Impact of restricted access to, and low awareness of, mexiletine on people with myotonia: a real-world European survey.

Although mexiletine effectively treats myotonia, supply disruptions affected Europe between 2008-2018. MyoPath was a mixed-methods, cross-sectional, market research survey conducted January-June 2018 to evaluate consequences of limited access to/awareness of mexiletine in people with myotonia. Part A: qualitative structured interviews (clinicians; advocates for adult patients); Part B: quantitative online questionnaire completed by people with self-reported history of myotonia. Part A: Interviews (clinicians, n=12; patient advocates, n=5; 12 countries) indicated poor mexiletine awareness among general neurologists. Patients chose between living with myotonia (other treatments were generally unsatisfactory) or importing mexiletine. Part B: Questionnaire respondents, myotonic dystrophy (DM)1, n=213; DM2, n=128; non-dystrophic myotonia (NDM), n=41; other n=8; (11 countries). Of the respondents, 76/390 (20%) people with awareness of/access to mexiletine described profound improvements in myotonia and health-related quality of life following treatment. Respondents with NDM had greatest mexiletine experience (n=28/41). Mexiletine was associated with fewer falls, less muscle stiffness, increased mobility. Treatment interruptions worsened myotonia and were associated with fatigue, pain, dysphagia, breathing difficulty, impaired digestion, poor sleep. However, 36/54 (67%) of currently treated people expressed anxiety about mexiletine's availability: this finding was expected (MyoPath was undertaken before mexiletine's approval in NDM). MyoPath provides the largest European exploration of patients' views regarding impact of mexiletine on myotonia. Anticipated effects of mexiletine differ between people with different myotonic disorders: myotonia is the main symptom in NDM but one of many potential symptoms affecting those with DM. Nevertheless, findings indicate substantial harm caused to people with myotonia when mexiletine awareness/access is limited.

C-Myc-independent restoration of multiple phenotypes by two C-Myc target genes with overlapping functions.

C-MYC, a transforming oncogene that is frequently overexpressed in many human cancers, regulates a variety of normal functions including cell cycle progression, apoptosis, and maintenance of cell size, morphology, and genomic integrity. Many target genes are modulated by c-Myc, and some can recapitulate a limited number of the above functions. Because most of these have been assessed in cells which also express endogenous c-Myc, however, it is not clear to what extent its proper regulation is also required. We show here that, in c-Myc nullizygous cells, two direct target genes, MT-MC1 and HMG-I, could each recapitulate multiple c-Myc phenotypes. Although these differ somewhat for the two genes, substantial overlap and cooperativity exist. The enforced expression of these two genes was also associated with the differential deregulation of some previously described c-Myc target genes, indicating the presence of a complex molecular circuitry. These observations argue that, despite the great diversity of gene regulation by c-Myc, many, although not all, of its functions can be phenocopied by a small subset of key downstream target genes. The approach described here should permit the identification of other target genes capable of further c-Myc-independent complementation.