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Table 1 Clinical and histological features of patients with RYR1 c.12083C>T (p.Ser4028Leu) mutation

From: A recurrent RYR1 mutation associated with early-onset hypotonia and benign disease course

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