small molecules
2024-02-28 | Readthrough Activators and Nonsense-Mediated mRNA Decay Inhibitor Molecules: Real Potential in Many Genetic Diseases Harboring Premature Termination Codons
Nonsense mutations that generate a premature termination codon (PTC) can induce both the accelerated degradation of mutated mRNA compared with the wild type version of the mRNA or the production of a truncated protein. One of the considered therapeutic strategies to bypass PTCs is their “readthrough” based on small-molecule drugs. These molecules promote the incorporation of a near-cognate tRNA at the PTC position through the native polypeptide chain. In this review, we detailed the various existing strategies organized according to pharmacological molecule types through their different mechanisms. The positive results that followed readthrough molecule testing in multiple neuromuscular disorder models indicate the potential of this approach in peripheral neuropathies.
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antibodies
2026-03-27 | Radiological phenotyping in patients with SOX10 pathogenic variants: insights into neck, brain and temporal bones abnormalities.
The SOX10 gene is essential for developing neural crest-derived tissues, including the temporal bone, peripheral and central nervous systems, and melanocytes. Pathogenic SOX10 variants are linked to a broad clinical spectrum, including Waardenburg syndrome (WS) in isolation, Kallmann syndrome (KS), as well as an entity characterised by the combination of peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH). This study aims to characterise the full spectrum of abnormalities in the brain, temporal bone and neck regions, and their syndromic associations. 15 pediatric patients with genetically confirmed SOX10 germline pathogenic variants were included. All underwent MRI, and 9 also had CT of the temporal bone. Imaging and clinical data were systematically analysed by two pediatric neuroradiologists. Phenotypic analysis revealed bilateral temporal bone abnormalities in all patients, mainly characterised by a specific combination of semicircular canal (SCC) dysplasia/hypoplasia (with high prevalence of severely hypoplastic or absent posterior SCC) and a very reproducible form of cochlear hypoplasia called "flattened cochlea". Olfactory bulb agenesis or hypoplasia was identified in all patients but two. Other abnormalities include white matter changes suggestive of a hypomyelination pattern or deficient myelination in four and neck findings typically characterised by parotid gland aplasia/hypoplasia (15/15, 100%) or lacrimal gland aplasia/hypoplasia (13/15, 86%). Clinical phenotypes ranged from SNHL to WS type II or IV and PCWH. These results confirm the strong correlation between pathogenic SOX10 variants and characteristic temporal bone malformations, which, in association with other radiological abnormalities, represent highly specific diagnostic markers. The constellation of findings reflects the shared neural crest origin of the affected tissues and should always be investigated to support appropriate genetic testing. Early identification of these features via MRI can aid diagnosis, especially in children without classic syndromic signs, and support the patients' management.
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