CACNA1S-associated triadopathy presenting with myalgia, muscle weakness, and asymptomatic hyperCKemia

Abstract

CACNA1S variants can alter the structure and function of the calcium channel, resulting in abnormal calcium influx and homeostasis. It is well established that pathogenic variants in CACNA1S can lead to hypokalemic periodic paralysis, malignant hyperthermia, and congenital myopathy. Nevertheless, the clinical presentations and disease progression of exertional myalgia and weakness associated with CACNA1S variants remain elusive. In this study, four affected individuals from an autosomal-dominant family were described, exhibiting symptoms of severe exertional myalgia, followed by flaccid weakness or rhabdomyolysis, along with asymptomatic hyperCKemia during the interictal period. Long exercise test showed a late decrease in compound muscle action potential amplitude. Muscle MRI revealed edema-like changes in the early stage, and fatty degeneration and substitution in prolonged disease courses, while closely aligned with the features of chronic myopathy. Ultrastructural examination revealed dilation of the sarcoplasmic reticulum and myofibrillar structural disarrangement. Genetic screening identified a c.3724A>G (p.Arg1242Gly) mutation in the CACNA1S gene. A literature review revealed that 15 patients exhibited the exertional myalgia and weakness phenotype associated with CACNA1S mutations, presenting similar clinical, electrophysiological, radiological, and pathological features. As the disease progressed, these patients developed severe muscle weakness, ultimately leading to wheelchair dependency. This exertional myalgia-weakness phenotype represented a unique CACNA1S-related phenotype that broadened the spectrum of CACNA1S-associated myopathy, bridging between periodic paralysis and congenital myopathies. The similarities between CACNA1S-associated myalgia-weakness and RyR1-associated myalgia-weakness underscored a shared pathogenesis of excitatory-contractile coupling at the triad of skeletal muscle.

Keywords: CACNA1S; hyperCKemia; myalgia; ryanodine receptor; triad.

Figure 1.

Pedigree of the family. The square represents male and the circle represents female. The filled symbol indicates affected. The arrow indicates the proband.

Figure 2.

Long exercise test in the index patient showed that the CMAP amplitude decreased by 17% at 5 min postexercise, and ultimately reached a decrease of 50% from its peak at 105 min. CMAP, compound muscle action potential.

Figure 3.

Muscle MRI changes in the four affected patients. Muscle MRI of the proband revealed fatty degeneration and edema (a). Muscle MRI of patient III-1 showed no evidence of fatty infiltration in the lower limbs, whereas significant muscle edema was observed in muscles (b). Muscle MRI of patient III-2 revealed focal edema in the left quadriceps femoris muscle, while the leg muscles showed no abnormalities (c). Muscle MRI of patient III-3’s lower limb showed no significant abnormalities (d).

Figure 4.

Myopathological features of two biopsies of the index patient. The first biopsy at age 24 revealed regenerative and degenerative changes of muscle fibers (a), occasionally accompanied by infiltration of phagocytic cells (b); and abnormalities in the structure of the sarcoplasmic reticulum on NADH stain (c). The second biopsy at age 38 showed chronic myopathy changes with many fresh necrotic myofibers (d); inflammatory cells infiltration in myofibers and perimysium (e); and numerous small vacuoles in myofibers (f), devoid of glycogen (g), mitochondria (h), and lysosome (i). NADH stain showed atypical tubular aggregation in some muscle fibers (j) and abnormalities of the sarcoplasmic reticulum (k). MHC-I was positive in some myofibers (l). NADH, nicotinamide adenine dinucleotide tetrazolium reductase.

Figure 5.

Ultrastructural examination revealed numerous dilated tubular SR of various sizes in myofibrils (a). Many fused bubbly SR with large vacuoles in transverse sections (b). The border zone between a vacuole and a muscle fiber contained various dense materials (c). Z-line disorganization and streaming in some myofibrils (d). SR, sarcoplasmic reticulum.

Figure 6.

Genetic analysis in the family. (a) The proband had a heterozygous c.3724A>G variant in the CACNA1S gene. The mother (I-1, b) and the father (I-2, c) of the proband were wild genotype. The daughter (III-1, d), the son (III-2, e), and the little son (III-3, f) all carried a heterozygousc.3724A>G variant. Residue arginine 1242 had high evolutionary conservation (g).