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Disease/Disorder

Definition

Central core myopathy (CCM) is a rare and widely variable genetic condition characterized by truncal and proximal muscle weakness. It is most commonly caused by an autosomal dominant (AD) mutation of the RYR1 gene and can place some patients at risk for malignant hyperthermia.1

Etiology

CCM is caused by an RYR1 gene mutation, resulting in a less functional RYR1 protein, thus impacting the sarcoplasmic reticulum’s regulation of calcium release in type 1 skeletal muscle. Inheritance can be via AD or autosomal recessive (AR) mutations.2

Epidemiology including risk factors and primary prevention

The incidence of all congenital myopathies is about 6 per 100,000 live births, with CCM being the most common congenital myopathy. It is thought that CCM is likely underdiagnosed, as initial biopsies may not reveal the histopathological findings typical of CCM, since typical histopathological findings of core myopathies can evolve over time and be absent initially.3,4 Autosomal dominant mutations are more common. Autosomal recessive mutations, while less common, are more phenotypically severe than AD mutations due to the mutation being present throughout the entire coding sequence.1,5 There is no known risk factor or primary prevention outside of family education of the disorder.

Patho-anatomy/physiology

The RYR1 gene encodes the skeletal muscle ryanodine receptor, which plays a crucial role in regulating cytosolic calcium levels.4 When mutated, calcium release is negatively impacted, leading to muscle weakness. The hallmark of CCM is the presence of well-demarcated cores on histology, which are round regions in a muscle fiber that lack oxidative enzyme activity.6 Muscles that primarily contain type 1 fibers are more impacted and experience more weakness than type IIa and IIb fibers.1

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

CCM is a slowly progressive or non-progressive disease characterized by weakness in truncal and proximal muscles.1 The disease progression depends on genetic inheritance, with AR inheritance being more severe and sometimes neonatal in onset.5 Almost all patients achieve independent walking.4

  • new onset/acute
    • Most patients present either clinically asymptomatic or with proximal or truncal weakness. The most common variant of this disease presents with mild proximal and axial weakness, ptosis, extraocular weakness, hypotonia, and delayed walking.7 Time of onset is variable and can be dependent on other risk factors and location of nuclei in type 1 fibers.1
  • Subacute
    • The severe AR form can progress to respiratory failure, congenital dislocations, and scoliosis.4 For the remainder of patients, there is typically no significant change in symptoms after initial diagnosis.
  • chronic/stable
    • CCM is usually stable over many years with possible progression in adulthood.6
  • pre-terminal
    • Patients with CCM have a normal life span and there is typically little progression of disease. For those that do have progressive muscle weakness, severe physical impairments can ensue.6

Specific secondary or associated conditions and complications

Patients with CCM are at high risk for malignant hyperthermia when given succinylcholine and volatile anesthetics.4 Patients are also at risk of environmental heat stroke.8 Additional associated conditions include congenital hip dislocations, club foot deformities, patellar instability, and scoliosis.1,4

Essentials of Assessment

History

When first evaluating a patient, it is important to ask about the pattern of weakness (proximal versus distal, and if the trunk is involved) and obtain a robust functional history. Furthermore, it is crucial to investigate if there is a family history of unexplained weakness of muscular issues.

Physical examination

The physical examination should focus on manual muscle testing with the understanding that CCM typically impacts the proximal muscles more than distal muscles. The muscles that are most commonly impacted include: rectus femoris, adductor longus, sartorius, and soleus muscles.1 The physical examination should also include an assessment of muscle bulk (evaluating atrophy or pseudohypertrophy), a full neurologic assessment, including reflexes, tone assessment, and gait analysis, and a scoliosis examination.

