Adrenal insufficiency and the use of mineralocorticoid treatment in male patients with adrenoleukodystrophy; a retrospective analysis of an institutional database.

INTRODUCTION: Adrenoleukodystrophy (ALD) patients exhibit three primary clinical phenotypes: primary adrenal insufficiency, adrenomyeloneuropathy, and cerebral demyelination due to the accumulation of saturated very long-chain fatty acids in the adrenal cortex and central nervous system white matter and axons. We investigated the diagnosis of adrenal insufficiency (AI) and the use of mineralocorticoid treatment in male ALD patients. METHODS: A retrospective chart review of electronic medical records was conducted for all ALD patients at a single institution between January 1, 2011, and December 6, 2021. RESULTS: Among the 437 ALD patients, 82% were male and 18% were female. Of the male ALD patients, 60% (213 out of 358) had a diagnosis of AI, and 39% (84 out of 213) of those with AI were prescribed mineralocorticoid replacement therapy. CONCLUSION: AI is highly prevalent among ALD patients, with approximately 40% of those with a diagnosis of AI undergoing mineralocorticoid replacement therapy. Further research is warranted to delineate the characteristics of patients predisposed to developing mineralocorticoid deficiency within the context of ALD and AI.

Adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene and characterized by impaired very long-chain fatty acid beta-oxidation. Clinically, male patients develop adrenal failure and progressive myelopathy in adulthood, although the age of onset and rate of progression are highly variable. In addition, 40% of male patients develop a leukodystrophy (cerebral ALD) before the age of 18 years. Women with ALD also develop myelopathy, but generally at a later age than men and with slower progression. Adrenal failure and leukodystrophy are exceedingly rare in women. Allogeneic hematopoietic cell transplantation (HCT), or more recently autologous HCT with ex vivo lentivirally transfected bone marrow, halts the leukodystrophy. Unfortunately, there is no curative treatment for the myelopathy. In this chapter, clinical spectrum of ALD is discussed in detail.

Peroxisomal leukodystrophy.

Peroxisomal disorders can be classified as single-enzyme deficiencies or peroxisomal biogenesis disorders (characterized by multiple peroxisomal enzyme deficiencies or complete absence of peroxisomes). Most peroxisomal disorders give rise to complex multisystem disorders. Peroxisomal disorders associated with leukodystrophy are discussed in more detail, specifically X-linked adrenoleukodystrophy, Zellweger spectrum disorders, D-bifunctional protein deficiency, Acyl-CoA oxidase 1 deficiency, and Alpha-Methylacyl-CoA Racemase (AMACR) deficiency.

Hematopoietic stem cell transplantation in leukodystrophies.

More than 50 leukodystrophies have been described. This group of inherited disorders affects myelin development and/or maintenance and can manifest from birth to adulthood. Neuroinflammation is a hallmark of some leukodystrophies, explaining in part the therapeutic benefit of hematopoietic stem cell transplantation (HSCT). Indeed, in addition to supplying the CNS with myelomonocyte donor cells expressing the deficient protein or enzyme, HSCT allows the restoration of normal microglia function, which may act on neuroinflammation. In this chapter, we explore the rationale, indication, and outcome of HSCT in Cerebral Adrenoleukodystrophy (CALD), Metachromatic Leukodystrophy (MLD), Krabbe Disease (KD), and Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP), which are among the most frequent leukodystrophies. For these leukodystrophies, HSCT may modify notably the natural history and improve CNS-related deficits, provided that the procedure is performed early into the disease course. In addition, we discuss the recent development of ex vivo gene therapy for CALD and MLD as a promising alternative to allograft.

Diffusion Tensor Imaging in Boys With Adrenoleukodystrophy: Identification of Cerebral Disease and Association With Neurocognitive Outcomes.

