Introduction

If you’re looking to know the difference between early and late onset of Central core disease, then you’re in the right place. This article will provide accurate and clear information about the different symptoms, causes and treatments, leaving you confident in recognising this disease.

Central Core Disease (CCD) is a rare congenital myopathy caused by mutations in the RYR1 gene which encodes the ryanodine receptor, a calcium channel involved in muscle contraction. It is usually characterised by the presence of central cores with muscle fibres lacking oxidative enzyme activity which can vary in severity and the age of onset. CCD presents challenges in diagnosis and management depending on when symptoms first appear. 

Early onset CCD usually presents itself in infancy or early childhood with hypotonia, delayed motor milestones and orthopaedic complications such as sclerosis. However, late onset CCD can occur during adulthood, presenting itself with muscle weakness, cramps or exercise intolerance and can go undiagnosed for years. Understanding the differences between these two onsets is crucial for accurate diagnosis, with the aim being to achieve long term patient care.

What is the onset and epidemiology of this disease?

The age of symptom onset for early onset CCD is infancy to childhood whereas for late onset CCD, it is not well defined but can be from adolescence to adulthood. The disease mainly affects male and women equally and is believed to be the most common form of congenital myopathy, which affects 6 out of every 100,000 live births.

In most people, CCD is inherited in an autosomal dominant manner. It can be inherited in an autosomal recessive pattern, yet this is rare and is presented with more severe symptoms.

What are the clinical presentations? 

For early onset CCD, it is typically characterised by hypotonia, motor development delays such as crawling, walking as well as muscle weaknesses and a variety of skeletal abnormalities such as scoliosis.

For late-onset CCD, early development tends to be normal. However, when symptoms develop in adulthood, it is presented as muscle weakness, often combined with skeletal deformities or contractures. Other symptoms can include myalgia (muscle pain), or extreme fatigue due to physical activity, known as exercise intolerance.

Some individuals can also develop malignant hyperthermia in which the individual can react to certain anaesthetic drugs during surgery.

What are histological findings to diagnose this disease?

To come to a diagnosis, physical examinations and further tests are used such as muscle biopsy, MRI or even genetic testing.

Histological staining of a muscle biopsy involves taking a small sample of the muscle tissue which is then examined under the microscope. Usually, muscle tissues have type 1and type 2 fibres in equal amounts, but with CCD, type 1 muscle fibres have damaged areas, known as central cores. There would additionally be an absence of oxidative enzymatic activity from the central core regions which run along the muscle fibre. Or the lack of mitochondria or sarcoplasmic reticulum.

MRI and imaging would show the involvement of the RYR1 gene, with mutations in the C terminal region of this gene forming a recognisable MRI pattern and is typically linked to muscle damage or weakness, helping with the diagnosis.

Genetic testing is also beneficial in checking for changes in the RYR1 gene to confirm the disease. Once this difference has been found, this can be used to quickly diagnose other family members.

What are genetic differences seen between both onsets?

In CCD, there are mutations in the RYR1 gene. Usually, this provides instructions for making the protein, ryanodine receptor 1 which is crucial in skeletal muscle contraction. This receptor forms a channel which releases calcium ions, stimulating the muscle fibres to contract and allowing movement. However, mutations in this gene changes the receptor’s structure and the calcium channel. Calcium ions are released slowly and cannot pass into the channels where they are needed. This prevents muscles from contracting normally, leading to muscle weakness.

Mutations can occur in three hotspot regions of the gene: N terminal, central domain and C terminal, with C terminal being strongly associated with early onset disease and producing more severe clinical features seen in infancy. Whereas for late onset, this can involve missense mutations outside the C terminal region and will manifest until adulthood.

How is this disease managed and treated? 

Currently, there is no cure for this disease. However, both onsets can be managed effectively in preventing complications and improving quality of life.

Regular physiotherapy is essential in preventing contractures and to preserve muscle function³. In early onset CCD, this can begin early to support motor development. Additionally, treatment for scoliosis, or joint contractures can be necessary. Speech and occupational therapy are also needed where hypotonia can affect daily life.

Currently, research into gene editing as well as drugs to stabilise calcium levels in muscle fibres can improve muscle function by targeting specific RYR1 mutations.

Summary

Central core disease is presented along a broad spectrum, with early and late onset differing in presentation, severity and progression. Early onset CCD usually occurs in early childhood, presenting itself as hypotonia, motor development delays and orthopaedic complications. Whereas late onset disease will begin in adulthood with subtler symptoms like progressive muscle weakness or exercise intolerance. However, they both share common histological features such as central cores in type 1 muscle fibres as well as MRI and other imaging showing mutations in the RYR1 gene. Although there is no cure currently, there are future 

therapies providing hope as more information is undiscovered. Thus, understanding the differences between early and late onset is crucial for accurate diagnosis and personalised care.

FAQs

Can people with CCD live a normal life?

Yes, many individuals, particularly those with late onset lead independent, normal lives with appropriate support. Early intervention with regular monitoring can greatly improve a patient’s quality of life.

Is life expectancy shortened with people experiencing CCD?

Not necessarily, although severe early onset with respiratory involvement may need closer monitoring.

Can CCD symptoms worsen over time?

Yes. Muscle weakness can worsen with age as well as complications such as fatigue. However, physiotherapy and regular monitoring can help slow this down.

What should CCD patients avoid?

• Anaesthetics as this could trigger malignant hyperthermia.
• High intensity exercise or extreme heat which can worsen symptoms
• Prolonged inactivity as this can worsen muscle weakness