Natural clusters of tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND): new findings from the TOSCA TAND research project.

BACKGROUND: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have unique, individual patterns that pose significant challenges for diagnosis, psycho-education, and intervention planning. A recent study suggested that it may be feasible to use TAND Checklist data and data-driven methods to generate natural TAND clusters. However, the study had a small sample size and data from only two countries. Here, we investigated the replicability of identifying natural TAND clusters from a larger and more diverse sample from the TOSCA study. METHODS: As part of the TOSCA international TSC registry study, this embedded research project collected TAND Checklist data from individuals with TSC. Correlation coefficients were calculated for TAND variables to generate a correlation matrix. Hierarchical cluster and factor analysis methods were used for data reduction and identification of natural TAND clusters. RESULTS: A total of 85 individuals with TSC (female:male, 40:45) from 7 countries were enrolled. Cluster analysis grouped the TAND variables into 6 clusters: a scholastic cluster (reading, writing, spelling, mathematics, visuo-spatial difficulties, disorientation), a hyperactive/impulsive cluster (hyperactivity, impulsivity, self-injurious behavior), a mood/anxiety cluster (anxiety, depressed mood, sleep difficulties, shyness), a neuropsychological cluster (attention/concentration difficulties, memory, attention, dual/multi-tasking, executive skills deficits), a dysregulated behavior cluster (mood swings, aggressive outbursts, temper tantrums), and an autism spectrum disorder (ASD)-like cluster (delayed language, poor eye contact, repetitive behaviors, unusual use of language, inflexibility, difficulties associated with eating). The natural clusters mapped reasonably well onto the six-factor solution generated. Comparison between cluster and factor solutions from this study and the earlier feasibility study showed significant similarity, particularly in cluster solutions. CONCLUSIONS: Results from this TOSCA research project in an independent international data set showed that the combination of cluster analysis and factor analysis may be able to identify clinically meaningful natural TAND clusters. Findings were remarkably similar to those identified in the earlier feasibility study, supporting the potential robustness of these natural TAND clusters. Further steps should include examination of larger samples, investigation of internal consistency, and evaluation of the robustness of the proposed natural clusters

Synthesis, characterization and biological evaluation of 7 alpha-perfluoroalkylestradiol derivatives

peer reviewedLinkage of a long CH(2 )side chain ('spacer') onto C-7 alpha of estradiol-17 beta (E(2)) does not abrogate the binding affinity of this hormone for its receptor. Our purpose was to assess whether the linkage of a CF(2 )side chain, which is more bulky and rigid, could also be accommodated by the estrogen receptor (ER). We describe here the synthesis of 7 alpha-perfluorohexylestradiol 7 by perfluoroalkylation of a key silylenolether 2 with FITS-6 (perfluorohexyl-phenyliodoniurn trifluoromethanesulfonate). 7 alpha-Trifluoromethylestradiol 10a was prepared as a fluorinated control compound by UV-light induced trifluoromethylation of 2 with Umemoto reagent (S-trifluoromethyldibenzo[b,d]thiophenium trifluoromethanesulfonate). Endocrine properties of these two E(2 )derivatives were tested on the MCF-7 breast cancer cell line. Our data reveal that rigidity of the side chain of 7 affected the association of its hormone moiety with the ER to the same extent as a long alkyl side chain. Rigidity also failed to abrogate estrogenicity, as demonstrated by the ability of 7 to enhance ERE-dependent transcription and cell growth. Compound retained the capacity of inducing down regulation of the receptor. Interestingly, no evidence of antiestrogenicity was recorded since this compound behaved like a weak estrogen, exerting a mitogenic effect at high concentration. Of note, control 10a displayed a higher binding affinity than 7 for ER and consequently acted like the latter, albeit with a higher efficiency. Selection of appropriate residues to be linked at the end of a long 7 alpha alkyl side chain is known to be essential for generating strong antiestrogenicity. One may hope that such a property may also hold for perfluorinated chains to produce antiestrogens with strong metabolic stabilit

Neuromuscular disease genetics in under-represented populations: increasing data diversity

Neuromuscular diseases (NMDs) affect similar to 15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management.We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions.We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' similar to 56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a similar to 59% 'solved' and similar to 13% 'possibly solved' outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research.In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.Wilson et al. present the findings of an international partnership established to study genetic causes of neuromuscular diseases in under-represented diverse populations from 12 low-middle income sites. A genetic cause was identified in similar to 55% of cases and similar to 30% of variants were novel, improving understanding of neuromuscular disease genetics.Functional Genomics of Muscle, Nerve and Brain Disorder