The biology underlying Friedreich ataxia begins with the FXN gene, which encodes frataxin, a mitochondrial protein essential for iron-sulfur cluster assembly and cellular energy metabolism. When functional frataxin falls below a critical threshold, patients develop progressive cerebellar ataxia, loss of deep sensory pathways, hypertrophic cardiomyopathy, scoliosis, and an elevated risk of diabetes. Roughly 96 percent of disease-causing alleles involve expansion of a GAA repeat in the first intron of FXN, which silences transcription without altering the protein sequence itself. The remaining 4 percent of pathogenic alleles consist of intragenic variants such as missense changes, nonsense mutations, splice variants, and deletions of varying size. Patients carrying two pure GAA expansions show a reasonably consistent relationship between the length of the shorter repeat, known as GAA1, and clinical severity, which has made genetic testing a powerful prognostic tool.

That predictability breaks down, however, in a subset of patients whose disease course is far more aggressive than their apparent repeat lengths would suggest. A recent investigation into this discrepancy uncovered a surprising mechanism: in roughly half of individuals who seemed by long-range PCR to carry two expanded alleles of the same size, one of the two alleles was not being amplified at all. The test was effectively blind to one allele, producing the false conclusion of homozygosity for identical repeats. Most of these individuals turned out to carry expanded composite repeats, complex rearranged repeat structures that evade standard amplification, but a small number harbored something even more consequential: deletions of the proximal portion of the FXN gene, encompassing the promoter and early exons, which abolish production of frataxin from that allele entirely.

The new report, led by investigators at the Children’s Hospital of Philadelphia using records from the Friedreich Ataxia Clinical Outcome Measures Study, presents the clinical features of patients carrying these covert proximal deletions alongside one expanded GAA allele. The prototypic case is particularly striking. Patient 1 was diagnosed at age six with ataxia superimposed on a pre-existing diagnosis of hypertrophic cardiomyopathy. He lost the ability to walk at age 12, developed diabetes at 13, and suffered severe vision loss at 16. Initial genetic testing had indicated that he inherited two GAA expansion alleles of similar length from his carrier parents. The unraveling of that conclusion came through his younger sister, who developed Friedreich ataxia at age 10 and was found to carry two pure GAA expansions of clearly distinct sizes, 490 and 990 repeats. The genetic mismatch between siblings who shared the same parents prompted deeper analysis.

Long-read whole genome sequencing using Oxford Nanopore Technology, confirmed by a custom PCR assay, resolved the puzzle. Patient 1 had inherited only one GAA-expanded allele; his second allele carried a de novo deletion removing the FXN promoter, exon 1, and part of intron 1. Because the deletion eliminated the sequences targeted by standard diagnostic PCR, the allele appeared simply absent from the analysis, mimicking homozygosity for two similar repeats. The contrast between the siblings is clinically dramatic: Patient 2, carrying two expanded repeats but no deletion, had a much milder course, with no cardiomyopathy and no loss of ambulation at her most recent clinic visit, while her brother with the silent deletion deteriorated rapidly through childhood and adolescence.

The researchers extended the comparison to a broader set of patients with null variants of FXN, alleles that produce no functional frataxin at all. Across sixteen patients with deletions ranging from the proximal promoter region to distal exons, and including frameshift and start codon mutations, a consistent pattern emerged. All affected individuals showed ataxia and at least mild dysarthria early in their course. Those with proximal deletions tended toward early disease onset, with cardiomyopathy and scoliosis appearing in childhood. Poor weight gain and appetite, a recognized endocrine feature of Friedreich ataxia, developed in all patients with deletions, and one patient with a small frameshift variant required placement of a gastric feeding tube for nutrition. Yet the picture was not uniformly grim: a few individuals carrying shorter GAA alleles on their second copy, including one patient with a start codon mutation paired with a repeat of only 68 triplets, remained remarkably mild, with onset as late as age 41 and none of the major complications.

To quantify the impact of null alleles, the team compared the deletion and null variant group with a large cohort of 478 patients homozygous for two expanded GAA alleles. The mean shorter repeat length was statistically indistinguishable between groups, 667 plus or minus 235 repeats in the homozygous cohort versus 734 plus or minus 228 in the deletion group, yet the clinical outcomes diverged sharply. Patients with null variants had a lower average age of onset, 8.3 years versus 12 years, and dramatically higher rates of cardiomyopathy, 93 percent versus 61 percent, a difference that reached statistical significance. Age at death also differed significantly, with 32 percent of the deletion group deceased compared with 9 percent of the homozygous repeat group. Trends toward more frequent diabetes, scoliosis surgery, and vision loss from optic neuropathy were also observed. The conclusion is inescapable: a null allele, which contributes no frataxin whatsoever, produces a more severe phenotype than a second expanded repeat, which still permits a trickle of residual gene expression.

These findings carry a direct message for clinical practice. Patients who appear by commercial testing to carry two identical expanded alleles but who show an unexpectedly severe, even if otherwise typical, Friedreich ataxia phenotype should be evaluated further for an undetected deletion. Conversely, patients with one expanded allele, one apparently normal allele, and a severe phenotype should prompt a search for a null non-GAA variant, while a single expanded allele with a normal second allele and an atypical phenotype more often points toward a missense variant, though exceptions exist. The diagnostic gap exists because standard PCR-based assays target sequences within the proximal gene that are precisely the regions missing in these covert deletions. Long-read whole genome sequencing, which can traverse the entire locus and reveal structural rearrangements, proved essential for detection, and the authors demonstrated that a targeted custom PCR assay can confirm the findings once the deletion is known.

Beyond diagnosis, the study refines the statistical architecture of Friedreich ataxia prognosis. Conventional severity models treat GAA1, the shorter of the two expanded repeats, as the primary determinant of disease course, and for good reason: GAA1 length alone accounts for an R-squared of roughly 0.4 to 0.5 in predicting various clinical parameters, because it best indexes residual FXN transcription. GAA2, the longer repeat, is usually omitted from models because its values are correlated with GAA1 and its independent contribution is difficult to isolate. The new data suggest that in extreme cases, particularly when one allele is a complete null, GAA2 length can further refine severity predictions, explaining some of the variance that GAA1 alone leaves unaccounted for. Patient 11, with a 68-repeat allele paired with a null variant and a remarkably mild course, illustrates how much protective information a short second allele can carry even when its partner produces no protein at all.

The broader significance of this work extends to the growing recognition that Friedreich ataxia is more genetically heterogeneous than standard testing implies. As long-read sequencing becomes more accessible, previously invisible structural variants such as composite repeats and proximal deletions are likely to be uncovered in increasing numbers, reshaping prevalence estimates and improving the accuracy of genetic counseling for families in which recurrence risk depends on knowing exactly what each parent carries. For patients, an accurate molecular diagnosis is the gateway to emerging therapies, including frataxin-enhancing compounds and gene-based approaches currently in development, many of which assume intact target sequences within the FXN gene. Knowing whether a patient’s second allele is a long repeat or a deletion may ultimately influence which therapeutic strategy is appropriate. What began as a puzzling discrepancy between two siblings has exposed a systematic blind spot in Friedreich ataxia genetics, one that the field can now begin to correct.

Subject of Research: Covert proximal FXN gene deletions in compound heterozygote Friedreich ataxia patients

Article Title: Compound Heterozygote Friedreich Ataxia Patients With Covert Proximal FXN Gene Deletions

Article References: Lazaropoulos, M. P., Devore, M. C., Lam, C., Park, C., Bidichandani, S., & Lynch, D. R. (2026). Compound Heterozygote Friedreich Ataxia Patients With Covert Proximal FXN Gene Deletions. Annals of Clinical and Translational Neurology, 13(10), 2134-2137. https://doi.org/10.1002/acn3.70408

Image Credits: AI Generated

DOI: 10.1002/acn3.70408

Keywords: Friedreich ataxia, FXN gene, frataxin, GAA repeat expansion, genetic testing, long-read sequencing, compound heterozygote, gene deletion, cardiomyopathy, ataxia, null variants, genetic diagnosis

The research team, led by Ziyao Liu of the Second Affiliated Hospital of Xi’an Jiaotong University, began with a simple premise. Oxidative stress, the imbalance that lets reactive oxygen species overwhelm cellular antioxidant defenses, is a well-established contributor to optic nerve degeneration. But which of the hundreds of oxidation-related genes actually matter in POAG? To find out, the investigators assembled a comprehensive set of 885 oxidative stress-related genes from the GeneCards and MSigDB databases, then mined five public transcriptomic datasets from the Gene Expression Omnibus, using optic nerve head astrocyte samples from the GSE9963 cohort as their discovery set.