Functional assessment

It is recommended that patients are seen in a multidisciplinary neuromuscular clinic that includes Physical Medicine and Rehabilitation (PM&R), neurology, and therapy services. Functional assessments should be performed at every visit using neuromuscular outcome measures such as the Performance of Upper Limb (PUL), Motor Function Measure (MFM), and North Star Ambulatory Assessment (NSAA).9

Laboratory studies

Diagnosis is performed through muscle biopsy, which displays centrally located nuclei and a lack of mitochondria and enzymatic activity.1,4 Genetic analysis can confirm an RYR1 gene mutation.4 Serum CK is usually normal but can be elevated in rare cases.4

Imaging

Imaging studies are only indicated in patients with an unclear clinical picture. First line imaging is muscle MRI of the anterior thigh. The posterior compartment of the thigh is more impacted by abnormal signal on MRI than the anterior. Patients with more clinical symptoms may display a more typical pattern on MRI, while mild/moderate symptoms will have heterogeneous imaging findings.5 Muscle ultrasound is usually not definitive but may show increased echogenicity, even in patients with mild symptoms.4

Supplemental assessment tools

There are no other supplemental assessment tools for the diagnosis of CCM.

Early predictions of outcomes

Number of central core nuclei does not correlate with disease severity or functional outcomes.10 There is, however, a correlation between core position and disease stage, with more severe cases showing more centralized nuclei.4 Most patients have non-progressive disease, so the functional level at initial assessment is highly correlated with their long-term functional outcome. Patients with C-terminal mutations have earlier onset of symptoms.10

Environmental

No known environmental factors are associated with this condition. However, it is important to consider environmental factors in preventing long term complications from this disease, such as respiratory irritants, especially in AR cases with pulmonary involvement. Additionally, patients should be educated about the risk of heat stroke in hot environments.

Social role and social support system

Family education is crucial, as especially when a patient is diagnosed with the AD form, the disease may be present in other family members in variable clinical presentations. In vitro contracture testing can be performed for all family members to determine malignant hyperthermia risk.

Professional issues

Whether family members of patients with CCM should be informed of their loved one’s condition poses an ethical dilemma. Since patients with CCM are at high risk for malignant hyperthermia, it is reasonable to communicate the potential risk to all family members so they can receive testing to prevent fatal anesthetic complications. Additionally, a positive diagnosis for the AD form of the disease will therefore inherently identify affected individuals (one or both of their parents) who did not consent to be tested.

Rehabilitation Management and Treatments

Available or current treatment guidelines

There is no known curative treatment for this condition. The majority of treatment is focused on supportive care and avoidance of malignant hyperthermia.

At different disease stages

  • new onset/acute
    • While no curative treatment is present, a patient’s pain can be managed with non-steroidal anti-inflammatories, gabapentin, and massage.11 Early therapies are vital to prevent worsening of muscle weakness. Many patients may benefit from mobility devices.
  • subacute
    • It is recommended to continue to assess pain during each visit. Follow up in a multidisciplinary neuromuscular clinic is recommended every 3-4 months while under the age of 1 year and every 6-12 months after the age of 1 year.11
  • chronic/stable
    • It is recommended to continue visits every 6-12 months to assess functional needs. It is recommended that scoliosis monitoring is done for non-ambulatory children with an anterior-posterior and lateral projection x-ray at the first clinical sign of scoliosis and every six months. In ambulatory children, x-rays can be obtained every year.11

Coordination of care

Due to the complexity and clinical variability associated with this genetic disorder, it is recommended that these patients be evaluated in a multidisciplinary neuromuscular disorder clinic that includes, at minimum, a PM&R physician, neurologist, and therapy services.11

Patient & family education

Family members should be educated about the risk of malignant hyperthermia for the patient and their immediate family members. Patients can have subclinical central core myopathy and still be at risk for malignant hyperthermia.4

Measurement of treatment outcomes

Although there is no curative treatment available, there are functional outcomes measures performed in the neuromuscular clinic (PUL, MFM, NSAA) that can track progression over time.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Although CCM is not associated with cardiomyopathy, clinical presentations similar to CCM can be associated with cardiomyopathy. Cardiac ultrasound studies are recommended in cases where the clinical presentation is unusual.4

Cutting Edge/Emerging and Unique Concepts and Practice

Recent literature has examined how the genetic diagnosis of central core myopathy can determine specific clinical outcomes and treatment options. Identifying specific genes (at least 19 have been identified to date) to gain better understanding of specific outcomes may assist in the future care of these patients. 