BACKGROUND AND OBJECTIVES: Childhood cerebral adrenoleukodystrophy (C-ALD) is a severe inflammatory demyelinating disease that must be treated at an early stage to prevent permanent brain injury and neurocognitive decline. In standard clinical practice, C-ALD lesions are detected and characterized by a neuroradiologist reviewing anatomical MRI scans. We aimed to assess whether diffusion tensor imaging (DTI) is sensitive to the presence and severity of C-ALD lesions and to investigate associations with neurocognitive outcomes after hematopoietic cell therapy (HCT). METHODS: In this retrospective cohort study, we analyzed high-resolution anatomical MRI, DTI, and neurocognitive assessments from boys with C-ALD undergoing HCT at the University of Minnesota between 2011 and 2021. Longitudinal DTI data were compared with an age-matched group of boys with ALD and no lesion (NL-ALD). DTI metrics were obtained for atlas-based regions of interest (ROIs) within 3 subdivisions of the corpus callosum (CC), corticospinal tract (CST), and total white matter (WM). Between-group baseline and slope differences in fractional anisotropy (FA) and axial (AD), radial (RD), and mean (MD) diffusivities were compared using analysis of covariance accounting for age, MRI severity (Loes score), and lesion location. RESULTS: Among patients with NL-ALD (n = 14), stable or increasing FA, stable AD, and stable or decreasing RD and MD were generally observed during the 1-year study period across all ROIs. In comparison, patients with mild posterior lesions (Loes 1-2; n = 13) demonstrated lower baseline FA in the CC splenium (C-ALD 0.50 ± 0.08 vs NL-ALD 0.58 ± 0.04; pBH = 0.022 adjusted Benjamini-Hochberg p-value), lower baseline AD across ROIs (e.g., C-ALD 1.34 ± 0.03 ×10-9 m2/s in total WM vs NL-ALD 1.38 ± 0.04 ×10-9 m2/s; pBH = 0.005), lower baseline RD in CC body and CST, and lower baseline MD across ROIs except CC splenium. Longitudinal slopes in CC splenium showed high sensitivity and specificity in differentiating early C-ALD from NL-ALD. Among all patients with C-ALD (n = 38), baseline Loes scores and DTI metrics were associated with post-HCT neurocognitive functions, including processing speed (e.g., FA WM Spearman correlation coefficient R = 0.64) and visual-motor integration (e.g., FA WM R = 0.71). DISCUSSION: DTI was sensitive to lesion presence and severity as well as clinical neurocognitive effects of C-ALD. DTI metrics quantify C-ALD even at an early stage.

Hematopoietic stem cell therapy and ex vivo gene therapy for X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder that leads to progressive neurodegeneration in brain and spinal cord. The most devastating phenotype of childhood cerebral ALD can be halted by allogeneic hematopoietic stem cell transplantation but the procedure remains cumbersome and limited by engraftment problems and graft versus host disease. This is particularly difficult for boys with more advanced brain lesions and neurologic impairment. Fortunately, newborn screening has led to regular monitoring and increased detection of cerebral ALD in early symptomatic or asymptomatic stages. Adults with ALD can also develop cerebral ALD but here implementation of HSCT is more challenging due to vulnerabilities not seen in childhood cerebral ALD. More recently the hematopoietic stem cell approach has given rise to a first ex vivo lentiviral gene therapy for this rare disorder. Over 60 boys with cerebral ALD have received ex vivo lentiviral gene therapy worldwide. While the approach is effective in halting progression of early-stage inflammatory demyelination in brain and prevents engraft problems and graft versus host disease, there have also been cases of myelodysplastic syndrome emerging. In September of 2022, the FDA granted accelerated approval of ex vivo lentiviral gene therapy to slow the progression of neurologic dysfunction in boys 4-17years of age with early, active cerebral ALD. We describe the history of these developments, outline the pathophysiology of the disorder and the corresponding rationale of hematopoietic stem cell therapy as well as current developments in the field.

Newborn Screening for X-Linked Adrenoleukodystrophy (X-ALD): Biochemical, Molecular, and Clinical Characteristics of Other Genetic Conditions.

