Introduction: Inherited myotonic disorders are genetically heterogeneous and associated with overlapping clinical features of muscle stiffness, weakness, and pain. Data on genotype-phenotype correlations are limited. In this study, clinical features and treatment patterns in genetically characterized myotonic disorders were compared. Methods: A retrospective chart review was completed in patients with genetic variants in CLCN1, SCN4A, DMPK , and CNBP to document clinical signs and symptoms, clinical testing, and antimyotonia medication use. Results: A total of 142 patients (27 CLCN1 , 15 SCN4A , 89 DMPK , and 11 CNBP ) were reviewed. The frequency of reported symptoms (stiffness, weakness, and pain) and electromyographic spontaneous activity were remarkably similar across genotypes. Most patients were not treated with antimyotonia agents, but those with non-dystrophic disorders were more likely to be on a treatment. Discussion: Among the features reviewed, we did not identify clinical or electrophysiological differences to distinguish CLCN1 - and SCN4A -related myotonia. Weakness and pain were more prevalent in non-dystrophic disorders than previously identified. In addition, our results suggest that medical treatments in myotonic disorders may be under-utilized.

Heterozygosity for missense variants and small in-frame deletions in GARS1 has been reported in patients with a range of genetic neuropathies including Charcot−Marie−Tooth disease type 2D (CMT2D), distal hereditary motor neuropathy type V (dHMN-V), and infantile spinal muscular atrophy (iSMA). We identified two unrelated patients who are each heterozygous for a previously unreported missense variant modifying amino-acid position 336 in the catalytic domain of GARS1. One patient was a 20-year-old woman with iSMA, and the second was a 41year-old man with CMT2D. Functional studies using yeast complementation assays support a loss-of-function effect for both variants; however, this did not reveal variable effects that might explain the phenotypic differences. These cases expand the mutational spectrum of GARS1-related disorders and demonstrate phenotypic variability based on the specific substitution at a single residue.

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes with a critical role in protein synthesis: charging tRNA molecules with cognate amino acids. Heterozygosity for variants in five genes (AARS1, GARS1, HARS1, WARS1, and YARS1) encoding cytoplasmic, dimeric ARSs have been associated with autosomal dominant neurological phenotypes, including axonal Charcot-Marie-Tooth disease (CMT). Missense variants in the catalytic domain ofYARS1were previously linked to dominant intermediate CMT, type C (DI-CMTC). Here, we report a patient with a missense variant of unknown significance predicted to modify residue 308 in the anticodon binding domain of YARS1 (p.Asp308Tyr). Interestingly, p.Asp308Tyr is associated with proximal-predominant motor neuropathy, which has not been reported in patients with pathogenicYARS1variants. We demonstrate that this allele causes a loss-of-function effect in yeast complementation assays when modeled inYARS1and the yeast orthologTYS1; structural modeling of this variant further supports a loss-of-function effect. Taken together, this study raises the possibility that certainYARS1variants cause proximal-prominent motor neuropathy and indicates that patients with this phenotype should be screened for genetic lesions inYARS1.