Core myopathies

Goknur Haliloglu MD (Dr. Haliloglu of Hacettepe Children's Hospital in Ankara, Turkey, has no relevant financial relationships to disclose.)
Haluk Topaloglu MD (Dr. Topaloglu of Hacettepe Children's Hospital in Ankara, Turkey, has no relevant financial relationships to disclose.)
Harvey B Sarnat MD FRCPC MS, editor. (

Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.

)
Originally released September 18, 1994; last updated July 11, 2018; expires July 11, 2021

This article includes discussion of core myopathies within the group of congenital myopathies (CM), central core disease (CCD), and multiminicore disease (MmD). The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Congenital myopathies represent a clinically and genetically heterogeneous group of early-onset neuromuscular diseases with characteristic, but not always specific, histopathological features, often presenting with stable and/or slowly progressive truncal and proximal weakness. It is often not possible to have a diagnosis on clinical ground alone. Additional extraocular, respiratory, distal involvement, scoliosis, and distal laxity may provide clues (Dowling et al 2014).

The core myopathies collectively represent the most common form of congenital myopathies, and the name pathologically corresponds to histochemical appearance of focally reduced oxidative enzyme activity and myofibrillar changes on ultrastructural studies. Because of the clinical, pathological, and molecular overlaps, central core disease and multiminicore disease will be discussed together. Of note, cores can be seen in combination with nemaline rods and are termed “core-rod myopathies,” which is associated with a variety of different mutations.

The scope of this section is pure core myopathies: central core disease and multiminicore disease often associated with mutations in the skeletal muscle ryanodine receptor 1 (RYR1) and selenoprotein N1 (SEPN1; also known as SELENON according to new nomenclature).

Mutations in the skeletal muscle ryanodine receptor 1 (RYR1) gene are associated with dominantly inherited central core disease and subgroups of recessively inherited multiminicore disease, centronuclear myopathy (CNM), and congenital fiber type disproportion. Malignant hyperthermia susceptibility trait is a dominantly inherited allelic trait and is described as a pharmacogenetic predisposition to severe and potentially life-threatening reaction in response to halogenated anesthetic agents and depolarizing muscle relaxants.

RYR1-related malignant hyperthermia susceptibility is allelic to central core disease and has also been described as a common cause of induced and episodic phenotypes such as exertional rhabdomyolysis or periodic paralysis, which present throughout life. Late-onset presentations in the adulthood period highlight relevance of the congenital myopathies for adult neuromuscular practice.

A number of distinct phenotypes are seen in multiminicore disease, which is most commonly caused by recessive mutations in the RYR1 and SEPN1 genes. It has been linked to dominant mutations in the gene for beta-myosin heavy chain protein (MYH7) and autosomal recessive mutations of titin (TTN). Recessive mutations of satellite cell gene (MEGF10) are defined in patients with early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARRD).

Key points

 

• Core myopathies represent the most common form of congenital myopathies and are characterized pathologically by the absence of oxidative enzyme activity in the central area of myofibers representing mitochondrial depletion.

 

Central core disease and multiminicore disease are the most common congenital myopathy forms.

 

• Central core disease is dominantly inherited in most cases. Recessive central core disease is less common and often more severe, and it presents at a younger age. Most cases of central core disease are due to mutations in the gene for ryanodine (RYR1), a skeletal muscle calcium channel receptor.

 

RYR1-related malignant hyperthermia susceptibility trait is an allelic condition to central core disease. RYR1 mutations may present in the adulthood period as induced and episodic phenotypes, such as exertional rhabdomyolysis and periodic paralysis.

 

• Major causes of multiminicore disease are recessively inherited mutations in the genes encoding selenoprotein N (SEPN1) and RYR1. Other rare causes are recessive mutations in TTN, MEGF10, and CACNA1S, and dominant mutations in MYH7 and CACNA1S.

 

Head lag and neck flexor weakness may evolve to rigid spine deformity. Patients with rigid spine deformity and scoliosis should be managed in terms of early respiratory insufficiency and nocturnal hypoventilation.

Historical note and terminology

In 1956, Shy and Magee described “a new congenital nonprogressive myopathy” characterized by a distinctive microscopic appearance on skeletal muscle biopsy (Shy and Magee 1956). It was the first recognition of the congenital myopathies, the diagnosis of which was based on the distinct structural or histochemical changes in biopsied skeletal muscle, as a distinct group of diseases.

This disorder was then named central core disease (Greenfield et al 1958), and an absence of oxidative enzyme and phosphorylase reactivity in the cores were demonstrated on muscle biopsy in these patients (Dubowitz and Pearse 1960).

In 1971, Engel and colleagues described a patient with multiple small cores within muscle fibers (Engel at al 1971), which were later renamed as “multicores,” “minicores,” “focal loss of cross-striation,” “target-like lesions,” and “miniature cores;” multiminicore disease is now the preferred terminology (Ferreiro et al 2002).

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