Diagnostic cues, histological traits, and genes associated with main subtypes of E-C coupling and SOCE-related myopathies
| E-C coupling–related myopathies . | Main clinical features . | Fiber phenotype . | Causative genes . | Inheritance . | Mechanism (RyR1 channel) . |
|---|---|---|---|---|---|
| CCD | ✓ Infantile nonprogressive hypotonia and motor development delay ✓ Mild proximal muscle weakness ✓ Respiratory distress ✓ High arched palate ✓ Craniofacial dysmorphism | ✓ Centrally located, well-demarcated cores, spanning the whole fiber axis ✓ Predominance in type 1 fibers ✓ Increased central nuclei | RYR1 >90% | AD or AR | GoF, LoF |
| MYH7 | AD | Altered assembly and function of myosin dimers | |||
| MmD | ✓ Axial muscle weakness, scoliosis, respiratory insufficiency, and limb joint hyperlaxity ✓ Ophthalmoplegia ✓ Arthrogryposis ✓ Hand amyotrophy | ✓ Numerous cores in a limited area on longitudinal section ✓ Multiple internally located nuclei ✓ Predominance in type 1 fibers | RYR1 ∼20% (homozygosity or compound heterozygosity) | AR | GoF, LoF, lower protein levels |
| SEPN1 ∼50% | AR | Altered redox activity | |||
| TTN (homozygosity or compound heterozygosity) | AR | M-line alteration | |||
| MYH7 | AD | Not defined | |||
| ACTA1 | AR | Not defined | |||
| MEGF10 | AD or AR | Not defined | |||
| CACNA1S | AD | Lower protein levels | |||
| CNM | ✓ Not progressive proximal muscle weakness ✓ Not progressive hypotonia | ✓ Centralized and internalized nuclei ✓ Peripheral halos depleted of oxidative activity ✓ Cores | RYR1 ∼15% (compound heterozygosity) | AR | Lower protein levels |
| MTM1 | XLR | Altered vesicle trafficking | |||
| DNM2 | AD | Altered membrane fission | |||
| BIN1 | AD | Altered membrane tubulation | |||
| TTN | AR | M-line alterations | |||
| SPEG | AR | Altered interaction with MTM1 and desmin | |||
| CFTD | ✓ Static or slowly progressive muscle weakness ✓ Respiratory and proximal axial weakness ✓ Ophthalmoplegia ✓ Dysphagia ✓ Facial muscle weakness | ✓ Fiber size disproportion (35–40% of type 1 fibers are smaller in size than type 2 fibers) ✓ Age-related development of rods, cores, and central nuclei | RYR1 ∼20% | AR | Lower protein levels |
| ACTA1 | AD | Altered interaction with TPM | |||
| TPM2 | AD or AR | Altered interaction with actin | |||
| TPM3 | AD or AR | Altered interaction with actin | |||
| SEPN1 | AR | Altered redox activity | |||
| MYH7 | AD | LoF, altered interaction with myosin binding protein | |||
| LMNA | AD | Not defined | |||
| ZAK | AR | LoF | |||
| SPEG | AR | LoF | |||
| DuCD | ✓ Ocular involvement (eyelid ptosis, ophthalmoplegia) | ✓ Irregularly sized/shaped “dusty” cores (reddish-purple granular material deposition) spanning 10–50 sarcomeres ✓ Myofibrillar disorganization | RYR1 | AR | Lower protein levels |
| CRM | ✓ Nonspecific clinical features, including hypotonia, muscle weakness, scoliosis, and respiratory insufficiency | ✓ Nemaline bodies (rods), clustered or widely distributed along the fibers ✓ Central cores | RYR1 | AD or AR | GoF, LoF |
| CFL2 | AR | Protein misfolding and degradation | |||
| ACTA1 | AD | Altered stability or function | |||
| TPM3 | AD or AR | Not defined | |||
| NEB | AR | Not defined | |||
| MH | ✓ Muscle rigidity and cardiac arrhythmia, occurring only following exposure to succinylcholine and volatile anesthetics ✓ Sustained contractures, ✓ Hyperthermia ✓ Hyperkalemia ✓ Hypermetabolism | ✓ No histological features can be found in muscle fibers from MH patients | RYR1 | AD | GoF |
| CACNA1S | AD | GoF | |||
| SOCE-related myopathies | |||||
| TAM/Stormorken syndrome | ✓ Muscle weakness ✓ Myalgia ✓ Cramps ✓ Increased creatine kinase levels ✓ Exercise intolerance | ✓ Single- or double-walled SR tubules arranged as honeycomb-like structures in type 2 fibers ✓ Prevalence of type 1 fibers | STIM1 | AD | GoF |
| ORAI | AD | GoF | |||
| CASQ1 | AD | Altered polymerization | |||
| RYR1 | AD | GoF | |||
