Core myopathies

Core myopathies are congenital muscle disorders historically classified by their biopsy appearance. Two principal patterns are recognised: central core disease, with single fibre-spanning cores predominantly in type-I muscle fibres, and multi-minicore disease, with multiple shorter cores lacking fibre-type specificity; additional patterns include dusty cores and combined core-rod histology. Clinical severity ranges from asymptomatic or paucisymptomatic hyperCKaemia to profound neonatal hypotonia with respiratory failure, with most affected individuals showing symmetric proximal weakness, variable facial and neck-muscle involvement, and delayed but ultimately independent ambulation. Age of onset spans the antenatal period (severe multi-minicore forms with arthrogryposis multiplex congenita) through infancy and early childhood to adolescent or adult presentation. Both nonsyndromic forms with isolated muscle involvement and syndromic forms (King-Denborough syndrome with dysmorphic features; STAC3 disorder with kyphoscoliosis and cleft palate) are recognised, and susceptibility to malignant hyperthermia is an important anaesthetic consideration in RYR1-related forms.

The estimated prevalence of core myopathy is approximately 1/270,000 (95% CI 1/476,000 to 1/189,000). By definition, all core myopathies are monogenic disorders.

A large number of genes have been associated with core myopathies. The genetic forms group into central core and multi-minicore patterns, with additional syndromic histologies; the most common cause is RYR1. Examples include central core disease (autosomal dominant; RYR1), multi-minicore disease (SELENON, rigid spine, respiratory failure), and STAC3 disorder (STAC3, kyphoscoliosis, malignant hyperthermia risk).

The genetic conditions associated with core myopathies follow heterogeneous inheritance patterns. Central core disease and King-Denborough syndrome are typically autosomal dominant, while classic multi-minicore disease, dusty core disease, and STAC3 disorder are autosomal recessive; some RYR1-related forms occur with biallelic recessive variants. De novo variants are reported in dominant forms.

• Where core myopathies are suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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