The state of California (CA) added X-linked adrenoleukodystrophy (X-ALD) to newborn screening (NBS) in 2016 via the measurement of C26:0-lysophosphatidylcholine (C26:0-LPC) in a two-tier fashion, followed by sequencing of the ABCD1 gene. This has resulted in the identification of individuals with genetic conditions beyond X-ALD that can also result in elevated C26:0-LPC by NBS. We describe the biochemical, molecular, and clinical characteristics of nine patients from two metabolic centers in California who screened positive by NBS for elevated C26:0-LPC between 2016 and 2022 and were ultimately diagnosed with a genetic condition other than X-ALD. Seven individuals were diagnosed with Zellweger spectrum disorder (ZSD) due to biallelic variants in PEX genes. One male was diagnosed with Klinefelter syndrome and one female was found to have an X chromosome contiguous gene deletion syndrome after the identification of a heterozygous VUS and hemizygous VUS variant in ABCD1, respectively. Patients with ZSD had significantly higher first- and second-tier C26:0-LPC levels compared to the two non-ZSD cases. Identification of children with ZSD and atypical patterns of ABCD1 variants is a secondary benefit of NBS for X-ALD, leading to earlier diagnosis, prompt therapeutic initiation, and more accurate genetic counseling. As screening for X-ALD continues via the measurement of C26:0-LPC, our knowledge of additional genetic conditions associated with elevated C26:0-LPC will continue to advance, allowing for increased recognition of other genetic disorders for which early intervention is warranted.

Burden of illness and mortality in men with Adrenomyeloneuropathy: a retrospective cohort study.

BACKGROUND: Adrenomyeloneuropathy (AMN) is a neurodegenerative disease phenotype of X-linked adrenoleukodystrophy (ALD), resulting in progressive myeloneuropathy causing spastic paraparesis, sensory ataxia, and bowel/bladder symptoms. We conducted a retrospective cohort study using two large administrative databases to characterize mortality and the burden of illness in adult men with AMN in the US. RESULTS: Healthcare resource use was assessed using a national commercial insurance claims database (2006-2021). Males with AMN ages 18-64 years and no evidence of cerebral ALD or other peroxisomal disorders were included and 1:4 matched on demographic characteristics to individuals without AMN. All study participants were followed for as long as observable. Patients with AMN were also identified in the Medicare Limited Dataset (2017-2022); mortality and age at death were compared with all Medicare enrollees. We identified 303 commercially insured men with AMN. Compared with non-AMN, individuals with AMN had significantly more inpatient hospital admissions (0.44 vs. 0.04 admissions/patient/year), outpatient clinic (8.88 vs. 4.1 visits/patient/year), outpatient hospital (5.33 vs. 0.99 visits/patient/year), and home healthcare visits (4.66 vs. 0.2 visits/patient/year), durable medical equipment claims (0.7 vs. 0.1 claims/patient/year), and prescription medication fills (18.1 vs. 5.4 fills/patient/year) (all p < 0.001). Average length-of-stay per hospitalization was also longer in AMN (8.88 vs. 4.3 days; p < 0.001). Rates of comorbidities were significantly more common in AMN compared to controls, including peripheral vascular disease (4.6% vs. 0.99%), chronic pulmonary disease (6.3% vs. 2.6%), and liver disease (5.6% vs. 0.88%), all p < 0.001. Among individuals age < 65 with Medicare disability coverage, mortality rates were 5.3x higher for adult AMN males (39.3% vs. 7.4%) and the age at death significantly younger (47.0 ± 11.3 vs. 56.5 ± 7.8 years), both p < 0.001. Among Medicare beneficiaries ages ≥ 65 mortality rates were 2.2x higher for men with AMN vs. those without AMN (48.6% vs. 22.4%), p < 0.001. CONCLUSION: AMN imposes a substantial and underrecognized health burden on men, with higher healthcare utilization, greater medical comorbidity, higher mortality rates, and younger age at death.

Allogeneic stem cell transplantation for inherited metabolic disorders: 35 years' experience at a single institution.

Hematopoietic stem cell transplants for inherited metabolic disorders performed at Tokai University Hospital between June 5, 1986, and May 28, 2021, were analyzed and compared between the period before 2007 and the period from 2007 onward based on availability of medical resources. Transplants were performed for 38 patients with mucopolysaccharidosis, 33 with adrenoleukodystrophy, and 16 with another disorder. Before 2007, oral busulfan-based regimens were mainly used. From 2007 onward, intravenous busulfan-based regimens or 4 Gy of thoracoabdominal irradiation (TAI), fludarabine, and melphalan (Mel)/treosulfan were adopted. Between 2002 and 2010, adrenoleukodystrophy was treated with 12 Gy of TAI and Mel. HLA-identical sibling bone marrow was used in 43% of cases before 2007 and 15% from 2007 onward, while alternative donors were selected for other transplants. Overall survival and event-free survival (EFS) before 2007 and from 2007 onward were 76% and 62%, and 97% and 85%, respectively (P = 0.006 and 0.017). Transplant era predicted superior overall survival and EFS, while myeloablative conditioning also predicted EFS. The incidence of primary graft failure decreased from 2007 onward, especially in cord blood transplant when 4 Gy of TAI with 150 mg/m2 fludarabine and 180 mg/m2 Mel or 42 g/m2 treosulfan were used as conditioning.

