CACNA1S Variant Associated With a Myalgic Myopathy Phenotype

Abstract

Background and objectives: This study aimed to characterize the phenotype of a novel myalgic myopathy encountered in a Finnish family.

Methods: Four symptomatic and 3 asymptomatic individuals from 2 generations underwent clinical, neurophysiologic, imaging, and muscle biopsy examinations. Targeted sequencing of all known myopathy genes was performed.

Results: A very rare CACNA1S gene variant c.2893G>C (p.E965Q) was identified in the family. The symptomatic patients presented with exercise-induced myalgia, cramping, muscle stiffness, and fatigue and eventually developed muscle weakness. Examinations revealed mild ptosis and unusual muscle hypertrophy in the upper limbs. In the most advanced disease stage, muscle weakness and muscle atrophy of the limbs were evident. In some patients, muscle biopsy showed mild myopathic findings and creatine kinase levels were slightly elevated.

Discussion: Myalgia is a very common symptom affecting quality of life. Widespread myalgia may be confused with other myalgic syndromes such as fibromyalgia. In this study, we show that variants in CACNA1S gene may be one cause of severe exercise-induced myalgia.

Figure 1. Pedigree of the Family

In addition to 4 living symptomatic patients, 3 sons of II:2 were examined. The deceased father I:1 had complained of symptoms similar to those of his sons but was never neurologically examined. There were no other family members than those in pedigree.

Figure 2. Changes in CMAP Amplitude in ADM Muscle During the Long Exercise Test

Small circles represent the mean of CMAP amplitude compared with each participant's own pre-exercise value. CI is 95%. Arrow indicates exercise beginning after baseline values were obtained. The following time intervals indicate the time that had passed after cessation of 5-minute exercise. The first postexercise value was recorded 2 seconds after cessation of exercise. ADM = abductor digiti minimi; CMAP = compound muscle action potential.

Figure 3. Muscle Biopsy

Muscle biopsy from the right deltoid muscle (cap. med.) from patient III:1. Light microscope images at 400× magnification. (A) Hematoxylin and eosin–stained biopsy section with slightly increased number of internalized nuclei. (B and C) Double myosin immunohistochemistry shows considerable fiber size variation being more pronounced in the fast fibers (red). (D) Mild central “moth-eaten” irregularity of oxidative enzyme activity in both fiber types by nicotinamide adenine dehydrogenase staining.

Figure 4. MRI

Transverse T1-weighted MR images of II:2 showing slightly increased generalized and diffuse fatty replacement being more pronounced than would be expected for a person his age in (A) all thigh muscles and (B) lower legs.