PubMed · 8275083
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A Sensi, N Ricci. 1993. Mitotic errors in trisomy 21.. https://doi.org/10.1038/ng1193-215a
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Down syndrome (DS) results from trisomy for human chromosome 21 and is the most frequent genetic cause of intellectual disability. No effective treatments currently exist that improve neurodevelopment and cognition. Atypical brain development in individuals with DS is apparent before birth, which suggests that the optimal time to begin administration of therapies is prenatally. Human neural progenitor cell (NPC) cultures provide a tractable in vitro model system to examine the effects of trisomy 21 (T21) on neurodevelopment and to measure the effects of pharmacological interventions. Here, we report the results of preclinical studies evaluating 24 candidate therapies. RNA sequencing analyses found that euploid and T21 NPCs showed different transcriptomic responses to five candidate pharmacotherapies. The Rho-associated coiled-coil kinase inhibitor fasudil increased proliferation of T21 NPCs, reduced expression of inflammatory pathway genes in T21 NPCs, and reduced markers of inflammation in LPS-stimulated microglial model systems. These results demonstrate that fasudil can alter multiple T21-associated abnormalities in a beneficial manner, suggesting that fasudil warrants further study as a candidate prenatal pharmacotherapy for DS.
Artistic representation of malformation syndromes has been of ongoing interest, often as a point of departure for discussion of medical history. We have identified a 16th-century Flemish Nativity painting in which one angelic figure appears distinctly different from other individuals in the painting with an appearance of Down syndrome. Several prior observers have identified Down syndrome in premodern art, sometimes stimulating ongoing discussions concerning its history, its prevalence, and its relationship to hypothyroidism. This may be one of the earliest European representations of Down syndrome. The depiction of an individual with Down syndrome as an angel raises several questions regarding the status of such an individual in late medieval times and societal recognition of minor anomalies, as contrasted with major malformations, in their predictive value for disabilities. In contrast, Langdon Down's description of the condition occurred only after evolution of concepts regarding the clinical significance of physical appearance and measurement.
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