Introduction: Paramyotonia congenita (PC; OMIM 168300) is a non-dystrophic myotonia caused by mutations in the SCN4A gene. Transient muscle stiffness, usually induced by exposure to cold and aggravated by exercise, is the predominant clinical symptom, and interictal persistent weakness is uncommon. Case presentation: We report a family with a history of PC accompanied by persistent distal hand dominant muscle weakness with masticatory muscle involvement. Persistent weakness was exacerbated with age, and MR analysis showed marked atrophy of temporal, masseter, and finger flexor muscles with fatty replacement. Cases within the family harbor the prevalent PC causative mutation, T1313M, in the SCN4A gene. Administration of acetazolamide chloride improved clinical
The abnormal expansion of GGGGCC hexanucleotide repeats within the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The accumulation of GGGGCC repeat-containing RNAs as RNA foci, and the deposition of dipeptide repeat proteins (DPR) produced from these repeat RNAs by unconventional translation are major pathological hallmarks of C9orf72-linked ALS/FTD (C9-ALS/FTD), and are both thought to play a crucial role in the pathogenesis of these diseases. Because GGGGCC repeat RNA is likely to be the most upstream therapeutic target in the pathogenic cascade of C9-ALS/FTD, lowering the cellular level of GGGGCC repeat RNA is expected to mitigate repeat RNA toxicity, and will therefore be a disease-modifying therapeutic strategy for the treatment of C9-ALS/FTD. In this study, we demonstrated using a Drosophila model of C9-ALS/FTD that elevated expression of a subset of human RNA-binding proteins that bind to GGGGCC repeat RNA, including hnRNPA3, IGF2BP1, hnRNPA2B1, hnRNPR, and SF3B3, reduces the level of GGGGCC repeat RNA, resulting in the suppression of neurodegeneration. We further showed that hnRNPA3-mediated reduction of GGGGCC repeat RNA suppresses disease pathology, such as RNA foci and DPR accumulation. These results demonstrate that hnRNPA3 and other RNA-binding proteins negatively regulate the level of GGGGCC repeat RNA, and mitigate repeat RNA toxicity in vivo, indicating the therapeutic potential of the repeat RNA-lowering approach mediated by endogenous RNA-binding proteins for the treatment of C9-ALS/FTD.
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