Central Core Myopathy

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BACKGROUND AND CLINICAL INFORMATION: Head  Clinical features    Genetics

Summary: This is the first congenital myopathy being recognized. Central core disease is most often seen in children but can also become symptomatic in adults. Some of them remain asymptomatic. Most of the cases are transmitted in an autosomal dominant fashion, some putative autosomal recessive cases have been reported. Mutations in the gene for the ryanodine receptor (RYR1) on chromosome 19q have been found in some patients with central core disease; all appear to be missense mutation. Patients are susceptible to develop malignant hyperthermia. The pathologic hallmark is a centrally located core in a muscle fiber that is composed of disorganized myofibrils. Histochemically, the core does not contain oxidative enzymes and appears as pale areas on NADH-TR, SDH and cytochrome C oxidase preparations. 

Clinical features:

·        Central core disease typically presents with mild and non-progressive muscle weakness during infancy or childhood and is associated with delayed development of motor milestones. The weakness is either proximal or generalized and there is usually a mild degree of facial weakness. Severe infantile hypotonia, however, is not a typical feature. Some cases may first present in adults or remain completely asymptomatic. Patients may have painless or almost pianless cramps after exercise.

·        Congenital dislocation hip dislocation, pes cavus, and kyphoscoliosis are common. Patients may have bizzare posture at presentation. Some patients may have significant disability and are wheelchair bound.

·        CPK is sometimes increased.

·        Malignant hyperthermia: Patients with central core disease are susceptible to malignant hyperthermia. Malignant hyperthermia is also autosomal dominant. Mutation of the sarcoplasmic reticulum ryanodine receptor (RYR1) gene is detected in about half of the families with malignant hyperthermia. In others, malignant hyperthermia is linked with the CACNAIS gene on chromosome 1q (encoding the a1-subunit of the human skeletal muscle dihydropyridine-sensitive L-type voltage-dependent calcium channel protein) and several other loci, including the CACNLA2 gene on chromosome 7q. The caffeine-halothane contracture test (CHCT) is the only recognized laboratory test to diagnose malignant hyperthermia (Allen GC et al., Anesthesiology. 1998 Mar;88(3):579-88). (Malignant Hyperthermia Society of the United States)

Pathogenesis: The relationship of RYR1 gene mutation and pathogenesis of central core disease has not been established. However, RYR 1 protein has been identified in core regions by immunohistochemistry.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head  

Cores:  

·        Morphology: Cores are not seen in paraffin HE sections. Typical cores are solitary round abnormal regions in the center of the fiber and have a smudgy appearance in Gomori’s modified trichrome. The core may be eccentric or central. Cores usually occupy 30-60% of the cross-sectional area of fibers. Typically type 1 fibers are involved and the proportion of fiber involved is quite variable from muscle to muscle. Structured cores refer to those with contracted myofibrils (under EM) that retain their striated pattern and preserved ATPase activity. Unstructured cores show severe disruption of myofibrils and lack of ATPase activity. The amount of cores increase with age.

·        Semithin sections: Cores are best seen on longitudinal sections but can also be seen in cross sections. Concentration of lipid droplets between the core and non-core zone may be present. Z-disc streaming is often present in the cores.  

·        Histochemistry: The cores have decreased oxidative enzyme activity and are thinly rimmed by areas with increased oxidative enzyme. They also stain pale on PAS and also thinly rimed with areas that that stain strongly with PAS. ATPase may be slightly less than normal but the staining is smudgy. It is very often that there is a type 1 fiber predominance.  

                Target fibers for comparison

·        Immunohistochemistry: Expression of desmin is reduced or in form of strongly positive spots within the cores. Desmin positive rims can also be observed. Increased expression of desmin is seen in the non-core zones. Immunohistochemistry is a good way to demonstrate the length of the cores in longitudinal sections since they are more available in paraffin sections.

·        EM: Cores are composed of myuofibrils with wavy Z-disc and contracted sarcomeres; Z-disc streaming may be present. Myofibrils of the cores are smller, less well defined, and more closely packed. The amount of mitochondria and glyocogen between the myofibrils are reduced. Mitochondria and lipid droplets may accumulate around the cores. All cores show an absence of mitochondria.

DIFFERENTIAL DIAGNOSIS: Head

Target fiber: Differences between target fibers and cores are as follows: