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

NETosis is a relatively recent addition to the immunology lexicon. First recognised as a mechanism for trapping and killing microbes, it involves the formation of neutrophil extracellular traps, or NETs, which are web-like lattices of DNA studded with antimicrobial proteins. The process can unfold in two distinct ways. In vital NETosis, the neutrophil remains alive and functional while deploying its DNA weapon, typically in response to pathogen-associated molecular patterns derived from microbes. In suicidal or lytic NETosis, the cell perishes: its nuclear envelope disintegrates, its plasma membrane ruptures, and DNA chains decorated with citrullinated histones, neutrophil elastase and myeloperoxidase spill into the extracellular space. The molecular choreography is intricate. An enzyme called peptidyl-arginine deiminase 4 citrullinates histones, loosening the grip of chromatin, while granule enzymes translocate to the nucleus to cleave histones further, allowing the genetic material to decondense before its dramatic release.

Although NETosis has been implicated in atherosclerosis and thromboinflammation, its role in chronic heart failure remained underexplored. The research team, led by Sawa Kostin and colleagues, examined left ventricular tissue from 21 patients undergoing orthotopic heart transplantation. The patients fell into three groups matched for age, symptom severity, medication and comorbidities: seven with inflammatory cardiomyopathy following histologically proven myocarditis, seven with idiopathic dilated cardiomyopathy, and seven with ischaemic cardiomyopathy caused by severe coronary artery disease. Crucially, in the ischaemic group the researchers analysed only tissue remote from previous infarcts, ensuring that observed inflammation reflected the failing heart as a whole rather than scarred regions. As controls, they used myocardial samples from five patients with aortic stenosis whose left ventricular function was fully preserved and whose tissue showed no damage, inflammation or fibrosis.

The results were striking. Using immunolabelling for CD66b, a neutrophil marker, the team found that control myocardium contained a median of just 2.48 neutrophils per square millimetre. In the failing hearts, that figure soared to 11.4 cells in dilated cardiomyopathy, 13.9 in ischaemic cardiomyopathy and 15.5 in inflammatory cardiomyopathy, a four- to six-fold increase. To detect NETosis directly, the researchers stained for citrullinated histone 3 and myeloperoxidase, two molecular signatures of NET formation. Confocal microscopy revealed thin, long NET structures, ranging from 5 to 50 micrometres, positive for both DNA and citrullinated histone 3, weaving through the failing myocardium. No such structures appeared in control tissue.

Biochemical and molecular assays corroborated the microscopy. Western blot analysis showed that citrullinated histone 3 protein levels were 4.8-fold higher in inflammatory cardiomyopathy, 4.4-fold higher in ischaemic cardiomyopathy and 2.7-fold higher in dilated cardiomyopathy compared with controls, with all differences statistically significant. Quantitative polymerase chain reaction confirmed that myeloperoxidase messenger RNA was three to four times more abundant in the failing hearts. When the researchers counted neutrophils positive for both CD66b and citrullinated histone 3, they found medians of 7.94 cells per square millimetre in inflammatory cardiomyopathy, 5.51 in dilated cardiomyopathy and 5.79 in ischaemic cardiomyopathy, against just 1.12 in controls. Triple staining for CD66b, citrullinated histone 3 and myeloperoxidase revealed a 4.6- to 6.1-fold increase across all heart failure groups, with no significant differences between aetiologies.

Macrophages told an equally compelling story. These highly plastic cells, which can polarise into classically activated M1-like macrophages that drive inflammation or alternatively activated M2-like macrophages that promote repair and phagocytosis, are among the most active immune participants in cardiac remodelling. Counting CD68-positive cells, the team found a median of 13.3 macrophages per square millimetre in control myocardium, rising to 47.1 in dilated cardiomyopathy, 55.4 in ischaemic cardiomyopathy and 69.4 in inflammatory cardiomyopathy. Remarkably, macrophage numbers correlated very strongly with neutrophil counts, with a Spearman coefficient of 0.918, suggesting the two cell populations accumulate in lockstep within the diseased heart.

