Pathogenic TNNI1 variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease.

Troponin I (TnI) regulates thin filament activation and muscle contraction. Two isoforms, TnI-fast (TNNI2) and TnI-slow (TNNI1), are predominantly expressed in fast- and slow-twitch myofibers, respectively. TNNI2 variants are a rare cause of arthrogryposis, whereas TNNI1 variants have not been conclusively established to cause skeletal myopathy. We identified recessive loss-of-function TNNI1 variants as well as dominant gain-of-function TNNI1 variants as a cause of muscle disease, each with distinct physiological consequences and disease mechanisms. We identified three families with biallelic TNNI1 variants (F1: p.R14H/c.190-9G>A, F2 and F3: homozygous p.R14C), resulting in loss of function, manifesting with early-onset progressive muscle weakness and rod formation on histology. We also identified two families with a dominantly acting heterozygous TNNI1 variant (F4: p.R174Q and F5: p.K176del), resulting in gain of function, manifesting with muscle cramping, myalgias, and rod formation in F5. In zebrafish, TnI proteins with either of the missense variants (p.R14H; p.R174Q) incorporated into thin filaments. Molecular dynamics simulations suggested that the loss-of-function p.R14H variant decouples TnI from TnC, which was supported by functional studies showing a reduced force response of sarcomeres to submaximal [Ca2+] in patient myofibers. This contractile deficit could be reversed by a slow skeletal muscle troponin activator. In contrast, patient myofibers with the gain-of-function p.R174Q variant showed an increased force to submaximal [Ca2+], which was reversed by the small-molecule drug mavacamten. Our findings demonstrated that TNNI1 variants can cause muscle disease with variant-specific pathomechanisms, manifesting as either a hypo- or a hypercontractile phenotype, suggesting rational therapeutic strategies for each mechanism.

Impact of prefrontal intermittent theta-burst stimulation on working memory and executive function in Parkinson's disease: A double-blind sham-controlled pilot study.

Cognitive impairment is a prevalent non-motor feature of Parkinson's disease (PD) which can present even in early stages of the disease. Impairments in executive processing and working memory (WM) are common and have been attributed, in part, to abnormalities within the dorsolateral prefrontal cortex (DLPFC) and broader fronto-striatal circuitry. Previous studies in cognitively normal adults have suggested intermittent Theta Burst Stimulation (iTBS), an excitatory plasticity-inducing non-invasive brain stimulation technique, can enhance these cognitive functions. Fourteen participants with a diagnosis of idiopathic PD received either Active or Sham iTBS over the left DLPFC across two separate experimental sessions as part of a double-blind sham-controlled crossover experimental design. The Berg's Card Sorting Test (BCST) and N-Back tasks, which measure executive function and WM respectively, were administered prior to iTBS and again five- and 30-minutes following stimulation. Despite being well-tolerated, iTBS failed to modulate performance on any of the cognitive outcome measures. This finding was further supported by Bayes Factor analyses which indicated moderate levels of support for the null hypothesis overall. This initial pilot study therefore does not support single-session iTBS as an efficacious method for modulating either executive processes or WM in PD. We discuss potential reasons for this finding along with directions for future research.