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BACKGROUND: X-linked adrenoleukodystrophy (ALD) is a neurometabolic disorder caused by pathogenic variants in ABCD1 resulting very long-chain fatty acids (VLCFA) accumulation in plasma and tissues. Males can present with various clinical manifestations, including adrenal insufficiency, spinal cord disease, and leukodystrophy. Female patients typically develop spinal cord disease and peripheral neuropathy. Predicting the clinical outcome of an individual patient remains impossible due to the lack of genotype-phenotype correlation and predictive biomarkers. METHODS: The availability of a large prospective cohort of well-characterized patients and associated biobank samples allowed us to investigate the relationship between lipidome and disease severity in ALD. We performed a lipidomic analysis of plasma samples from 24 healthy controls, 92 male and 65 female ALD patients. RESULTS: Here we show that VLCFA are incorporated into different lipid classes, including lysophosphatidylcholines, phosphatidylcholines, triglycerides, and sphingomyelins. Our results show a strong association between higher levels of VLCFA-containing lipids and the presence of leukodystrophy, adrenal insufficiency, and severe spinal cord disease in male ALD patients. In female ALD patients, VLCFA-lipid levels correlate with X-inactivation patterns in blood mononuclear cells, and higher levels are associated with more severe disease manifestations. Finally, hematopoietic stem cell transplantation significantly reduces, but does not normalize, plasma C26:0-lysophosphatidylcholine levels in male ALD patients. Our findings are supported by the concordance of C26:0-lysophosphatidylcholine and total VLCFA analysis with the lipidomics results. CONCLUSIONS: This study reveals the profound impact of ALD on the lipidome and provides potential biomarkers for predicting clinical outcomes in ALD patients.

X-linked adrenoleukodystrophy (ALD) affects the brain, spinal cord, and adrenal glands. ALD is caused by too many very long-chain fatty acids (VLCFAs) in the body. We don't know how ALD progresses in individual patients. We have analyzed blood samples from male and female ALD patients. We found that certain changes in fatty acid (or lipid) composition are associated with more severe symptoms. Our findings may lead to new ways to predict which symptoms are likely to change over time and to monitor the effectiveness of treatment. This research increases our understanding of ALD and may improve patient care in the future.

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BACKGROUND: Dyskeratosis congenita/telomere biology disorders (DC/TBD) often manifest as bone marrow failure (BMF) or myelodysplastic syndrome (MDS). Allogeneic hematopoietic cell transplant (alloHCT) rescues hematologic complications, but radiation and alkylator-based conditioning regimens cause diffuse whole-body toxicity and may expedite DC/TBD-specific non-hematopoietic complications. Optimization of conditioning intensity in DC/TBD to allow for donor hematopoietic cell engraftment with the least amount of toxicity remains a critical goal of the alloHCT field. OBJECTIVES/STUDY DESIGN: We report prospectively collected standard alloHCT outcomes from a single-center, single-arm, open-label clinical trial of bone marrow or peripheral blood stem cell alloHCT for DC/TBD-associated BMF or MDS. Conditioning was reduced intensity (RIC), including alemtuzumab 1 mg/kg, fludarabine 200 mg/m2, and cyclophosphamide 50 mg/kg. A previous single-arm, open-label phase II clinical trial for the same patient population conducted at the same center, differing only by inclusion of 200 cGy of total body irradiation (TBI), served as a control cohort. RESULTS: The non-TBI cohort included 10 patients (ages 1.7-65.9 years, median follow-up of 3.9 years) compared with the control TBI cohort, which included 12 patients (ages 2.2-52.2 years, median follow-up of 10.5 years). Baseline characteristics differed only in total CD34+ cells received, with a median of 5.6 (non-TBI) compared with 2.6 (TBI) x 106/kg (P = .02; no difference in total nucleated cells). The cumulative incidence of day +100 grade II-IV acute and 4-year chronic graft-versus-host disease (GvHD) were low at 0% and 10% (non-TBI) and 8% and 17% (TBI), respectively (acute, P = .36; chronic, P = .72). Primary graft failure was absent. Secondary non-neutropenic graft failure occurred in one (non-TBI cohort). The non-TBI cohort demonstrated delayed achievement of full donor chimerism but superior lymphocyte recovery. There was no difference in 4-year overall survival at 80% (non-TBI) and 75% (TBI; P = .78). MDS as an indication for alloHCT was uncommon but overall associated with poor outcomes. There were 3 MDS patients in the non-TBI cohort: 1 relapsed and died at day +387; 1 relapsed at day +500 and is alive 5.5 years later following salvage with a second alloHCT; 1 relapsed at day +1093 and is alive at day +100 after a second alloHCT. There was 1 MDS patient in the TBI cohort who achieved 100% donor myeloid engraftment without relapse but died at day +827 from a bacterial infection in the setting of immune-mediated cytopenia. CONCLUSION: Elimination of TBI from the RIC regimen for DC/TBD was not associated with significant changes in rates of graft failure, GvHD, and overall survival but was associated with delayed achievement of full donor chimerism and improved lymphocyte reconstitution. For DC/TBD-associated BMF, TBI appears to be dispensable. Optimal approaches to DC/TBD-associated MDS remain unclear. Larger cohorts are needed to better assess the unique contribution of TBI and donor CD34+ cell dose. Longer follow-up is required to assess differences in DC/TBD complications and late effects.

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Objective: To report 3 cases of adrenoleukodystrophy (ALD) in children conceived by in vitro fertilization (IVF) and egg donation. Design: A case report. Patients: Patients aged 4-5 years old, evaluated by the University of Minnesota Leukodystrophy Center, who were diagnosed with ALD after being conceived by IVF with oocytes provided by the same donor. Interventions: One patient received a hematopoietic stem cell transplant from a human leukocyte antigen-matched donor, and 1 patient received autologous lentiviral corrected hematopoietic cells. The disease state in 1 patient was unfortunately too advanced for effective treatment to be administered. Main Outcome Measures: Progression of disease after diagnosis or treatment was observed by cerebral magnetic resonance imaging and monitoring the development or advancement of any cognitive, adaptive, and motor deficits. Results: Patients who received a transplant for ALD successfully experienced little to no disease progression at least 6 months to 1 year after treatment. Conclusions: These 3 cases of transmission of ALD through oocyte donation and IVF highlight the potential need to implement more comprehensive genetic screening of gamete donors to prevent the transfer of rare but severe genetic diseases through IVF. Further, these cases highlight limitations in carrier screening guidelines that limit reportable variants to pathogenic and likely pathogenic variants.