Table 1.

Clinical and histological features of patients with RYR1 c.12083C>T (p.Ser4028Leu) mutation

Family	Patient	Inheritance	Onset	First signs	Age at last examination	Signs at last examination	Age at muscle biopsy	Muscle morphology	Additional signs
1	1	Dominant	Childhood	Elongated face, dysmorphy, proximal muscle weakness	72	Proximal and distal muscle weakness, steppage gait, requires cane, difficulties climbing stairs, VC 40%	66	Type I fiber atrophy, fiber size variability, mitochondrial mispositioning, elongated mitochondria with crystalloid inclusions, lipid droplets	Ventricular hypertrophy
	2		Childhood	Delayed motor milestones	53	Facial weakness, proximal and axial muscle weakness, difficulties climbing stairs, no running, no jumping, Gowers’s sign	-	N.A	High-arched palate, low serum CK
	3		Infancy	Hypotonia, elongated face, delayed motor milestones	14	Proximal and axial muscle weakness, difficulties climbing stairs, no running, no jumping, hypotonia,	-	N.A	High-arched palate, low serum CK
2	4	Dominant	Infancy	Delayed motor milestones	39	Mild axial muscle weakness, myalgia, joint hyperlaxity, difficulties climbing stairs, MH episode	-	N.A	High-arched palate
	5		Neonatal	Severe hypotonia, delayed motor milestones, recurrent infections	3	Axial muscle weakness, hypotonia, joint hyperlaxity, difficulties climbing stairs	1	Type I and II fiber atrophy	Cardiorespiratory arrest at age 4
	6		Neonatal	Severe hypotonia, delayed motor milestones, respiratory distress, recurrent infections	5	Axial muscle weakness, joint hyperlaxity, fatigability, difficulties climbing stairs, Gowers’s sign	4	Type I fiber predominance, fiber size variability	-
3	7	De novo	Antenatal	Hydramnios, fetal macosomia, severe neonatal hypotonia, respiratory distress, elongated face	20	Facial diplegia, ophthalmoplegia, axial and limb girdle weakness, difficulties climbing stairs, no running, no jumping, Gowers’s sign, VC 70%		Type I fiber predominance, lipid droplets	High-arched palate, scoliosis
4	8	De novo	Neonatal	Hypotonia	3	Delayed motor milestones, joint hyperlaxity	1	Type I fiber predominance, rods, lipid droplets, lipofuscin granules	Pes planus
5	9	De novo	Neonatal	Hypotonia, delayed motor milestones	16	Mild ptosis, axial weakness, no running, no jumping, Gowers’s sign, VC 72%	3	Type II fiber atrophy, internal nuclei	Hallux valgus
6	10	Possibly dominant	Infancy	Delayed motor milestones, frequent falls	48	Ophthalmoparesis, axial and distal weakness, myalgia, steppage gait, fatigability, joint hyperlaxity, VC 75%	28	Type I fiber predominance, internal nuclei	High-arched palate, mild scoliosis
7	11	Possibly dominant	Infancy	Delayed motor milestones, elongated face	43	Mild facial weakness, mild ophthalmoparesis, axial and proximal weakness, frequent falls, fatigability, difficulties climbing stairs, myalgia, Gowers’s sign, VC 83%	33	Type I fiber predominance, fiber size variability, mitochondrial mispositioning	High-arched palate, mild scoliosis
8	12	De novo	Neonatal	Hypotonia, delayed motor milestones	15	Mild axial, girdle, and lower limb weakness, fatigability, Gowers’s sign, joint hyperlaxity	3	Type I fiber predominance, fiber size variability, cores	Moderate asthma, scoliosis, pes cavus
9	13	Sporadic	Infancy	Frequent falls, abnormal gait	15	Mild facial and limb girdle weakness, fatigability, difficulties climbing stairs, joint hyperlaxity, VC 65%	9	Fiber size variability, internal nuclei	High-arched palate, pes cavus

NA = not assessed; CK = creatine kinase; VC = vital capacity