Understanding the Impact of Non-Dystrophic Myotonia on Patients and Caregivers: Results from a Burden of Disease Healthcare Survey

Non-dystrophic myotonias (NDM) manifest as delayed muscle relaxation leading to muscle stiffness. This may diminish or worsen with repeated contractions, depending on NDM subtype. These are divided into those affecting the chloride channel CLC-1, due to CLCN1 gene mutations, and those affecting the sodium channel NaV1.4, due to SCN4A gene mutations. Depending on NDM subtype, additional symptoms and clinical signs of NDM can include transient weakness, myalgia, cramps, fatigue, dysphagia, dysphonia, and muscle hypertrophy. Two surveys, carried out independently but collectively named IMPACT (Impact of non-dystrophic Myotonia on PAtients and Caregivers’ qualiTy of life), were conducted to help elucidate how symptoms affect adults with NDM and those who care for adults or children with this condition. The patient survey not only confirmed NDM symptoms experienced by participants, but also highlighted how such symptoms affect a person’s quality of life, mental health, and abilities including problems with work, study, childcare, and socialising. Additionally, details of the diagnostic pathway, treatment, and healthcare professionals involved in NDM were revealed. The caregiver survey found that almost one-third of those who cared for someone with NDM did so for at least 10 hours per week. It also highlighted how a carer’s physical and mental health could be impacted by caregiving, potentially due to the finding that half of respondents felt that they had little or no support. Presented here are highlights of the IMPACT survey along with insights from five NDM clinical experts: Jordi Diaz-Manera, Channa Hewamadduma, Giovanni Meola, Federica Montagnese, and Sabrina Sacconi

Association of the Charcot–Marie–Tooth disease gene ARHGEF10 with paclitaxel induced peripheral neuropathy in NCCTG N08CA (Alliance)

The predisposition of patients to develop polyneuropathy in response to toxic exposure may have a genetic basis. The previous study Alliance N08C1 found an association of the Charcot-Marie-Tooth disease (CMT) gene ARHGEF10 with paclitaxel chemotherapy induced peripheral neuropathy (CIPN) related to the three non-synonymous, recurrent single nucleotide variants (SNV), whereby rs9657362 had the strongest effect, and rs2294039 and rs17683288 contributed only weakly. In the present report, Alliance N08CA was chosen to attempt to replicate the above finding. N08CA was chosen because it is the methodologically most similar study (to N08C1) performed in the CIPN field to date. N08CA enrolled patients receiving the neurotoxic chemotherapy agent paclitaxel. Polyneuropathy was assessed by serial repeat administration of the previously validated patient reported outcome instrument CIPN20. A study wide, Rasch type model was used to perform extreme phenotyping in n=138 eligible patients from which “cases” and “controls” were selected for genetic analysis of SNV performed by TaqMan PCR. A significant association of ARHGEF10 with CIPN was found under the pre-specified primary endpoint, with a significance level of p=0.024. As in the original study, the strongest association of a single SNV was seen for rs9657362 (odds ratio=3.56, p=0.018). To further compare results across the new and the previous study, a statistical “classifier” was tested, which achieved a ROC area under the curve of 0.60 for N08CA and 0.66 for N08C1, demonstrating good agreement. Retesting of the primary endpoint of N08C1 in the replication study N08CA validated the association of ARHGEF10 with CIPN