Lancet neurology
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Duchenne muscular dystrophy is an X-linked disease caused by the absence of functional dystrophin in the muscle cells. Major advances have led to the development of gene therapies, tools that induce exon skipping, and other therapeutic approaches, including treatments targeting molecular pathways downstream of the absence of functional dystrophin. However, glucocorticoids remain the only treatment unequivocally shown to slow disease progression, despite the adverse effects associated with their long-term use. ⋯ Several compounds with promising results in early-phase clinical trials have not met their efficacy endpoints in late-phase trials, but the clinical development of many other compounds is ongoing. The current landscape is complicated by the number of compounds in various stages of development, their various mechanisms of action, and their genotype-specific applicability. The difficulties of clinical development that arise from both the rarity and variability of Duchenne muscular dystrophy might be overcome in the future by use of sensitive biomarkers, natural history data, and ameliorated trial designs.
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Large-scale mapping studies have identified 236 independent genetic variants associated with an increased risk of multiple sclerosis. However, none of these variants are found exclusively in patients with multiple sclerosis. They are located throughout the genome, including 32 independent variants in the MHC and one on the X chromosome. ⋯ No single variant is necessary or sufficient to cause multiple sclerosis; instead, each increases total risk in an additive manner. This combined contribution from many genetic factors to disease risk, or polygenicity, has important consequences for how we interpret the epidemiology of multiple sclerosis and how we counsel patients on risk and prognosis. Ongoing efforts are focused on increasing cohort sizes, increasing diversity and detailed characterisation of study populations, and translating these associations into an understanding of the biology of multiple sclerosis.
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Tuberous sclerosis complex is a rare genetic disease associated with mutations in the TSC1 or TSC2 genes, which cause overactivation of the mTOR complex. In the past 5 years, understanding has increased of the cellular consequences of TSC1 and TSC2 genetic variants and the mTORC1 overactivation in neurons and glial cells and their contribution to network dysfunction. Infants and young children (aged 1-5 years) with tuberous sclerosis complex might now benefit from early assessment of gene variant status and mosaicism. ⋯ Vigabatrin has been used successfully as a treatment in infants with tuberous sclerosis complex who showed abnormalities on EEG before seizure onset. The scope for mitigation of tuberous sclerosis complex-associated symptoms has expanded, including the use of mTOR inhibitors such as sirolimus and everolimus. Close cooperation between clinical and basic neuroscientists has provided new opportunities for future advances.