Brainstem dominant form of X-linked adrenoleukodystrophy with a novel ABCD1 missense variant: A case report and literature review.

BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder attributed to ABCD1 mutations. Case reports with predominant brainstem involvement are rare. CASE PRESENTATION: In this study, we reported a plateau male worker of X-ALD characterized by progressive weakness accompanied by gait instability, mild nystagmus, and constipation. After 2 years of onset, a brain Magnetic Resonance Image (MRI) scan showed no abnormality but genetic analysis revealed a heterozygous mutation (c.1534G>A) in the ABCD1 gene. After 7 years of onset, although the patient was given aggressive dietary and symptomatic treatment in the course of the disease, a brain MRI scan showed predominantly brainstem damage, but serum concentrations of very long-chain fatty acids were normal, and he had been bedridden for almost 2 years with severe bladder dysfunction, forcing him to undergo cystostomy. The patient was discharged with improved urinary retention and renal function. CONCLUSIONS: We reported an X-ALD patient with a novel ABCD1 variation characterized by brainstem damage and retrospectively summarized the clinical manifestation, MRI features, and genetic features of X-ALD patients with brainstem damage.

Easily misdiagnosed X-linked adrenoleukodystrophy.

BACKGROUND: Addison's disease and X-linked adrenoleukodystrophy (X-ALD) (Addison's-only) are two diseases that need to be identified. Addison's disease is easy to diagnose clinically when only skin and mucosal pigmentation symptoms are present. However, X-ALD (Addison's-only) caused by ABCD1 gene variation is ignored, thus losing the opportunity for early treatment. This study described two patients with initial clinical diagnosis of Addison's disease. However, they rapidly developed neurological symptoms triggered by infection. After further genetic testing, the two patients were diagnosed with X-ALD. METHODS: We retrospectively analyzed X-ALD patients admitted to our hospital. Clinical features, laboratory test results, and imaging data were collected. Whole-exome sequencing was used in molecular genetics. RESULTS: Two patients were included in this study. Both of them had significantly increased adrenocorticotropic hormone level and skin and mucosal pigmentation. They were initially clinically diagnosed with Addison's disease and received hydrocortisone treatment. However, both patients developed progressive neurological symptoms following infectious disease. Further brain magnetic resonance imaging was completed, and the results suggested demyelinating lesions. Molecular genetics suggested variations in the ABCD1 gene, which were c.109_110insGCCA (p.C39Pfs*156), c.1394-2 A > C (NM_000033), respectively. Therefore, the two patients were finally diagnosed with X-ALD, whose classification had progressed from X-ALD (Addison's-only) to childhood cerebral adrenoleukodystrophy (CCALD). Moreover, the infection exacerbates the demyelinating lesions and accelerates the onset of neurological symptoms. Neither the two variation sites in this study had been previously reported, which extends the ABCD1 variation spectrum. CONCLUSIONS: Patients with only symptoms of adrenal insufficiency cannot be simply clinically diagnosed with Addison's disease. Being alert to the possibility of ABCD1 variation is necessary, and complete genetic testing is needed as soon as possible to identify X-ALD (Addison's-only) early to achieve regular monitoring of the disease and receive treatment early. In addition, infection, as a hit factor, may aggravate demyelinating lesions of CCALD. Thus, patients should be protected from external environmental factors to delay the progression of cerebral adrenoleukodystrophy.

Phase I clinical trial of intracerebral injection of lentiviral-ABCD1 for the treatment of cerebral adrenoleukodystrophy.

