Insights into DNA repeat expansions among 900,000 biobank participants

Hujoel, M.L.A., Handsaker, R.E., Tang, D. et al. Insights into DNA repeat expansions among 900,000 biobank participants. Nature (2026). doi:10.1038/s41586-025-09886-z 

 Expansions and contractions of tandem DNA repeats generate genetic variation in human populations and in human tissues. Some expanded repeats cause inherited disorders and some are also somatically unstable. Here we analysed DNA sequencing data from over 900,000 participants in the UK Biobank and the All of Us Research Program using computational approaches to recognize, measure and learn from DNA-repeat instability.

Pathological frataxin deficiency in mice causes tissue-specific alterations in iron homeostasis

Pazos-Gil, M., Medina-Carbonero, M., Sanz-Alcázar, A., Portillo-Carrasquer,M., Oliveira-Jorge, L., Hernández, G., Sánchez, M., Delaspre, F., Cabiscol, E., Ros, J., Tamarit, J.,Pathological frataxin deficiency in mice causes tissue-specific alterations in iron homeostasis, iScience(2026), doi: doi:10.1016/j.isci.2025.11462 

Our results reveal tissue-specific alterations of Iron Regulatory Proteins. In the heart, IRP2 accumulation is observed, likely triggered by iron-sulfur deficiency, while IRP1 is decreased in the cerebellum and liver. We also found elevated iron levels in mutant mice. Accumulation was particularly pronounced in the cerebellum, where increases were already evident at 10 weeks. Hepatic accumulation was not manifested until 21 weeks and was more pronounced in females. Overall, these findings indicate that frataxin deficiency disrupts iron homeostasis in a tissue-, age-, and sex- dependent manner, and provide novel insights into the mechanisms causing these perturbations.

Microgliopathy as a primary mediator of neuronal death in models of Friedreich's Ataxia

Pernaci C, Johnson A, Gillette S, Warden AS, McCormick C, Weiser-Novak S, Ramirez G, Broersma EH, Mishra P, Sivakumar A, Cherqui S, Coufal NG. Microgliopathy as a primary mediator of neuronal death in models of Friedreich's Ataxia. Nat Commun. 2025 Nov 29;17(1):81. doi: 10.1038/s41467-025-66710-y. PMID: 41318543; PMCID: PMC12770375. 

 In a murine xenograft model, transplanted human FRDA microglia accumulate in white matter and the Purkinje cell layer, resulting in Purkinje neuron loss in otherwise healthy brains. Notably, CRISPR/Cas9-mediated correction of the GAA repeat reverses microglial defects and mitigates neurodegeneration. Here, we suggest that microglial dysfunction serve as a disease driver and a promising therapeutic target in FRDA.

Nanobodies as tools for studying human frataxin biology

Pignataro, M.F., Fernández, N.B., Garay-Alvarez, A. et al. Nanobodies as tools for studying human frataxin biology. Commun Biol (2026). doi:10.1038/s42003-025-09458-x 

As a whole, our results suggest that nanobodies can serve as binding partners for mitochondrial FXN. However, the specific effect of the nanobodies on the conformational stability of FRDA-related FXN variants in cells should be investigated.

Ataxia with hypertonia and absent deep tendon reflexes (DTRs)

Maddela, Chakradhar. (2026). Ataxia with hypertonia and absent deep tendon reflexes (DTRs) -DD. 10.13140/RG.2.2.12440.66562. 

It is an important localization clue-suggesting central cerebellar involvement with concomitant peripheral neuropathy or dorsal root involvement. Pathophysiologic Pattern • Ataxia → Cerebellar dysfunction • Hypertonia → Central (UMN / extrapyramidal) involvement • Absent DTRs → Peripheral neuropathy / dorsal root ganglion involvement Combined central + peripheral nervous system disease Common & Important Causes 1. Friedreich Ataxia (MOST COMMON) • Onset: 5-15 years • Progressive gait and limb ataxia • Absent DTRs (early) • Extensor plantar, increasing tone later • Sensory loss (proprioception, vibration) • Associated: cardiomyopathy, scoliosis, diabetes • Mechanism: Spinocerebellar + posterior column + peripheral nerve degeneration 2. Ataxia-Telangiectasia (Late Stage) • Early hypotonia → later rigidity / hypertonia • Peripheral neuropathy → absent reflexes • Oculocutaneous telangiectasia • Recurrent sinopulmonary infections • Raised AFP

Patient-reported, psychosocial and health economic outcomes in mild to moderate Friedreich's ataxia: baseline results of the PROFA study

Grobe-Einsler M, Borel S, Buchholz M, Sayah S, Hilab R, Pierron L, Iskandar A, Humphries B, Ewenczyk C, Heinzmann A, Atencio M, Feldmann K, Maas V, Faber J, Boesch S, Indelicato E, Reetz K, Schulz JB, Bischoff AT, Klopstock T, Schöls L, Minnerop M, Timmann D, Davies EH, Klockgether T, Durr A, Xie F, Michalowsky B. Patient-reported, psychosocial and health economic outcomes in mild to moderate Friedreich's ataxia: baseline results of the PROFA study. Lancet Reg Health Eur. 2025 Dec 11;61:101552. doi: 10.1016/j.lanepe.2025.101552. PMID: 41488489; PMCID: PMC12756708. 