The screening pipeline was deliberately redundant. Weighted gene co-expression network analysis grouped genes into modules correlated with disease status, while two independent machine learning algorithms, LASSO regression and support vector machine recursive feature elimination, each flagged candidate genes under ten-fold cross-validation. When the three approaches were intersected, only two genes survived: FXN and CYP1B1. Of these, FXN proved the sharper diagnostic blade. Receiver operating characteristic analysis in the discovery cohort yielded an area under the curve of 0.945 for FXN, far exceeding CYP1B1’s 0.700, and the result held up across four independent validation datasets with AUC values ranging from 0.708 to 0.946.

A diagnostic meta-analysis pooling the five datasets strengthened the case further. Elevated FXN expression was significantly associated with POAG status, with an overall odds ratio of 6.35. Notably, FXN levels tracked with disease sample type but not with race, gender, or age, suggesting the signal reflects disease biology rather than demographic confounders. Bioinformatic characterization placed the protein in the cytosol and mitochondria, consistent with its known role in mitochondrial iron transport and respiration, and the team retrieved its three-dimensional structure from the AlphaFold database to support future drug design efforts.

The immune dimension added another layer of intrigue. CIBERSORT deconvolution showed that POAG samples with high FXN expression differed in estimated immune cell abundance, with M1 and M2 macrophage subtypes significantly reduced in the discovery cohort. Single-sample gene set enrichment analysis linked high FXN expression to signatures including antigen-presenting cell function, chemokine receptor interaction, and inflammation promotion, although these immune associations were less consistent across the validation cohorts. Metabolic profiling told a clearer story: gene set enrichment analysis repeatedly tied high FXN expression to glycolysis and pyruvate metabolism gene sets, hinting that FXN may participate in the metabolic reprogramming that accompanies glaucomatous degeneration.

Bioinformatics alone, however, could not establish causation. The team turned to an in vitro model in which retinal ganglion cell-derived R28 cells are injured by a 12-hour exposure to 200 micromolar hydrogen peroxide, a widely used simulation of oxidative stress injury in glaucoma research. Interestingly, while FXN was upregulated in patient tissue samples, hydrogen peroxide sharply decreased FXN expression in the cultured cells. That inverse response suggested a defensive role: the stressed cells were losing a protective factor. The researchers tested this by manipulating FXN with overexpression vectors and short hairpin RNAs, verifying the changes by quantitative PCR and western blot.

The functional assays were strikingly consistent. CCK8 and EdU assays showed that hydrogen peroxide suppressed cell survival, that FXN overexpression blunted this loss of viability, and that FXN knockdown made it worse. Flow cytometry using the BODIPY-C11 probe revealed that FXN overexpression significantly reduced the reactive oxygen species surge induced by peroxide treatment, while silencing FXN accelerated ROS accumulation. Annexin V staining and TUNEL assays confirmed the anti-apoptotic effect, with FXN overexpression defending cells against both early and late apoptosis. Western blots added a mechanistic clue: FXN overexpression increased levels of the antioxidant proteins NRF2, HO-1, and SOD1, while knockdown decreased them, indicating that frataxin bolsters the cell’s endogenous antioxidant defenses.

The deeper question was who controls FXN in the first place. Mining the hTFtarget and GeneCards databases produced four candidate transcription factors: MAX, YY1, RAD21, and CTCF. Cross-referencing public knockdown data from the KnockTF database and expression correlations in the discovery dataset narrowed the field, and PCR experiments in R28 cells delivered the verdict: only silencing CTCF downregulated FXN. CTCF, a zinc-finger protein famous for organizing chromatin into loops and insulating genes from inappropriate regulatory influences, emerged as the upstream switch. Chromatin immunoprecipitation sealed the argument, showing that CTCF antibody pulled down the FXN promoter sequence spanning bases 1797 to 1815 upstream of the transcription start site, one of four predicted binding sites.

The rescue experiments tied the axis together. CTCF expression itself dropped in the hydrogen peroxide model, mirroring FXN. Overexpressing CTCF preserved cell viability, reduced ROS accumulation, and curbed apoptosis just as FXN overexpression did, but when the researchers simultaneously knocked down FXN, much of that protection evaporated. In other words, CTCF shields retinal ganglion cells largely by switching on frataxin. Because CTCF is a global regulator, the team also intersected their 125 oxidative stress-related differentially expressed genes with predicted CTCF targets and found 79 overlaps, suggesting the CTCF-FXN axis may sit within a broader oxidative stress transcriptional network in POAG.