This was a single-arm, multicenter, open-label phase I trial. Lentiviral vectors (LV) carrying the ABCD1 gene (LV-ABCD1) was directly injected into the brain of patients with childhood cerebral adrenoleukodystrophy (CCALD), and multi-site injection was performed. The injection dose increased from 200 to 1600 µL (vector titer: 1×109 transduction units per mL (TU/mL)), and the average dose per kilogram body weight ranges from 8 to 63.6 µL/kg. The primary endpoint was safety, dose-exploration and immunogenicity and the secondary endpoint was initial evaluation of efficacy and the expression of ABCD1 protein. A total of 7 patients participated in this phase I study and were followed for 1 year. No injection-related serious adverse event or death occurred. Common adverse events associated with the injection were irritability (71%, 5/7) and fever (37.2-38.5 â„ƒ, 57%, 4/7). Adverse events were mild and self-limited, or resolved within 3 d of symptomatic treatment. The maximal tolerable dose is 1600 µL. In 5 cases (83.3%, 5/6), no lentivirus associated antibodies were detected. The overall survival at 1-year was 100%. The ABCD1 protein expression was detected in neutrophils, monocytes and lymphocytes. This study suggests that the intracerebral injection of LV-ABCD1 for CCALD is safe and can achieve successful LV transduction in vivo; even the maximal dose did not increase the risk of adverse events. Furthermore, the direct LV-ABCD1 injection displayed low immunogenicity. In addition, the effectiveness of intracerebral LV-ABCD1 injection has been preliminarily demonstrated while further investigation is needed. This study has been registered in the Chinese Clinical Trial Registry (https://www.chictr.org.cn/, registration number: ChiCTR1900026649).

Targeting VEGF-mediated blood-brain barrier disruption in advanced cerebral leukodystrophy.

The earliest clinical manifestation of cerebral adrenoleukodystrophy (CALD) is adrenal insufficiency (AI) characterized by elevations in ACTH and loss of cortisol. We showed high (though physiologically achievable) levels of ACTH increases endothelial permeability, increases anisotropy, and increases VEGF secretion. An ACBD1 knockout endothelial cell line had increased sensitivity to ACTH and VEGF. Inhibition of VEGF via application of anti-VEGF (bevacizumab) improved permeability. Six boys with advanced CALD were treated with bevacizumab combined with dexamethasone and ruxolitinib as immune suppressants. Most boys had decreases in gadolinium enhancement on MRI indicating improvement in endothelial function, though all boys continued to progress symptomatically.

Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy.

The peroxisomal disease adrenoleukodystrophy (X-ALD) is caused by loss of the transporter of very-long-chain fatty acids (VLCFAs), ABCD1. An excess of VLCFAs disrupts essential homeostatic functions crucial for axonal maintenance, including redox metabolism, glycolysis and mitochondrial respiration. As mitochondrial function and morphology are intertwined, we set out to investigate the role of mitochondrial dynamics in X-ALD models. Using quantitative 3D transmission electron microscopy, we revealed mitochondrial fragmentation in corticospinal axons in Abcd1- mice. In patient fibroblasts, an excess of VLCFAs triggers mitochondrial fragmentation through the redox-dependent phosphorylation of DRP1 (DRP1S616). The blockade of DRP1-driven fission by the peptide P110 effectively preserved mitochondrial morphology. Furthermore, mRNA inhibition of DRP1 not only prevented mitochondrial fragmentation but also protected axonal health in a Caenorhabditis elegans model of X-ALD, underscoring DRP1 as a potential therapeutic target. Elevated levels of circulating cell-free mtDNA in patients' CSF align this leukodystrophy with primary mitochondrial disorders. Our findings underscore the intricate interplay between peroxisomal dysfunction, mitochondrial dynamics and axonal integrity in X-ALD, shedding light on potential avenues for therapeutic intervention.

Four-dimensional lipidomics profiling in X-linked adrenoleukodystrophy using trapped ion mobility mass spectrometry.

