Table 1. Diagnostic cues, histological... | Rockefeller University Press

Table 1.

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
CCD			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
MH			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
CCD			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
MH			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.

[ViewLarge]