Phenotyping revealed a decisive shift. In control tissue, only about 3 percent of macrophages displayed the M1-like profile, identified by co-expression of CD68 with tumour necrosis factor alpha or interleukin-6, while roughly 6.5 percent were M2-like, marked by CD206 or arginase-1. In the failing hearts, M1-like macrophages dominated: 78.5 percent in inflammatory cardiomyopathy, 54.5 percent in ischaemic cardiomyopathy and 53.2 percent in dilated cardiomyopathy. M2-like macrophages also increased, reaching roughly 21 to 23 percent, but never matched the proinflammatory surge. The resulting M1-to-M2 ratio, a measure of inflammatory balance, stood at 3.19 in inflammatory cardiomyopathy and around 2.5 to 2.6 in the other groups, compared with just 0.63 in controls, all differences statistically significant.

The pivotal finding emerged when the researchers correlated NETosis with macrophage polarisation. The percentage of M1-like macrophages correlated positively and significantly with the number of neutrophils undergoing NETosis, with a correlation coefficient of 0.79 for triple-positive citH3/MPO/CD66b cells and 0.68 for citH3/CD66b cells. In contrast, M2-like macrophages showed no meaningful association with NETosis, with coefficients near zero and non-significant p-values. Triple immunolabelling for citrullinated histone 3, tumour necrosis factor alpha and CD206 provided visual confirmation: NET-forming neutrophils were consistently surrounded by far more TNF-alpha-positive M1-like macrophages than CD206-positive M2-like cells.

What might this interplay mean mechanistically? Prior work offers intriguing clues. Co-culture experiments have shown that both M1- and M2-like macrophages can degrade NETs, with M1-like cells dominating the early phagocytic response and M2-like cells completing clearance later. Studies in acute pulmonary ischaemia-reperfusion injury have described a mutual feedback loop in which NETosis drives M1-like polarisation, which in turn promotes further NETosis. The authors suggest that in chronic heart failure this reciprocal interaction may create a positive feedback loop that sustains low-grade myocardial inflammation, a recognised hallmark of the disease. Alternatively, the M1 skewing could represent a compensatory attempt to clear excessive NETs, one that fails to suppress NET formation itself. The concurrent rise in M2-like macrophages, albeit more modest, may reflect involvement in clearing dead cardiomyocytes and contributing to fibrosis, given that the failing heart loses an estimated 20 percent of its cardiomyocytes each year in terminal stages.

The authors are careful to note that correlation does not establish causation, and that the observed associations may be consequences of chronic heart failure rather than drivers of it. The study’s limitations include the small number of patients, the differing aetiologies across groups and considerable interindividual variability. Nevertheless, the consistency of the findings across inflammatory, dilated and ischaemic forms of the disease, and the earlier observation that neutrophil and macrophage accumulation precedes overt heart failure in compensated hypertrophy, lend weight to the idea that this immune axis matters. Recent research also implicates extracellular vesicles released by injured cardiomyocytes in promoting neutrophil-driven inflammation and macrophage polarisation, suggesting multiple routes by which tissue damage could ignite the NETosis-macrophage circuit. If future studies confirm a causal role, inhibiting NETosis or restoring the balance between M1- and M2-like macrophages could become genuine therapeutic strategies for chronic heart failure, a condition that still lacks treatments targeting its inflammatory underpinnings. For now, the study provides a rigorous anatomical and molecular map of that circuit in human tissue, and a clear hypothesis for the next generation of experiments.

Subject of Research: The association between neutrophil extracellular trap formation and proinflammatory macrophage polarisation in human heart failure

Article Title: Increased NETosis in Patients With Heart Failure Is Associated With Macrophage Activation Towards a Proinflammatory Phenotype

Article References: Kostin, S., Cabrera‐Fuentes, H. A., Richter, M., Krizanic, F., Ritter, O., Boisvert, W. A., Preissner, K. T., Kelesidis, T., Siasos, G., & Pagonas, N. (2026). Increased NETosis in Patients With Heart Failure Is Associated With Macrophage Activation Towards a Proinflammatory Phenotype. Journal of Cellular and Molecular Medicine, 30(17), Article e71306. https://doi.org/10.1111/jcmm.71306

Image Credits: AI Generated

DOI: 10.1111/jcmm.71306

Keywords: heart failure, NETosis, neutrophils, macrophages, M1 polarisation, myocardial inflammation, citrullinated histone 3, myeloperoxidase, cardiac remodelling, innate immunity, cardiomyopathy, immunohistochemistry