2026-08-13 | Survival benefit and immune-related toxicities after hematopoietic stem cell transplantation in Krabbe disease: a systematic review and meta-analysis
Background Krabbe disease is a rare, rapidly progressive leukodystrophy with high early mortality. Hematopoietic stem cell transplantation (HSCT) is the main disease-modifying intervention used in clinical practice and may act through donor-derived myeloid and immune-cell replacement, enzymatic cross-correction, and immunomodulation. However, its benefits and immune-related toxicities remain incompletely quantified. Methods We conducted a systematic review and meta-analysis of studies reporting HSCT outcomes in genetically or enzymatically confirmed Krabbe disease. The primary outcome was overall survival (OS). Secondary outcomes included 5-year OS, transplant-related mortality (TRM), acute and chronic graft-versus-host disease (aGVHD and cGVHD), neurological stability, and MRI stability. For OS, publication bias or small-study effects were assessed using funnel-plot inspection and Egger’s regression test. Exploratory univariable meta-regression examined total study sample size, publication year, and Newcastle–Ottawa Scale (NOS) score, and robustness was assessed using leave-one-out sensitivity analysis. Results Fifteen studies involving 141 patients were included. Pooled OS after HSCT was 84% (95% CI, 75%–93%), 5-year OS was 80% (69%–92%), and TRM was 7% (1%–13%). The pooled incidences of aGVHD and cGVHD were 53% (16%–90%) and 25% (0%–53%), respectively. Neurological stability was reported in only four studies including 15 patients (77%; 31%–100%), and MRI stability in four studies including 32 patients (49%; 7%–90%); both estimates showed substantial heterogeneity and wide confidence intervals. Subgroup analyses by disease-onset age, pre-transplant symptom status, and age at HSCT showed no statistically significant OS differences. Egger’s test detected no significant funnel-plot asymmetry (P = 0.569). Leave-one-out estimates ranged from 82% to 86%. Meta-regression showed inverse associations of reported OS with total study sample size and NOS score (both P < 0.001), whereas publication year was not significant (P = 0.118). Conclusion HSCT is associated with favorable survival and relatively low pooled TRM in selected patients with Krabbe disease. However, survival should not be interpreted as preservation of neurological function, because neurological, MRI, and GVHD outcomes were reported in few studies and patients and remained heterogeneous and imprecisely estimated. These findings require cautious interpretation but provide clinically useful benchmark data for counseling and comparison with emerging cellular and gene-based therapies. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD420261285624.
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2026-08-13 | Metabolomic, lipidomic, and N-glycomic analyses of a human cell model of Krabbe disease reveal treatable deficits in glycosylation and serine-ceramide metabolism
Krabbe disease is a rare autosomal recessive lysosomal disease caused by deficiency of galactocerebrosidase (GALC), leading to accumulation of galactosylceramide and formation of the toxic metabolite galactosylsphingosine (psychosine). While psychosine accumulation is well-established as a primary pathogenic mechanism, the broader metabolic consequences of GALC deficiency remain incompletely understood. In this study, we used stable isotope tracing to comprehensively characterize metabolic perturbations in a human oligodendrocellular Krabbe disease model. This approach revealed elevated de novo ceramide synthesis in GALC knock-out cells, characterized by increased incorporation of glucose-derived serine into ceramide biosynthetic pathways. This enhanced ceramide production was amenable to pharmacological intervention by tezacaftor, an inhibitor of sphingolipid Δ4-desaturate (DEGS); tezacaftor administration also normalized psychosine levels, raising the possibility of its use as substrate reduction therapy. Additionally, we identified significant disruption of UDP-hexose metabolism, manifesting as an overabundance of truncated and hypogalactosylated glycans. These findings suggest impaired protein glycosylation as a previously unrecognized pathogenic mechanism in Krabbe disease. Our findings reveal novel metabolic dysregulation in Krabbe disease extending beyond established psychosine toxicity. The identification of enhanced de novo ceramide synthesis presents a new therapeutic target, while the discovery of galactose-deficient glycosylation defects supports galactose supplementation as a potential therapeutic intervention. These metabolic insights provide new mechanistic understanding and therapeutic opportunities for this devastating neurodegenerative disorder.
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2026-06-11 | Validating a Human Cell Model of Null Galactosylceramidase (GALC) Enzyme Activity That Recapitulates Krabbe Disease.
Krabbe Disease (KD) is a lysosomal leukodystrophy characterized by the production of psychosine in oligodendrocytes, leading to neurodegeneration and ultimately death. The only treatment modality currently available for this disease is hematopoietic stem cell transplantation (HSCT), a procedure with high morbidity, highlighting the need for further therapies to be developed. In this study, we established and characterized GALC knockout MO3.13 cells, a cell line derived from human oligodendrocytes, as a model for KD. Clonal MO3.13 cells with GALC KO were obtained via CRISPR/Cas9-mediated gene editing. GALC activity was measured by a 4-methylumbellyferyl (4-MU)-based assay, and morphology analyses were performed using light microscopy and transmission electron microscopy. Psychosine was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The GALC KO cells have elevated levels of psychosine and an increased number of autophagosomes, autolysosomes, and cytoplasmic granules on transmission electron microscopy. Glycogen abundance was decreased in GALC KO cells compared to controls. After administration of BMN-S202, a ceramide galactosyltransferase inhibitor, psychosine levels in GALC KO cells were reduced back to WT levels. In conclusion, we demonstrated that the GALC KO MO3.13 cell line recapitulates the KD phenotype and biochemical response to SRT and may be a useful KD model for mechanistic studies and therapeutic development for KD.
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2026-06-09 | Pediatrician Involvement in Communicating Positive Newborn Screening Results for Krabbe Disease: Barriers, Facilitators, and Ideas for Interventions (P4-8.002)
In this study, we aimed to understand pediatrics clinicians’ perspectives on barriers, facilitators, and ideas for interventions regarding their integration in disclosing positive NBS results for Krabbe disease.
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2026-04-28 | Data from "A new CRISPR/Cas9 GALC Knockout cellular Model Reveals Lactosylceramide Accumulation Similar to Twitcher Mice."
Krabbe disease (KD) is a lysosomal sphingolipidosis caused by the deficiency of galactocerebrosidase (GALC), leading to profound alterations in sphingolipid metabolism and severe neurodegeneration. While psychosine (Psy) accumulation is a well-established hallmark of KD, emerging evidence suggests that lactosylceramide (LacCer) may also contribute to disease pathogenesis. Here, we generated a novel human oligodendrocytic model of GALC deficiency by CRISPR/Cas9-mediated GALC knockout in MO3.13 cells and used it to investigate sphingolipid alterations associated with impaired GALC activity. GALC−/− MO3.13 cells showed a marked reduction in GALC transcript levels and enzymatic activity, confirming the successful establishment of a disease-relevant cellular model. Our results demonstrated that a) GALC knockout MO3.13 cells accumulated Psy and LacCer, and b) LacCer content was increased in the brain and heart isolated from twitcher (TWI) mice, the most widely used spontaneous animal model of KD. In parallel, AKT signalling was evaluated in both systems, supporting a link between LacCer dysregulation and altered cellular signalling pathways. Overall, these findings identify LacCer accumulation as a conserved feature of GALC deficiency across cellular and animal models and support the use of GALC−/− MO3.13 cells as a novel in vitro platform to investigate KD pathogenesis and candidate therapeutic strategies.
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