Refined exercise testing can aid dna‐based diagnosis in muscle channelopathies

Abstract

Objective-To improve the accuracy of genotype prediction and guide genetic testing in patients with muscle channelopathies we applied and refined specialised electrophysiological exercise test parameters.Methods-We studied 56 genetically confirmed patients and 65 controls using needle electromyography, the long exercise test, and short exercise tests at room temperature, after cooling, and rewarming.Results-Concordant amplitude-and-area decrements were more reliable than amplitude-only measurements when interpreting patterns of change during the short exercise tests. Concordant amplitude-and-area pattern I and pattern II decrements of >20% were 100% specific for PMC and MC respectively. When decrements at room temperature and after cooling were <20%, a repeat short exercise test after rewarming was useful in patients with myotonia congenita. Area measurements and rewarming distinguished true temperature sensitivity from amplitude reduction due to cold-induced slowing of muscle fibre conduction. In patients with negative short exercise tests, symptomatic eye closure myotonia predicted sodium channel myotonia over myotonia congenita. Distinctive 'tornado-shaped' neuromyotonia-like discharges may be seen in patients with paramyotonia congenita. In the long exercise test, area decrements from pre-exercise baseline were more sensitive than amplitude decrements-from-maximum-CMAP in patients with Andersen-Tawil syndrome. Possible ethnic differences in the normative data of the long exercise test argue for the use of appropriate ethnically-matched controls.Interpretation-Concordant CMAP amplitude-and-area decrements of >20% allow more reliable interpretation of the short exercise tests and aid accurate DNA-based diagnosis. In patients

Heterozygous CLCN1 mutations can modulate phenotype in sodium channel myotonia

“…Hundred percent of the recessive and 71% of the dominant MC patients displayed pattern II after combination of tests performed at room temperature and cold [7]. Moreover, the area decrement was 27% in the first case and 57.9% in the second case which, according to Tan et al [9], is specific to the type II pattern. In patient 3, the provocative tests showed a type III pattern, in this case the mixed clinical presentation led us to perform CLCN1 sequencing.…”

“…It comprised short and long exercise tests and needle examination. Short exercise test (SET) has been shown to be a reliable biomarker to distinguish between SCN4A and CLCN1 mutations [6][7][8][9]. Molecular testing was performed after informed consent of the patients or their parents, accordingly to bioethics laws.…”

Electrodiagnosis of Myotonic Disorders

“…In addition to myotonic discharges, low-amplitude (100-600 mV), high-frequency (150-250 Hz) discharges resembling neuromyotonic discharges have recently been observed in some NDM patients. 16 Occasionally, repetitive firing of muscle fibers following a single stimulus termed "postexercise myotonic potentials" can be observed as delayed lower amplitude motor responses following the compound motor action potential (CMAP) during performance of routine nerve conduction studies. 14 Postexercise myotonic potentials are described in both SCN4A and CLCN1 mutations.…”

“…10,13 SCM can also be distinguished from PC and chloride channelopathies based on electrodiagnostic testing(see later discussion). [14][15][16] Electrodiagnosis of NDM Commercial genetic testing is available for some of the causative mutations in NDM, but there is a false-negative rate in these conditions as high as 20%. 17 Electrodiagnostic studies are extremely helpful in directing genetic testing and also making the diagnosis of NDM in patients with negative genetic testing.…”

“…12,14,15 Repeating the protocol with limb cooling (to 20-25 C) improves the sensitivity in MC (70%-100%) and exaggerates the abnormality observed in PC. 15,16 Three patterns are observed in patients with NDM, Fournier I, II, and III. 10,14,15 Patients with PC exhibit Fournier pattern I with a decrement in CMAP amplitude (19%-40% less than preexercise baseline CMAP), which persists for 60 seconds and which increases with subsequent trials and with cooling ( Fig.…”