Lipids play pivotal roles in an extensive range of metabolic and physiological processes. In recent years, the convergence of trapped ion mobility spectrometry and MS has enabled 4D-lipidomics, a highly promising technology for comprehensive lipid analysis. 4D-lipidomics assesses lipid annotations across four distinct dimensions-retention time, collisional cross section, m/z (mass-to-charge ratio), and MS/MS spectra-providing a heightened level of confidence in lipid annotation. These advantages prove particularly valuable when investigating complex disorders involving lipid metabolism, such as adrenoleukodystrophy (ALD). ALD is characterized by the accumulation of very-long-chain fatty acids (VLCFAs) due to pathogenic variants in the ABCD1 gene. A comprehensive 4D-lipidomics strategy of ALD fibroblasts demonstrated significant elevations of various lipids from multiple classes. This indicates that the changes observed in ALD are not confined to a single lipid class and likely impacts a broad spectrum of lipid-mediated physiological processes. Our findings highlight the incorporation of mainly saturated and monounsaturated VLCFA variants into a range of lipid classes, encompassing phosphatidylcholines, triacylglycerols, and cholesterol esters. These include ultra-long-chain fatty acids with a length of up to thirty carbon atoms. Lipid species containing C26:0 and C26:1 were the most frequently detected VLCFA lipids in our study. Furthermore, we report a panel of 121 new candidate biomarkers in fibroblasts, exhibiting significant differentiation between controls and individuals with ALD. In summary, this study demonstrates the capabilities of a 4D-lipid profiling workflow in unraveling novel insights into the intricate lipid modifications associated with metabolic disorders like ALD.

In vivo adenine base editing rescues adrenoleukodystrophy in a humanized mouse model.

X-linked adrenoleukodystrophy (ALD), an inherited neurometabolic disorder caused by mutations in ABCD1, which encodes the peroxisomal ABC transporter, mainly affects the brain, spinal cord, adrenal glands, and testes. In ALD patients, very-long-chain fatty acids (VLCFAs) fail to enter the peroxisome and undergo subsequent ß-oxidation, resulting in their accumulation in the body. It has not been tested whether in vivo base editing or prime editing can be harnessed to ameliorate ALD. We developed a humanized mouse model of ALD by inserting a human cDNA containing the pathogenic variant into the mouse Abcd1 locus. The humanized ALD model showed increased levels of VLCFAs. To correct the mutation, we tested both base editing and prime editing and found that base editing using ABE8e(V106W) could correct the mutation in patient-derived fibroblasts at an efficiency of 7.4%. Adeno-associated virus (AAV)-mediated systemic delivery of NG-ABE8e(V106W) enabled robust correction of the pathogenic variant in the mouse brain (correction efficiency: ∼5.5%), spinal cord (∼5.1%), and adrenal gland (∼2%), leading to a significant reduction in the plasma levels of C26:0/C22:0. This established humanized mouse model and the successful correction of the pathogenic variant using a base editor serve as a significant step toward treating human ALD disease.

A novel ABCD1 gene mutation causes adrenomyeloneuropathy presenting with spastic paraplegia: A case report.

RATIONALE: X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene leading to very long chain fatty acid (VLCFA) accumulation. The disease demonstrates a spectrum of phenotypes including adrenomyeloneuropathy (AMN). We aimed to identify the genetic basis of disease in a patient presenting with AMN features in order to confirm the diagnosis, expand genetic knowledge of ABCD1 mutations, and elucidate potential genotype-phenotype associations to inform management. PATIENT CONCERNS: A 29-year-old male presented with a 4-year history of progressive spastic paraplegia, weakness of lower limbs, fecal incontinence, sexual dysfunction, hyperreflexia, and positive Babinski and Chaddock signs. DIAGNOSES: Neuroimaging revealed brain white matter changes and spinal cord thinning. Significantly elevated levels of hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0) suggested very long chain fatty acids (VLCFA) metabolism disruption. Genetic testing identified a novel hemizygous ABCD1 mutation c.249dupC (p.F83fs). These findings confirmed a diagnosis of X-linked ALD with an AMN phenotype. INTERVENTIONS: The patient received dietary counseling to limit VLCFA intake. Monitoring for adrenal insufficiency and consideration of Lorenzo's oil were advised. Genetic counseling and testing were offered to at-risk relatives. OUTCOMES: At present, the patient continues to experience progressive paraplegia. Adrenal function remains normal thus far without steroid replacement. Family members have undergone predictive testing. LESSONS: This case expands the known mutation spectrum of ABCD1-linked X-ALD, providing insight into potential genotype-phenotype correlations. A thoughtful diagnostic approach integrating clinical, biochemical and genetic data facilitated diagnosis. Findings enabled genetic counseling for at-risk relatives regarding this X-linked disorder.