| E-C coupling–related myopathies . | Main clinical features . | Fiber phenotype . | Causative genes . | Inheritance . | Mechanism (RyR1 channel) . |
|---|---|---|---|---|---|
| CCD | ✓ Infantile nonprogressive hypotonia and motor development delay ✓ Mild proximal muscle weakness ✓ Respiratory distress ✓ High arched palate ✓ Craniofacial dysmorphism | ✓ Centrally located, well-demarcated cores, spanning the whole fiber axis ✓ Predominance in type 1 fibers ✓ Increased central nuclei | RYR1 >90% | AD or AR | GoF, LoF |
| MYH7 | AD | Altered assembly and function of myosin dimers | |||
| MmD | ✓ Axial muscle weakness, scoliosis, respiratory insufficiency, and limb joint hyperlaxity ✓ Ophthalmoplegia ✓ Arthrogryposis ✓ Hand amyotrophy | ✓ Numerous cores in a limited area on longitudinal section ✓ Multiple internally located nuclei ✓ Predominance in type 1 fibers | RYR1 ∼20% (homozygosity or compound heterozygosity) | AR | GoF, LoF, lower protein levels |
| SEPN1 ∼50% | AR | Altered redox activity | |||
| TTN (homozygosity or compound heterozygosity) | AR | M-line alteration | |||
| MYH7 | AD | Not defined | |||
| ACTA1 | AR | Not defined | |||
| MEGF10 | AD or AR | Not defined | |||
| CACNA1S | AD | Lower protein levels | |||
| CNM | ✓ Not progressive proximal muscle weakness ✓ Not progressive hypotonia | ✓ Centralized and internalized nuclei ✓ Peripheral halos depleted of oxidative activity ✓ Cores | RYR1 ∼15% (compound heterozygosity) | AR | Lower protein levels |
| MTM1 | XLR | Altered vesicle trafficking | |||
| DNM2 | AD | Altered membrane fission | |||
| BIN1 | AD | Altered membrane tubulation | |||
| TTN | AR | M-line alterations | |||
| SPEG | AR | Altered interaction with MTM1 and desmin | |||
| CFTD | ✓ Static or slowly progressive muscle weakness ✓ Respiratory and proximal axial weakness ✓ Ophthalmoplegia ✓ Dysphagia ✓ Facial muscle weakness | ✓ Fiber size disproportion (35–40% of type 1 fibers are smaller in size than type 2 fibers) ✓ Age-related development of rods, cores, and central nuclei | RYR1 ∼20% | AR | Lower protein levels |
| ACTA1 | AD | Altered interaction with TPM | |||
| TPM2 | AD or AR | Altered interaction with actin | |||
| TPM3 | AD or AR | Altered interaction with actin | |||
| SEPN1 | AR | Altered redox activity | |||
| MYH7 | AD | LoF, altered interaction with myosin binding protein | |||
| LMNA | AD | Not defined | |||
| ZAK | AR | LoF | |||
| SPEG | AR | LoF | |||
| DuCD | ✓ Ocular involvement (eyelid ptosis, ophthalmoplegia) | ✓ Irregularly sized/shaped “dusty” cores (reddish-purple granular material deposition) spanning 10–50 sarcomeres ✓ Myofibrillar disorganization | RYR1 | AR | Lower protein levels |
| CRM | ✓ Nonspecific clinical features, including hypotonia, muscle weakness, scoliosis, and respiratory insufficiency | ✓ Nemaline bodies (rods), clustered or widely distributed along the fibers ✓ Central cores | RYR1 | AD or AR | GoF, LoF |
| CFL2 | AR | Protein misfolding and degradation | |||
| ACTA1 | AD | Altered stability or function | |||
| TPM3 | AD or AR | Not defined | |||
| NEB | AR | Not defined | |||
| MH | ✓ Muscle rigidity and cardiac arrhythmia, occurring only following exposure to succinylcholine and volatile anesthetics ✓ Sustained contractures, ✓ Hyperthermia ✓ Hyperkalemia ✓ Hypermetabolism | ✓ No histological features can be found in muscle fibers from MH patients | RYR1 | AD | GoF |
| CACNA1S | AD | GoF | |||
| SOCE-related myopathies | |||||
| TAM/Stormorken syndrome | ✓ Muscle weakness ✓ Myalgia ✓ Cramps ✓ Increased creatine kinase levels ✓ Exercise intolerance | ✓ Single- or double-walled SR tubules arranged as honeycomb-like structures in type 2 fibers ✓ Prevalence of type 1 fibers | STIM1 | AD | GoF |
| ORAI | AD | GoF | |||
| CASQ1 | AD | Altered polymerization | |||
| RYR1 | AD | GoF | |||
Proteins encoded by the indicated genes and relative references are reported in the text. AD, autosomal dominant; AR, autosomal recessive; GoF, gain-of-function; LoF, loss-of-function; XLR, X-linked recessive.