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Core Myopathies

Klinische Symptomatik

Core myopathies are a clinically and genetically heterogeneous group of congenital myopathies. The name derives from the characteristic regions (“cores”) with focal reduction of oxidative enzyme activity found in muscle biopsies. Depending on to how pronounced these regions are, a distinction can be made between “central core myopathies” (CCD) and “multiminicore myopathies” (MmD). However, a clear histological classification is not always possible; the histology can change over the course of the disease and may show some overlap. In early clinical stages, often only one type 1 fiber predominance can be identified.

Genetically, CCD is associated with mutations in the gene RYR1; MmD is predominantly associated with mutations in the gene SEPN1. Finally, the histological presence of “cores” is not considered to be specific to these genes, as cores have also been described in connection with pathogenic mutations in other genes (MYH7, ACTA1, TNNT1, CFL2).

Central Core Myopathy (CCD)

The clinical manifestation of central core myopathy can be varied. In many cases, the course of the disease is mild, with symmetrical weakness of the proximal musculature and varying involvement of the facial musculature, usually without affecting the extra-ocular musculature and without bulbar and diaphragmatic involvement. Life expectancy is normal; the course of the disease often stabilizes in adulthood.

Severe clinical manifestation of CCD, however, exhibits features of “floppy infant” syndrome, often accompanied by reduced fetal movement, deformities of the spine, congenital hip malposition, joint contractures, difficulties swallowing, and respiratory insufficiency requiring mechanical ventilation. Motor development is delayed. The course of the disease varies from early infant death to survival beyond the first year. This form of CCD is typically without progressive muscle weakness.

Creatine kinase (CK) in blood serum is often normal or only slightly high in both forms of CCD. Cognitive abilities are not impaired.

Since RYR1 mutations are also associated with a risk for malignant hyperthermia, patients with RYR1 mutations require trigger-free anesthesia.

Multiminicore Myopathy (MmD)

Multiminicore myopathy is characterized by axial and proximal muscle weakness, usually with slow progression. Four forms have been identified:

Classic MmD (approx. 75 % of all affected patients): Hypotonia and delayed motor development (especially delayed head control) at birth or in early childhood. In approximately two-thirds of affected patients, axial muscle weakness leads to progressive scoliosis, often beginning around the age of 8. As with any “rigid spine” syndrome, the leading symptom is an inability to bend the spine, especially in the lumbar and cervical regions, brought about by constant contracture of the extensors. A marked failure to thrive in childhood is also typical; many patients remain small and slender. There is varying involvement of the facial musculature with exception of the extra-ocular muscles. As a result of restricted respiration, secondary cardiac involvement is common. Despite respiratory insufficiency, patients often retain the ability to walk, made possible by the relative strength of the limb-girdle musculature and by the stabilization of the progression of the disease in late childhood. Late manifestation is normally associated with a better prognosis.

Moderate MmD with Hand Involvement (less than 10 % of all affected patients): Characteristic of this subgroup is distal weakness of the upper limbs and hyperlaxity of the joints. The lower extremities are relatively unaffected. Scoliosis and respiratory involvement are mild or absent.

Prenatal MmD with Arthrogryposis multiplex congenita (AMC) (less than 10 % of all affected patients): Characteristic of this form is generalized joint contractures at birth as the result of reduced fetal movement.

MmD with External Ophthalmoplegia (less than 10 % of all affected patients): Characteristic of this subgroup is hypotonia, axial and proximal muscle weakness, hyperlaxity of the joints, failure to thrive, and involvement of ocular musculature with external ophthalmoplegia at birth or in early childhood. Moderate respiratory involvement.

Genetik

Central core myopathies are caused by genetic mutations in the gene RYR1 (ryanodine receptor 1) located on chromosome 19q13.1. Autosomal dominant inheritance is common, autosomal recessive rare. The percentage of dominant de novo mutations that lead to sporadic cases of the disease with negative family history is unknown. Disease-causing mutations are most often missense mutations and rare in-frame deletions of one or more amino acids.

Genetic mutations in the genes SEPN1 (selenoprotein N) and RYR1 (ryanodine receptor 1) are responsible for approx. 50 % of all affected patients with multiminicore myopathy. Broad genetic heterogeneity is assumed. Mutations in SEPN1 are autosomal recessively inherited, are often truncated, and cause approx. 30 % of all cases of MmD in total and approx. 50% of all cases of classic MmD.

Moderate MmD with hand involvement and MmD with external ophthalmoplegia have been described in connection with autosomal recessive mutations in RYR1.

Häufigkeit

According to a study in the USA, MmD represents approx. 17 % of all congenital myopathies, CCD approx. 15 % (Amburgey K. et al. Ann Neurol 2011). In nearly 50 % of the cases of clinical myopathy in this study the biopsy was non-specific.

Methodik Next Generation Sequencing (NGS)

Parallele Sequenzierung mehrerer Gene


Material 2-4 ml EDTA-Blut
Dauer
3-6 Wochen

 

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