Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Core Myopathies - RYR1-related Myopathies [M62.5]

OMIM numbers: 117000 (central core disease, CCD),  255320 (multiminicore myopathy, MmD), 255310 (congenital fiber-type disproportion, CFTD), 160150 (centronuclear myopathy, CNM), 180901 RYR1

Dr. rer. biol. hum. S. Chahrokh-Zadeh

Scientific Background

The congenital myopathies represent an own disease entity among the myopathies, which generally are present from birth on with a slow or non-progressive course. Fatal and late adult-onset forms are known as well. It is a rare heterogenous group of disease with an estimated prevalence of 1:25,000 and a very variable spectrum of symptoms. So far mutations in more than 20 genes are known which can cause a muscle disease from this group.

Main symptoms are muscle weakness and wasting as well as symmetrical, proximal paresis without sensory symptoms. Historically it was tried to classify the different (sub)types based on muscle biopsies. Structural abnormalities within the muscle fibers like structural defects, abnormal inclusions and/or core anomalies may be found. A common feature is a basic myopathological pattern of fibre type disproportion, i.e. a numeric predominance and selective hypertrophia of the type 1 fibres compared to the norm (reduction of the diameter of the type I muscle fibres of at least 12% compared to type II muscle fibers). A distinct classification is often difficult, on the one hand some types may be caused by mutations in different genes and on the other mutations in one gene may give rise to different types. In most cases a definit diagnosis can be made or confirmed by molecular genetic analysis.

Central core disease (CCD), centronuclear myopathy (CNM) and nemaline myopathy belong to the more common, longer known and therefore classical congenital myopathies. Other histopathological variants are for example multiminicore disease (MmD), congenital fiber-type disproportion (CFTD), and the King Denborough syndrome.

Autosomal dominant as well as autosomal recessive mutations in the RYR1 gene are the most common cause of the congenital myopathies. The gene product is a calcium releasing channel in the skeletal muscle, which is associated with the coupling of excitation and contraction. Dominant mutations in this gene are linked with CCD and or susceptibility for malignant hyperthermia (MHS), whereas recessive mutations can be found in patients with MmD, CNM and CFTD.

CCD usually presents from birth on with hypotonia and motor developmental delay. Mainly affected are proximal muscle groups. In muscular biopsy substrate defective cores can be found under oxidative enzymatic staining due to missing mitochondria. It is of special clinical significance that patients with central core myopathy often show a predisposition for malignant hyperthermia, a clinical syndrome which can emerge as a life threatening complication of an inhalation anesthesia (see malignant hyperthermia).

Sanger sequencing of the RYR1 gene can be requested if a congenital myopathy, a core myopathy or CCD/MmD/CNM/CFTD is suspected.

Alternatively parallel sequencing of the following genes can be requested either as a complete NGS panel or as a subpanel:

1. subpanel core myopathies (CCD/MmD): SEPN1, RYR1, ACTA1, TTN
2. subpanel CNM: RYR1, MTM1, DNM2, BIN1
3. subpanel CFTD: RYR1, TPM3, ACTA1, TPM2, SEPN1