, which are the internal structure of muscle cells that help them move properly. ^1,5 Due to the BIN1 gene mutation, the muscle fibres don’t form correctly, and they have trouble sending signals to help them contract, leading to muscle weakness.^1,5

Common symptoms

Symptoms may vary, but are similar to DNM2-Related CNM. This can include:

• Long face
• High arched palate (roof of the mouth)
• Facial weakness, such as ptosis, and trouble moving the eyes (ophthalmoplegia)
• Chewing difficulties
• Delayed development - Some children may take longer to sit, walk, or climb stairs
• Feeding problems - due to weak mouth and throat muscles
• Breathing difficulties

How does it progress?

In milder cases, individuals may be active with only slight muscle weakness, while in more severe cases, walking can become harder over time, and some individuals may even need support to walk by their twenties.¹

RYR1-related CNM

This type of CNM is caused by an autosomal recessive mutation in the RYR1 gene.^1,6 This gene is involved in producing a protein called the ryanodine receptor, which plays an important role in how muscles contract by controlling the release of calcium inside muscle cells.^1,6 This calcium is needed to help the muscles tighten and relax.^1,6

In RYR1-related CNM, the muscles have trouble managing calcium correctly, leading to muscle weakness and other related symptoms. ^1,6

What are the symptoms?

The symptoms can differ between individuals, but many babies with RYR1-related CNM are born with:¹

• Very weak muscles (hypotonia)
• Trouble moving or holding their head up
• Feeding difficulties
• Breathing problems or frequent chest infections
• Face and eye muscles may be weak, leading to a V-shaped mouth appearance

Despite this initial weakness, some children show big improvements and have only mild symptoms by teenhood.¹ Though this is not the case for all children, as some may not improve as they grow.^1,6

MTM1-related CNM

MTM1-Related CNM, otherwise known as myotubular myopathy (XLMTM), is inherited in an X-linked pattern, where there is a gene mutation in the MTM1 gene.⁷ The MTM1 gene is involved in the making of a protein called myotubularin, which is involved in keeping muscle cells healthy.⁷

The X-linked inheritance pattern means males are usually affected as they only have one chromosome, whereas females are typically carriers of the gene as they have 2 chromosomes and usually don’t have symptoms.⁷

Common symptoms

Symptoms usually start at birth, with XLMTM being the most severe form of the CNMs.

• Very weak muscles (low muscle tone or "floppy baby")
• Trouble breathing, often needing a ventilator
• Poor sucking or feeding
• Delayed development or trouble reaching milestones like sitting or crawling

Due to breathing and muscle weakness, many infants with XLMTM require intensive medical support early in life.⁷ This can be life-threatening, especially in the first few years of life, though the severity can vary, and some children may show slight improvement as they age.⁷

Living with CNM

While the different types of CNM vary, the symptoms are all generally similar; therefore, most of the treatments used to help improve quality of life are the same for the different CNM types:^1,3,5,7

• Physical therapy to keep muscles strong and joints flexible
• Speech or feeding therapy
• Breathing support in severe cases
• Regular checkups to monitor strength, breathing, and posture
• Wheelchairs

There is no cure for CNMs, but these treatments can help manage symptoms.

Conclusion

Centronuclear myopathy (CNM) is a group of rare inherited muscle disorders that typically begin from birth or early childhood. CNMs cause various levels of symptoms, depending on the individual and the cause. The main cause of CNMs is genetic mutations, with 4 main known genes that are changed to cause CNMs: MTM1, DNM2, BIN1, and RYR1. These differences can be inherited through autosomal recessive, autosomal dominant and X-linked inheritance patterns and cause differences in the CNMs and their symptoms. A few common symptoms are muscle weakness, breathing and feeding difficulties, and eye movement problems. There is currently no cure for these conditions, but there are some ways to help manage symptoms, including physical therapy and breathing support. Each individual's experience with CNM can differ, varying from mild to severe experiences, so treatment varies.