Understanding central core disease: An overview 

Central Core Disease (CCD) is a rare genetic disorder that affects the muscles and nerves involved in muscle movement. The two main symptoms presented in the clinic are congenital myopathy and the presence of ‘central cores’ in muscle cells. Congenital myopathy is characterised by dysfunctional (cramping, stiffness, spasms) and weak muscles that are present at birth (hypotonia).¹ The ‘central cores’ within the muscle cells are darker-looking, disorganised areas at the centre of the cell. The common muscles affected by hypotonia are in the hip, which connect the pelvic bone to the spine. In some patients, orthopaedic complications such as hip displacement can be a secondary outcome of this muscle weakness. Stagnant muscle weakness from birth or slow progression of disease symptoms is common for most patients, making this rare condition have a favourable life expectancy.² 

Why genetics change the whole story? 

The pathological features of CCD are the result of molecular dysfunction within the muscle cells due to the genetic mutations linked to the disorder. With the presence of the two main symptoms discussed above, the diagnosis can be confirmed using a genetic analysis test. It is extremely important to understand the genetic basis of CCD as it can affect prognosis and clinical features, requiring genetic counselling later on.²

In a bit, we will dive deeper into the genetic basis of CCD, discussing the gene involved, types of mutation and inheritance patterns, clinical features associated with them, and what one can do about it. 

How genes shape CCD

The main culprit: RYR1 gene

As you might know, certain features, such as our eye colour or our tendency to develop some health conditions, are inherited from both biological parents. These features are determined by genes. The DNA sequence on these genes may vary from person to person, and are called alleles. We all have two alleles, one from each parent, and the combination of these alleles is integral in determining our features. Sometimes the variation in our genes arise from mutations, i.e., changes in DNA sequence, that can affect how the gene functions.³ In the case of CCD, the symptoms arise from mutations in the RYR1 gene (ryanodine receptor 1). The RYR1 gene is responsible for coding a receptor protein called ryanodine receptor 1, which controls calcium levels in skeletal muscle cells. Receptor proteins sit on the cell membrane, receiving signals from the body and relaying them to the cell for it to respond. The correct function of RYR1 is critical for regular muscle contraction and function. However, mutations in the gene cause abnormal muscle function.⁵

In the next section, we will discuss the nature of these mutations and their inheritance patterns. 

Mutation types

The majority of mutations associated with CCD are missense mutations, meaning that the change in the DNA sequence alters the amino acid sequence (the building blocks of proteins), thereby altering protein function. The predominant inheritance pattern of these mutations in CCD is Autosomal Dominant type (AD). Additionally, in the Autosomal Recessive type (AR) CCD, there could be compound heterozygous or homozygous mutations. This means that the individual can have two mutated alleles inherited one from each parent, that either have the same exact mutation (homozygous) or two different mutations.²

Autosomal Dominant (AD) CCD: When one changed allele is enough

Inheritance pattern

In autosomal dominant (AD) inheritance, carrying one mutated allele (heterozygous) is enough to develop the disease. This means that the child affected has to have at least one affected parent, and their child has a 50% chance of inheriting the mutated allele, which means that a family history is often present.⁶

Clinical features

The majority of AD-CCD cases present symptoms later in childhood and have a slower prognosis. However, there is a possibility of developing lower leg muscle weakness, hypertrophy in the calves, weakness in the hip and upper thigh muscles, and related hip displacement issues in the future. Another symptom that patients with AD-CCD experience is a high risk of developing malignant hyperthermia, in which they can have negative reactions to anaesthetics.⁴

Muscle biopsy findings

The microscopic images of the muscle biopsy show well-defined central cores in the middle of the muscle cells. The presence of these central cores is consistent across different muscle fibres. Even though central cores are a common clinical feature of the disease, especially in individuals with AD-CCD, it is not proven how they cause muscle weakness.⁷

Prognosis

Despite the high risk of malignant hyperthermia, patients with AD-CCD generally show a favourable prognosis. The muscle weakness progression is mostly slow, and in some cases, stable. Through correct diagnosis and care, patients with AD-CCD can live a long life.⁴

Autosomal Recessive (AR) CCD: When two genes are needed

Inheritance pattern

Unlike AD-CCD, in autosomal recessive (AR) CCD two mutated alleles are required for the disease to develop.⁶ Patients with recessive mutations often have no family history of muscle disease. This is because each parent would have only one mutated allele, which is not enough to develop the disease.⁴ The risk of recurrence is significantly lower in AR-CCD compared to AD-CCD. If one parent has the condition and the other one is a carrier, there is a 25% chance for the child to develop AR-CCD.⁶

Clinical features

Clinical features seen in AR-CCD tend to be more severe. The condition shows itself as early as pregnancy (neonatal) if not, in infancy. The early onset of muscle weakness can, in turn, lead to delayed motor milestones for children. This can mean issues with crawling, walking, and coordination. In classic AD-CCD, the heart, lung and facial muscles are not affected. On the other hand, in some severe cases, individuals with AR-CCD can develop breathing difficulties due to muscle weakness, which can be life-threatening. Additionally, some facial muscles specifically affecting the eyes can be affected.⁴

Prognosis

The prognosis for AR-CCD is highly variable. The outcome of the patient almost entirely depends on the severity of their condition. In more severe cases where heart and lung muscles are affected, the treatment needs to be more hands-on and possibly requires invasive procedures.⁴

Genetic differences at a glance

RYR1 mutation sites and their effects

You may ask, why is there a big difference in the clinical presentation of CCD between the autosomal dominant and recessive types when it is the same gene that is affected? This is actually due to dominant and recessive mutations affecting different parts of the RYR1 protein. Proteins have different compartments that have different functions; hence, mutations affecting different parts have different functional outcomes. In dominant RYR1 mutations, the N-terminus and the central domains of the protein are affected. On the other hand, recessive RYR1 mutations mainly affect the C-terminal of the protein. These changes can alter the regulation of the channel, reduce the amount of protein and its function.² 

Diagnostic approach

Diagnosis of CCD follows a multidisciplinary approach. The first step is assessing the family history of muscle weakness diseases. If there is a family history, there is a good chance that the patient has AD-CCD. Afterwards, some clinical and laboratory tests will be conducted. A muscle biopsy will validate the presence of central cores. Additionally, blood tests can help. Studies show that patients with CCD show higher levels of an enzyme called creatine kinase (CK) in their blood. However, to fully confirm the type of CCD, genetic testing must be done. Through next-generation sequencing (NGS), a targeted sequencing of the RYR1 gene can be done, and mutations can be determined.⁴

Management and counseling

The treatment of CCD is decided based on the clinical symptoms; hence, it can differ for each patient. Most patients benefit from physiotherapy, where physical activities that help maintain the range of motion and muscle health are performed with the help of a professional physical therapist. Depending on the symptoms, splints and casts can be used to assist in correcting joint placement. In addition to these clinical treatments, patients must get counseling on setting functional and realistic goals. Maintaining bone health, sustaining realistic physical activity and getting sufficient pain management can play a crucial role in the progression of the disease. Specifically for patients with autosomal dominant AD, it is critical to be informed about malignant hyperthermia and take precautions. Lastly, through family screening, both the patient and relatives who are ‘at-risk’ can be informed of the risk of recurrence.⁸

Autosomal dominant vs. recessive CCD: A summary