“CACNA1S-related myopathy is a rare heterogeneous disorder characterized by the onset of muscle weakness in early childhood. Typically, patients exhibit generalized hypotonia, delayed motor development, progressive axial and limb muscle weakness, swallowing difficulties, respiratory failure, ophthalmoplegia and ptosis. CACNA1S variants are also associated with hypokalemic periodic paralysis.
We present a 5-year-old boy born at full term from a regular pregnancy via vaginal delivery, no signs of generalized hypotonia. Motor development was regular, except for the lack of proper head control. With the acquisition of independent walking he developed severe scoliosis (progressed to a Cobb angle of 35°), experienced frequent falls, easy fatigue and mild limb-girdle weakness worsening with prolonged exertion. He shows neither facial weakness, ophthalmoplegia, nor ptosis. CK value was normal. Muscle MRI of the pelvis, thighs, shoulders and neck did not show muscular atrophy or fat replacement. Electromyography showed mixed neurogenic-myogenic signs and a decremental response to repetitive stimulation (RNS) in the right deltoid muscle. Salbutamol treatment was started, resulting in improved exercise tolerance.
Next Generation Sequencing identified a heterozygous pathogenic variant c.3334T>G (p.Trp1112Gly) in CACNA1S. The CACNA1S gene encodes the α-1s subunit of the dihydropyridine receptor (DHPR), which serves as a voltage-gated calcium channel and voltage sensor for calcium release in skeletal muscle. DHPR plays a crucial role in the triad system essential for effective excitation–contraction coupling. This mechanism likely explains the response to Salbutamol. To our knowledge, a decremental response to RNS was not previously reported in CACNA1S-related myopathy and may account for the exercise intolerance.”