The authors are candid about the limitations. There is no animal model yet, the acute hydrogen peroxide model cannot fully reproduce the chronic oxidative environment of human glaucoma, and the regulatory mechanism still needs confirmation through promoter mutation assays and in vivo work. The immune findings require experimental validation, and whether FXN directly modulates mitochondrial ROS production remains open. Even so, the study delivers something glaucoma research has lacked: a biomarker with validated diagnostic performance across multiple cohorts, a plausible mechanistic story connecting oxidative stress, mitochondrial biology, and chromatin regulation, and a therapeutic hypothesis that could be tested. If frataxin’s protective power holds up in living retinae, the CTCF-FXN axis may become more than a molecular curiosity. It could become a target, and for a disease that currently can only be slowed, that would be a genuinely new frontier.

Subject of Research: The role of the CTCF-FXN regulatory axis in oxidative stress, diagnosis, and progression of primary open-angle glaucoma

Article Title: CTCF-FXN regulatory axis plays critical roles in clinical assessments and disease progression of primary open-angle glaucoma

Article References: Cai, D., Yu, Y., Ma, J., Li, T., & Liu, Z. (2026). CTCF-FXN regulatory axis plays critical roles in clinical assessments and disease progression of primary open-angle glaucoma. Journal of Molecular Medicine, 104(1), Article 114. https://doi.org/10.1007/s00109-026-02717-2

Image Credits: AI Generated

DOI: 10.1007/s00109-026-02717-2

Keywords: primary open-angle glaucoma, FXN, frataxin, CTCF, oxidative stress, retinal ganglion cells, reactive oxygen species, biomarker, transcriptional regulation, machine learning, mitochondria, neurodegeneration

Friedreich’s ataxia is a recessive genetic disorder that strikes in childhood or adolescence, progressively robbing patients of coordination, strength, and sensation. In roughly 96 percent of cases, it is caused by biallelic expansions of a GAA repeat sequence within the FXN gene, which silences production of frataxin, a protein essential to mitochondrial function in cells. The deficit cascades across multiple organ systems: the central and peripheral nervous systems degenerate, the heart muscle thickens into hypertrophic cardiomyopathy, the pancreas falters toward diabetes, and scoliosis, spasticity, and optic neuropathy often follow. Most therapeutic strategies now in development aim either to soften the downstream consequences of frataxin loss or to restore frataxin expression directly, through gene therapy delivered by adeno-associated viral vectors, protein replacement, or epigenetic reactivation of the damaged gene.

The idea that transplanted blood-forming cells might help the brain rests on an intriguing biological premise. Cells of the monocyte lineage can, under certain conditions, migrate into the central nervous system and potentially exchange material with resident brain cells, raising the possibility that donor-derived cells could act as delivery vehicles for frataxin to deficient tissue. The concept carries real appeal but also unresolved risks, and the mechanisms that would make it work have never been fully defined. The patient described in the new report, who underwent a complete stem cell replacement for reasons entirely unrelated to her ataxia, offered a natural test of whether such replacement could alter the disease course.

Her medical odyssey began at age ten, when chest pain and a racing heartbeat landed her in the intensive care unit with thyrotoxicosis. During that hospitalization, doctors noted persistent cytopenias, and a bone marrow aspirate revealed acute myeloid leukemia carrying the t(6;9) translocation, a high-risk subtype with a strong tendency to relapse. At the same time, subtle neurological signs emerged: a slightly wide-based gait with externally rotated legs, ataxia, faint tremors confined to her fingers, diminished vibratory sensation, and absent deep tendon reflexes. Genetic testing confirmed biallelic GAA expansions in FXN of 699 and 1066 repeats, establishing the diagnosis of Friedreich’s ataxia, and an echocardiogram revealed moderate left ventricular hypertrophy, the disease’s characteristic cardiac signature.

Treating the leukemia in a child with a fragile heart demanded a delicate balancing act. Induction chemotherapy with a dose-adjusted regimen of cytarabine, daunorubicin, and etoposide failed to achieve remission, forcing a switch to a salvage combination of topotecan, vinorelbine, thiotepa, and clofarabine, which succeeded in driving the leukemia to minimal residual disease negativity after two cycles. She then received an allogeneic hematopoietic stem cell transplant from an 11-of-12 HLA-matched unrelated male donor, using CD34-positive selected peripheral blood stem cells. Her conditioning regimen combined rabbit anti-thymocyte globulin, clofarabine, melphalan, and thiotepa. Remarkably, the procedure proceeded without major unexpected complications, no graft-versus-host disease developed, and she has remained in leukemia remission for the entire decade since.