There is also the potential for gene therapies (either gene replacement or gene knockdowns) for treating congenital myopathies. There are currently clinical trials underway for centronuclear myopathies, and animal trials have been conducted for gene therapies for CCM.12

Additionally, preliminary research has demonstrated functional improvements following functional electrical stimulation (FES), suggesting its use to provide additional support for maintaining muscle function.13

Gaps in the Evidence-Based Knowledge

One major gap in the literature is the development of novel treatments or gene therapies that can slow or prevent symptom progression. Additionally, the literature is lacking in discussing functional outcomes and the specific proportion of people with CCM who are at each functional level (non-ambulatory vs. ambulatory). Lastly, there is a dearth of research about the type, frequency, and intensity of exercise that is most beneficial for these individuals.

References

  1. Ogasawara M, Nishino I. A review of core myopathy: central core disease, multiminicore disease, dusty core disease, and core-rod myopathy. Neuromuscul Disord. Oct 2021;31(10):968-977. doi:10.1016/j.nmd.2021.08.015
  2. Wilmshurst JM, Lillis S, Zhou H, et al. RYR1 mutations are a common cause of congenital myopathies with central nuclei. Ann Neurol. Nov 2010;68(5):717-26. doi:10.1002/ana.22119
  3. Mah JK, Joseph JT. An Overview of Congenital Myopathies. Continuum (Minneap Minn). Dec 2016;22(6, Muscle and Neuromuscular Junction Disorders):1932-1953. doi:10.1212/CON.0000000000000404
  4. Jungbluth H. Central core disease. Orphanet J Rare Dis. May 15 2007;2:25. doi:10.1186/1750-1172-2-25
  5. Klein A, Lillis S, Munteanu I, et al. Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies. Hum Mutat. Jun 2012;33(6):981-8. doi:10.1002/humu.22056
  6. Topaloglu H. Core myopathies – a short review. Acta Myol. Dec 2020;39(4):266-273. doi:10.36185/2532-1900-029
  7. Braddom RL, Chan L, Harrast MA. Physical medicine and rehabilitation. 4th ed. Saunders/Elsevier; 2011:xxiv, 1506p.
  8. Ogasawara M, Ogawa M, Nonaka I, Hayashi S, Noguchi S, Nishino I. Evaluation of the Core Formation Process in Congenital Neuromuscular Disease With Uniform Type 1 Fiber and Central Core Disease. J Neuropathol Exp Neurol. Dec 4 2020;79(12):1370-1375. doi:10.1093/jnen/nlaa104
  9. Cavallina IDA, Rossella ; Brusa, Chiara ; Panero, Elisa ; Rolle, Enrica ; Rossi, Francesca ; Mongini, Tiziana; Ricci, Federica Silvia. Motor Outcome Measures in Pediatric Patients with Congenital Muscular Dystrophies: A Scoping Review. Applied Sciences. 2023;13(2):1204.
  10. Wu S, Ibarra MC, Malicdan MC, et al. Central core disease is due to RYR1 mutations in more than 90% of patients. Brain. Jun 2006;129(Pt 6):1470-80. doi:10.1093/brain/awl077
  11. Wang CH, Dowling JJ, North K, et al. Consensus statement on standard of care for congenital myopathies. J Child Neurol. Mar 2012;27(3):363-82. doi:10.1177/0883073812436605
  12. Maani N, Karolczak S, Dowling JJ. Genetic therapy for congenital myopathies. Curr Opin Neurol. Oct 1 2021;34(5):727-737. doi:10.1097/WCO.0000000000000978
  13. Iodice P, Boncompagni S, Pietrangelo L, et al. Functional Electrical Stimulation: A Possible Strategy to Improve Muscle Function in Central Core Disease? Front Neurol. 2019;10:479. doi:10.3389/fneur.2019.00479

 Author Disclosures

Cara Vernacchia, DO
Nothing to Disclose

Jeffrey Kepple, MD
Nothing to Disclose