Central Core Disease

At a glance

A congenital myopathy with a specific histologic pattern and high susceptibility to malignant hyperthermia (MH).

Synonyms

Muscle Core Disease; Muscular Central Core Disease; Central Fibrillary Myopathy; Shy-Magee Syndrome.

History

First described in 1956 by the American physicians G. Milton Shy and Kenneth R. Magee in four males and one female from three generations of one family.

Incidence

Unknown, but Central Core Disease (CCD) accounts for approximately 15% of all congenital myopathies and is considered the most common congenital myopathy. No sexual predilection.

Genetic inheritance

Most cases are inherited in an autosomal dominant manner, but autosomal recessive transmission has also been reported. CCD results from missense mutations in the RYR1 (Skeletal Muscle Ryanodine Receptor 1) gene, which has been mapped to chromosome 19q13.2. The proportion of de novo mutations (autosomal dominant variant) causing CCD is unknown, but most patients with autosomal dominant CCD have a (symptomatic or asymptomatic) parent with a pathogenic RYR1 variant. Inter- and even intrafamilial expression is highly variable. CCD and MH-susceptibility are allelic conditions. Pathogenic RYR1 variants associated with MH-susceptibility are typically located in the hydrophilic N-terminal or central portions of the RYR1 protein, whereas RYR1 variants associated with CCD mainly affect the hydrophobic C-terminal, pore-forming region of the Ca²⁺-release channel.

Pathophysiology

CCD can be caused by more than 80 different mutations in the RYR1 gene. The ryanodine receptor is a protein that is involved in Ca²⁺-release from the sarcoplasmic reticulum into the sarcoplasm. According to one common hypothesis, the RYR1 mutations result in extremely leaky Ca²⁺-release channels in the sarcoplasmic reticulum. It has been postulated that after the exposure to trigger agents, the ryanodine receptor releases excessive amounts of calcium leading to sustained muscle contraction (muscle rigidity), rhabdomyolysis, hyperkalemia, hypermetabolism, metabolic acidosis, and potentially death.

Diagnosis

Based on the clinical picture, muscle histology, molecular genetic testing, and family history. The “central core” is a histopathological description referring to an area of decreased staining and oxidative activity that extends the length of the muscle fiber and is devoid of mitochondria and other cell organelles. Central cores are predominately found in Type 1 muscle fibers. Marked Type 1 predominance or uniformity and hypotrophy are characteristic and may be the only abnormal features at presentation. In addition, it is known that the number and position of the cores can change with age. Molecular genetic testing is used to confirm one of the pathogenic mutations in the RYR1 gene. Nerve conduction studies are normal and electromyography nonspecific. Serum levels of creatinine phosphokinase (CPK) are generally normal, which does not rule out CCD, but baseline concentrations up to 6 to 14 times higher than normal have ...