The neurological story, however, unfolded exactly as it would have without the transplant. Over ten years, her speech became mildly affected, her gait and arm function worsened, and her reflexes and peripheral neuropathic components showed no reversal. Quantitative measures told the same story: her modified Friedreich Ataxia Rating Scale score climbed by 20 points, and her nine-hole peg test times doubled, tracking the trajectory of six comparator patients at the same institution who had similar GAA repeat lengths and ages of onset but received no transplant. She now uses a wheelchair and cannot ambulate independently, and she developed diabetes and sleep apnea along the way. In short, a fully successful bone marrow replacement did nothing to touch the degeneration in her nervous system.

The authors of the report point to several converging reasons why. The blood-brain barrier excludes most donor-derived cells from entering the brain’s parenchyma, and conventional stem cell transplantation does not achieve the deep microglial and monocyte depletion that some researchers believe would be necessary for donor cells to meaningfully repopulate the central nervous system. Frataxin itself is an intracellular mitochondrial protein, which means donor cells cannot perform the kind of cross-correction seen in some other metabolic storage diseases, where secreted enzymes rescue neighboring cells. Friedreich’s ataxia also carries significant developmental components, so replacing frataxin after the developmental window may simply come too late to rescue already-compromised neural circuits. Finally, the chemotherapy required to conquer her leukemia may itself have aggravated her neuropathy, and her secondary diabetes could have blunted any residual benefit.

Yet the case contains one genuinely striking observation. While her neurological scores marched steadily downward, her cardiac hypertrophy stabilized. Ten years after the transplant, her echocardiogram was read as normal, and comparisons of her ejection fraction and intraventricular septal diameter against the six matched comparator patients suggested her heart measures had held steady where others continued to change. The authors urge caution in interpreting this, noting that wall thickness in Friedreich’s ataxia is only modestly predictive of long-term outcome, that reductions in wall thickness can occur without lasting benefit, and that some comparator subjects showed similar stabilization. Ejection fraction changes are typically late phenomena in the disease, so a decade of stability is notable but not definitive proof of cardiac protection.

The clearest confirmation of the transplant’s biological success came from her blood. Genetic testing performed ten years after the procedure showed GAA repeat lengths of 10 and 16, entirely normal values reflecting the donor’s healthy genome, and her blood frataxin levels had returned to the control range, measured at 4.79 nanograms per milliliter for the mature form and 9.25 for the extended form. Her hematopoietic system had been completely rebuilt from genetically unaffected donor cells, demonstrating that full donor chimerism and normalized frataxin production in blood are achievable in a Friedreich’s ataxia patient, even if the nervous system remained beyond reach.

Because Friedreich’s ataxia is not known to elevate cancer risk, the co-occurrence of leukemia in this patient was almost certainly coincidental, but it dramatically complicated her treatment, given the cardiac sensitivity and neurotoxicity risks posed by many chemotherapy agents. The successful outcome nonetheless establishes that Friedreich’s ataxia patients can survive allogeneic stem cell transplantation, just as they have survived heart and liver transplantation in prior reports, opening a door for treating hematologic malignancies in this population. And the hint of cardiac stabilization, combined with the procedure’s relative safety, keeps alive the possibility that stem cell approaches could one day benefit the disease, if deployed in paradigms specifically engineered to deliver frataxin to the central nervous system. The authors are careful to stress that the present observations cannot be taken as evidence of neurological benefit, but the case stands as a rare, decade-long natural experiment that maps both the promise and the hard biological limits of replacing a patient’s blood to heal a brain.

Subject of Research: Allogeneic stem cell transplantation in a patient with Friedreich's ataxia and acute myeloid leukemia

Article Title: Stem Cell Transplantation in Friedreich Ataxia: Cure for Leukemia but No Effect on Neurological Progression

Article References: Gitman, A., Bhandari, N., Castellaro, M., Schadt, K., Cancio, M., & Lynch, D. R. (2026). Stem Cell Transplantation in Friedreich Ataxia: Cure for Leukemia but No Effect on Neurological Progression. Annals of Clinical and Translational Neurology, 13(8), 1733-1735. https://doi.org/10.1002/acn3.70455

Image Credits: AI Generated

DOI: 10.1002/acn3.70455

Keywords: Friedreich's ataxia, stem cell transplantation, frataxin, acute myeloid leukemia, FXN gene, neurodegeneration, cardiomyopathy, blood-brain barrier, gene therapy, GAA repeat expansion, hematopoietic stem cells, case report