Biology subjects

Delatycki, M. B.

Publications and source records attributed to Delatycki, M. B..

4 recordsLinked to original sources

bioRxiv2026

Friedreich ataxia transcriptomic dysregulation and identification of cell type-specific biomarkers: A systematic review and meta-analysis

Friedreich ataxia (FRDA) is a progressive multisystem neurodegenerative disease mostly caused by a homozygous GAA repeat expansion in the FXN gene, leading to deficiency of the protein frataxin. Despite ubiquitous frataxin expression, FRDA pathology is tissue-specific, disproportionately affecting dorsal root ganglia sensory neurons, dentate nuclei of the cerebellum, corticospinal tracts and cardiomyocytes. The molecular basis for this selective vulnerability remains unresolved, suggesting that cell-type specific responses to frataxin deficiency shape disease susceptibility. This incomplete understanding is compounded by the lack of molecular biomarkers that capture FRDA biology beyond frataxin deficiency, thereby limiting therapeutic development and evaluation. Here, we integrated all available human bulk RNA-seq datasets in FRDA (23 datasets across 10 cell types), spanning disease-related (cardiomyocytes, sensory neurons) and relatively FRDA-spared cell types (fibroblasts, lymphoblastoid cells) under a unified analytical framework to identify transcriptional dysregulation underlying selective vulnerability and candidate biomarkers. Meta-analysis revealed recurrent transcriptional perturbations beyond FXN, involving long non-coding RNAs, translational control and cytoskeletal organisation. While shared transcriptional themes were observed, the specific biological programmes engaged were strongly cell-type dependent. The top candidate biomarkers, MYH14, MEG9, and MEG8 showed preferential upregulation in disease-relevant cell types including sensory neurons and cardiomyocytes, supporting their potential relevance to selective vulnerability. Therapeutic responsiveness to these candidates were assessed across RNA-seq datasets from FRDA models exposed to diverse therapeutic strategies, including epigenetic modulation and FXN-targeting approaches, revealing that transcriptional alterations in FRDA are pharmacologically modifiable. To facilitate transparent exploration and reuse of these findings, we developed an interactive FRDA Transcriptomic Atlas, providing a community-accessible resource for investigating gene and pathway-level dysregulation across FRDA studies: https://marniemaddock.github.io/FRDATranscriptomicAtlas/. Together, these findings implicate cell type specific transcriptional programs as potential drivers of selective vulnerability and establish a framework for prioritising biomarkers in FRDA. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/712785v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@26138org.highwire.dtl.DTLVardef@3cbc27org.highwire.dtl.DTLVardef@164dbf5org.highwire.dtl.DTLVardef@a4b59d_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2021

The responsiveness of gait and balance outcomes to disease progression in Friedreich ataxia

ObjectiveTo identify gait and balance measures that are responsive to change during the timeline of a clinical trial in Friedreich ataxia (FRDA) we administered a battery of potential measures three times over a 12-month period. MethodsSixty-one ambulant individuals with FRDA underwent assessment of gait and balance at baseline, six months and 12 months. Outcomes included: GAITRite(R) spatiotemporal gait parameters; Biodex Balance System Postural Stability Test (PST) and Limits of Stability; Berg Balance Scale (BBS); Timed 25 Foot Walk Test; Dynamic Gait Index (DGI); SenseWear MF Armband step and energy activity; and the Friedreich Ataxia Rating Scale Upright Stability Subscale (FARS USS). The standardised response mean (SRM) or correlation coefficients were reported as effect size indices for comparison of internal responsiveness. Internal responsiveness was also analysed in subgroups. ResultsSenseWear Armband daily step count had the largest effect size of all the variables over six months (SRM=-0.615), while the PST medial-lateral index had the largest effect size (SRM=0.829) over 12 months. The FARS USS (SRM=0.824) and BBS (SRM=-0.720) were the only outcomes able to detect change over 12 months in all subgroups. The DGI was the most responsive outcome in children, detecting a mean change of -2.59 (95% CI -3.52 to -1.66, p<0.001, SRM=-1.429). ConclusionsThe FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

neuroscience↗

bioRxiv2018

Longitudinal dentate nuclei iron concentration and atrophy in Friedreich ataxia: IMAGE-FRDA

BackgroundFriedreich ataxia is a recessively inherited, progressive neurological disease characterised by impaired mitochondrial iron metabolism. The dentate nuclei of the cerebellum are characteristic sites of neurodegeneration in the disease, but little is known of the longitudinal progression of pathology in these structures.\n\nMethodsUsing in vivo magnetic resonance imaging, including quantitative susceptibility mapping, we investigated changes in iron concentration and volume in the dentate nuclei in individuals with Friedreich ataxia (n=20) and healthy controls (n=18) over a two-year period.\n\nResultsThe longitudinal rate of iron concentration was significantly elevated bilaterally in participants with Friedreich ataxia relative to healthy controls. Atrophy rates did not differ significantly between groups. Change in iron concentration and atrophy both correlated with baseline disease severity or duration, indicating sensitivity of these measures to disease stage. Moreover, atrophy was maximal in individuals early in the disease course, while the rate of iron concentration increased with disease progression.\n\nConclusionsProgressive dentate nuclei pathology is evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a two-year period highlights the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool.

neuroscience↗

bioRxiv2017

Detecting known repeat expansions with standard protocol next generation sequencing, towards developing a single screening test for neurological repeat expansion disorders

Repeat expansions cause over 30, predominantly neurogenetic, inherited disorders. These can present with overlapping clinical phenotypes, making molecular diagnosis challenging. Single gene or small panel PCR-based methods are employed to identify the precise genetic cause, but can be slow and costly, and often yield no result. Genomic analysis via whole exome and whole genome sequencing (WES and WGS) is being increasingly performed to diagnose genetic disorders. However, until recently analysis protocols could not identify repeat expansions in these datasets.\n\nA new method, called exSTRa (expanded Short Tandem Repeat algorithm) for the identification of repeat expansions using either WES or WGS was developed and performance of exSTRa was assessed in a simulation study. In addition, four retrospective cohorts of individuals with eleven different known repeat expansion disorders were analysed with the new method. Results were assessed by comparing to known disease status. Performance was also compared to three other analysis methods (ExpansionHunter, STRetch and TREDPARSE), which were developed specifically for WGS data. Expansions in the STR loci assessed were successfully identified in WES and WGS datasets by all four methods, with high specificity and sensitivity, excepting the FRAXA STR where expansions were unlikely to be detected. Overall exSTRa demonstrated more robust/superior performance for WES data in comparison to the other three methods. exSTRa can be applied to existing WES or WGS data to identify likely repeat expansions and can be used to investigate any STR of interest, by specifying location and repeat motif. We demonstrate that methods such as exSTRa can be effectively utilized as a screening tool to interrogate WES data generated with PCR-based library preparations and WGS data generated using either PCR-based or PCR-free library protocols, for repeat expansions which can then be followed up with specific diagnostic tests. exSTRa is available via GitHub (https://github.com/bahlolab/exSTRa).

bioinformatics↗