GM1 gangliosidosis type II: Results of a 10-year prospective study.

PURPOSE: GM1 gangliosidosis (GM1) a lysosomal disorder caused by pathogenic variants in GLB1, is characterized by relentless neurodegeneration. There are no approved treatments. METHODS: Forty-one individuals with type II (late-infantile and juvenile) GM1 participated in a single-site prospective observational study. RESULTS: Classification of 37 distinct variants using American College of Medical Genetics and Genomics criteria resulted in the upgrade of 6 and the submission of 4 new variants. In contrast to type I infantile disease, children with type II had normal or near normal hearing and did not have cherry-red maculae or hepatosplenomegaly. Some older children with juvenile onset disease developed thickened aortic and/or mitral valves. Serial magnetic resonance images demonstrated progressive brain atrophy, more pronounced in late infantile patients. Magnetic resonance spectroscopy showed worsening elevation of myo-inositol and deficit of N-acetyl aspartate that were strongly correlated with scores on the Vineland Adaptive Behavior Scale, progressing more rapidly in late infantile compared with juvenile onset disease. CONCLUSION: Serial phenotyping of type II GM1 patients expands the understanding of disease progression and clarifies common misconceptions about type II patients; these are pivotal steps toward more timely diagnosis and better supportive care. The data amassed through this 10-year effort will serve as a robust comparator for ongoing and future therapeutic trials.

GM1 Gangliosidosis Type II: Results of a 10-Year Prospective Study.

Purpose: GM1 gangliosidosis (GM1) is an ultra-rare lysosomal storage disease caused by pathogenic variants in galactosidase beta 1 (GLB1; NM_000404), primarily characterized by neurodegeneration, often in children. There are no approved treatments for GM1, but clinical trials using gene therapy (NCT03952637, NCT04713475) and small molecule substrate inhibitors (NCT04221451) are ongoing. Understanding the natural history of GM1 is essential for timely diagnosis, facilitating better supportive care, and contextualizing the results of therapeutic trials. Methods: Forty-one individuals with type II GM1 (n=17 late infantile and n=24 juvenile onset) participated in a single-site prospective observational study. Here, we describe the results of extensive multisystem assessment batteries, including clinical labs, neuroimaging, physiological exams, and behavioral assessments. Results: Classification of 37 distinct variants in this cohort was performed according to ACMG criteria and resulted in the upgrade of six and the submission of four new variants to pathogenic or likely pathogenic. In contrast to type I infantile, children with type II disease exhibited normal or near normal hearing and did not have cherry red maculae or significant hepatosplenomegaly. Some older children with juvenile onset developed thickened aortic and/or mitral valves with regurgitation. Serial MRIs demonstrated progressive brain atrophy that were more pronounced in those with late infantile onset. MR spectroscopy showed worsening elevation of myo-inositol and deficit of N-acetyl aspartate that were strongly correlated with scores on the Vineland Adaptive Behavior Scale and progress more rapidly in late infantile than juvenile onset disease. Conclusion: The comprehensive serial phenotyping of type II GM1 patients expands the understanding of disease progression and clarifies some common misconceptions about type II patients. Findings from this 10-year endeavor are a pivotal step toward more timely diagnosis and better supportive care for patients. The wealth of data amassed through this effort will serve as a robust comparator for ongoing and future therapeutic trials.

C5 methylation confers accessibility, stability and selectivity to picrotoxinin.

Minor changes to complex structures can exert major influences on synthesis strategy and functional properties. Here we explore two parallel series of picrotoxinin (PXN, 1) analogs and identify leads with selectivity between mammalian and insect ion channels. These are the first SAR studies of PXN despite its >100-year history and are made possible by advances in total synthesis. We observe a remarkable stabilizing effect of a C5 methyl, which completely blocks C15 alcoholysis via destabilization of an intermediate twist-boat conformer; suppression of this secondary hydrolysis pathway increases half-life in plasma. C5 methylation also decreases potency against vertebrate ion channels (γ-Aminobutyric acid type A (GABAA) receptors) but maintains or increases antagonism of homologous invertebrate GABA-gated chloride channels (resistance to dieldrin (RDL) receptors). Optimal 5MePXN analogs appear to change the PXN binding pose within GABAARs by disruption of a hydrogen bond network. These discoveries were made possible by the lower synthetic burden of 5MePXN (2) and were illuminated by the parallel analog series, which allowed characterization of the role of the synthetically simplifying C5 methyl in channel selectivity. These are the first SAR studies to identify changes to PXN that increase the GABAA-RDL selectivity index.