Haploidentical hematopoietic stem cell transplantation with busulfan, cyclophosphamide, and fludarabine conditioning for X-linked adrenal cerebral leukodystrophy.

OBJECTIVE: We investigated the safety and efficacy of haploidentical stem cell transplantation (SCT) in pediatric patients with X-linked adrenoleukodystrophy (ALD). METHODS: A retrospective analysis of transplantation data from 29 cases of ALD, treated between December 2014 and April 2022, was conducted. Neurologic function scores (NFS) were assessed. The conditioning regimen was busulfan 9.6 mg/kg, cyclophosphamide 200 mg/kg, and fludarabine 90 mg/m2 (BFC). Graft-versus-host disease prophylaxis consisted of anti-human thymocyte globulin, cyclosporine A, mycophenolate mofetil, and short course of methotrexate. RESULTS: Among the 29 cases, 14 cases (NFS = 0) were asymptomatic, and 15 (NFS ≥ 1) were symptomatic. The median age at SCT was 8 years (range: 4-16 years); the median follow-up time was 1058 days (range: 398-3092 days); 28 cases were father donors and 1 case was a grandfather donor. Hematopoietic reconstitution was successful in all patients, and all of them achieved complete donor chimerism at the time of engraftment. The leading cause of death was still primary disease progression (n = 4). Survival free of major functional disabilities was 100% in asymptomatic patients versus 66.67% in the symptomatic group (p = .018). CONCLUSION: BFC regimen used in haploidentical SCT was administered safely without major transplant-related complications even in symptomatic patients, and neurological symptoms were stabilized after SCT.

Experiences of patients with metachromatic leukodystrophy, adrenoleukodystrophy, or Krabbe disease and the experiences of their family members: a qualitative systematic review.

OBJECTIVE: This review aimed to synthesize the experiences of patients with metachromatic leukodystrophy, adrenoleukodystrophy, or Krabbe disease and the experiences of their families. INTRODUCTION: Leukodystrophies are metabolic diseases caused by genetic mutations. There are multiple forms of the disease, varying in age of onset and symptoms. The progression of leukodystrophies worsens central nervous system symptoms and significantly affects the lives of patients and their families. INCLUSION CRITERIA: Qualitative studies on the experiences of patients with leukodystrophies and their family members were included. These experiences included treatments such as enzyme replacement therapy and hematopoietic stem cell transplantation; effects of tracheostomy and gastrostomy; burdens on the family, coordinating care within the health care system, and family planning due to genetic disorders. This review considered studies in any setting. METHODS: MEDLINE (Ovid), CINAHL Plus (EBSCOhost), APA PsycINFO (EBSCOhost), Scopus, and MedNar databases were searched on November 18, 2022. Study selection, critical appraisal, data extraction, and data synthesis were conducted in accordance with the JBI methodology for systematic reviews of qualitative evidence, and synthesized findings were evaluated according to the ConQual approach. RESULTS: Eleven studies were eligible for synthesis, and 45 findings were extracted corresponding with participants' voices. Of these findings, 40 were unequivocal and 5 were credible. The diseases in the included studies were metachromatic leukodystrophy and adrenoleukodystrophy; no studies were identified for patients with Krabbe disease and their families. These findings were grouped into 11 categories and integrated into 3 synthesized findings, including i) providing care by family members and health care providers as physical symptoms progress, which relates to the effects of the characteristics of progressive leukodystrophies; ii) building medical teamwork to provide appropriate support services, comprising categories related to the challenges experienced with the health care system for patients with leukodystrophy and their families; and iii) coordinating family functions to accept and cope with the disease, which included categories related to family psychological difficulties and role divisions within the family. According to the ConQual criteria, the second synthesized finding had a low confidence level, and the first and third synthesized findings had a very low confidence level. CONCLUSIONS: The synthesized findings of this review provide evidence on the experiences of patients with metachromatic leukodystrophy or adrenoleukodystrophy and their families. These findings indicate that there are challenges in managing a patient's physical condition and coordinating the health care system and family functions. REVIEW REGISTRATION: PROSPERO CRD42022318805. SUPPLEMENTAL DIGITAL CONTENT: A Japanese-language version of the abstract of this review is available [ http://links.lww.com/SRX/A49 ].