One hundred one patients (mean [SD]: age 35.0 [11.5]; GAA-repeat size 657 [299]; 50.5% women) were included. Activities of daily living, HRQoL, communication disabilities, and informal care utilization worsened significantly across disability stages with moderate to high effect sizes. Cognitive-affective impairments and mental well-being showed significant associations with small effect sizes. Twenty-three patients (33.3%) received formal care, while 40 (58.0%) received informal care (mean 12.2 h/week). Omaveloxolone was used by 33 patients (32.7%). Annual healthcare costs excluding Omaveloxolone were €13,620 (payer) and €32,679 (societal perspective, including informal care and productivity losses).

 

Development of a secretable frataxin for enhanced efficacy in treating Friedreich’s Ataxia

Daniel M. DuBreuil, Michael Fleming, Yashvi Parikh, Mikaela Woo, Jie Bu, Swathi Ayloo, Ingeborg M. Langohr, Dinesh S. Bangari, Christian Mueller, Shyam Ramachandran, Development of a secretable frataxin for enhanced efficacy in treating Friedreich’s Ataxia, Molecular Therapy Advances, 2025, 201661, ISSN 3117-387X, doi:10.1016/j.omta.2025.201661. 

No disease-modifying therapies are approved for FA, and current gene therapy approaches fail to address the full disease, forcing patients to choose between cardiac protection or neurological benefit. Here, we present ‘Engineered Cross-Correction,’ in which the therapeutic protein is bioengineered for secretion, expanding the therapeutic footprint. We apply this approach to FA by engineering a secretable frataxin and delivering it via a single intra-cerebrospinal fluid (CSF) injection of an adeno-associated viral (AAV) vector equipped with a novel capsid and tissue-selective promoter. We achieved broad protein repletion across key target tissues—heart, dorsal root ganglia, and cerebellum—in mouse and non-human primate. In FA mouse models, we observed rescue of cardiac and neurological phenotypes, marking the first demonstration of dual correction with a single, minimally invasive administration. These benefits were achieved without widespread transduction, reducing vector burden and associated toxicity. Our findings establish a scalable platform that contrasts with intravenous BBB-penetrant gene delivery and offers a generalizable strategy for multi-system disorders. Beyond FA, this positions Engineered Cross-Correction as a new frontier for the next generation of gene therapies.

Using a discrete choice experiments to explore societal preferences for valuing new drugs for rare diseases

Vargas, C., Goodall, S., Street, D.J. et al. Using a discrete choice experiments to explore societal preferences for valuing new drugs for rare diseases. Orphanet J Rare Dis 20, 631 (2025). doi:10.1186/s13023-025-04141-0 

Results In general, respondents had a greater preference for drugs that increase survival, where there was greater confidence in the effectiveness of the new drug and which increased patients’ capacity to do their usual activities. Preferences were not homogenous, the latent class analysis identified three groups: Class 3 (58%) demonstrated a strong preference for improvements in survival; Class 2 (21%) showed a strong preference for confidence in the evidence; and Class 1 (21%) positively valued increased government expenditure. 

Conclusion These results are consistent with previous studies that used different methodologies in showing a preference for drugs with improved survival and quality of life. However, addressing a societal preference for greater confidence in the evidence - reducing evidential uncertainty - represents a methodological and policy challenge for the evaluation of drugs in rare diseases.

Progressive scoliosis in a pediatric patient with cerebellar ataxia: surgical challenges and literature review

Asunis E, Vitulli F, Nicotra R, Rubino A, Cicala D, Cinalli G, Colella G. Progressive scoliosis in a pediatric patient with cerebellar ataxia: surgical challenges and literature review. Childs Nerv Syst. 2025 Dec 15;41(1):418. doi: 10.1007/s00381-025-07091-x. PMID: 41396316. 

 Spinal fusion can be performed safely in pediatric SCA/FA patients when meticulous multidisciplinary planning, individualized neuromonitoring strategies, and aggressive postoperative rehabilitation are adopted. Early recognition of underlying ataxia is critical for risk stratification and the timing of intervention. Prospective, longitudinal studies are warranted to refine guidelines and optimize neurological and orthopedic results in this complex population.

Digital Gait Measures Discriminate People with Friedreich's Ataxia from Healthy Controls

Casey HL, Shah VV, Muzyka D, McNames J, El-Gohary M, Sowalsky K, Safarpour D, Carlson-Kuhta P, Schmahmann JD, Rosenthal LS, Perlman S, Rummey C, Horak FB, Gomez CM. Digital Gait Measures Discriminate People with Friedreich's Ataxia from Healthy Controls. Mov Disord Clin Pract. 2025 Dec 17. doi: 10.1002/mdc3.70465. Epub ahead of print. PMID: 41408995. 

Digital gait measures from wearable sensors were discriminative, reliable, and showed concurrent validity for evaluating ataxia severity during an instrumented walk test. These results suggest promising utility of digital gait outcomes for use in FRDA clinical trials.