Cerebral Adrenoleukodystrophy Research Articles

Cost/effectiveness of elivaldogene autotemcel vs. hematopoietic stem cells transplantation in patients with cerebral adrenoleukodystrophy (CALD)

Cerebral adrenoleukodystrophy (CALD) is a severe, rare neurological disease with a progressive course and poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT) is still considered the standard of care for CALD. Elivaldogene autotemcel is a novel gene therapy for the treatment of childhood-onset CALD. Since many novel gene therapies are associated with high costs, our aim was to compare costs and effectiveness of elivaldogene autotemcel with the costs and effectiveness of allogeneic HSCT treatment of childhood-onset CALD. The analysis used an 80-year horizon and the perspective of the Serbian Republic Health Insurance Fund. Quality-adjusted life years (QALYs) gained with elivaldogene autotemcel and HSCT, as well as direct treatment costs, were our major outcomes. For the purposes of the economic analysis, we constructed and simulated a discrete-event simulation model to calculate the outcomes. We obtained the results of the model using a Monte Carlo simulation, which we conducted on 1000 virtual CALD patients. The analysis indicated that elivaldogene autotemcel was not cost-effective when compared to HSCT, and the net monetary benefit was negative. The base case incremental cost/effectiveness ratio was 259,848,512 RSD/QALY. Elivaldogene autotemcel is not more cost-effective than HSCT for the treatment of CALD from the perspective of the Serbian Republic Health Insurance Fund, according to classic pharmacoeconomic analysis and criteria. To ensure that the treatment is affordable for all patients for whom it is prescribed, a differentiated pricing strategy with lower drug prices in developing nations seems to be required.

Evaluation of Mobilization, Apheresis, and Conditioning Regimen and Engraftment in Patients Receiving One-Time Gene Therapy with Elivaldogene Autotemcel (Eli-cel) for Cerebral Adrenoleukodystrophy (CALD)

Evaluation of Mobilization, Apheresis, and Conditioning Regimen and Engraftment in Patients Receiving One-Time Gene Therapy with Elivaldogene Autotemcel (Eli-cel) for Cerebral Adrenoleukodystrophy (CALD)

Gene Therapy for Genetic Syndromes: Understanding the Current State to Guide Future Care.

Gene therapy holds promise as a life-changing option for individuals with genetic variants that give rise to disease. FDA-approved gene therapies for Spinal Muscular Atrophy (SMA), cerebral adrenoleukodystrophy, β-Thalassemia, hemophilia A/B, retinal dystrophy, and Duchenne Muscular Dystrophy have generated buzz around the ability to change the course of genetic syndromes. However, this excitement risks over-expansion into areas of genetic disease that may not fit the current state of gene therapy. While in situ (targeted to an area) and ex vivo (removal of cells, delivery, and administration of cells) approaches show promise, they have a limited target ability. Broader in vivo gene therapy trials have shown various continued challenges, including immune response, use of immune suppressants correlating to secondary infections, unknown outcomes of overexpression, and challenges in driving tissue-specific corrections. Viral delivery systems can be associated with adverse outcomes such as hepatotoxicity and lethality if uncontrolled. In some cases, these risks are far outweighed by the potentially lethal syndromes for which these systems are being developed. Therefore, it is critical to evaluate the field of genetic diseases to perform cost-benefit analyses for gene therapy. In this work, we present the current state while setting forth tools and resources to guide informed directions to avoid foreseeable issues in gene therapy that could prevent the field from continued success.

Accelerated Course of Cerebral Adrenoleukodystrophy After Coronavirus Disease 2019 Infection

BackgroundCoronavirus disease 2019 (COVID-19) can not only infect the respiratory system but also affect the nervous system through the release of inflammatory factors. Our study aimed to investigate the effect of COVID-19 infection on cerebral adrenoleukodystrophy (ALD). MethodsChanges in the neurological symptoms of cerebral ALD after infection with COVID-19 from January 2022 to February 2023 were retrospectively analyzed. The primary assessment indicator was the Neurologic Function Scale (NFS) score. ResultsA total of 17 male patients with cerebral ALD were enrolled, with a median age of 101 months (80 to 151 months). Among them, 11 (11 of 17, 64.7%) developed an exacerbation of neurological symptoms after COVID-19 infection. Two patients with NFS = 0 started presenting with neurological symptoms after infection. Fifteen patients were in the advanced stage (NFS >1 and/or Loes score >9), of which nine did not progress to major functional disabilities (MFDs). Seven of the nine patients (77.8%) experienced an increase in NFS scores, ranging from 1 to 9 points, within two weeks of COVID-19 infection, with four of them experiencing MFDs. For the other six patients who had progressed to MFDs, there was not much room for further degeneration, so the NFS score did not increase after COVID-19 infection. No deaths related to COVID-19 infection occurred. ConclusionsCOVID-19 infection may aggravate neurological symptoms of cerebral ALD, particularly among patients who have not yet progressed to MFDs. Therefore, COVID-19 may accelerate the course of cerebral ALD, so protecting patients from infection is essential for maintaining the stability of the disease.

Generation and characterization of induced pluripotent stem cell lines derived from skin fibroblasts of patients with adrenoleukodystrophy

X-linked adrenoleukodystrophy (ALD) is a rare peroxisome disease with phenotypic heterogeneity. There is a lack of suitable in vitro models to study its pathogenesis. We established two strains of iPSCs from skin fibroblasts of patients with childhood cerebral ALD and Addison’s disease, respectively. CytoTune™2.0 Sendai reprogramming kit was used. The iPSC lines showed typical stem cell morphology, normal karyotype, and carrying ABCD1 variation. The iPSC lines express pluripotency markers, and have the capacity to differentiate into three germ layers. iPSCs can be used as an alternative cell source for ALD in vitro model to study its pathogenesis and therapeutic strategies.

Diagnosing X-Linked Adrenoleukodystrophy after Implementation of Newborn Screening: A Reference Laboratory Perspective.

Adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, encoding for the adrenoleukodystrophy protein (ALDP), leading to defective peroxisomal β-oxidation of very long-chain and branched-chain fatty acids (VLCFA). ALD manifests in both sexes with a spectrum of phenotypes, but approximately 35% of affected males develop childhood cerebral adrenoleukodystrophy (CCALD), which is lethal without hematopoietic stem cell transplant performed before symptoms start. Hence, ALD was added to the Recommended Uniform Screening Panel after the successful implementation in New York State (2013-2016). To date, thirty-five states have implemented newborn screening (NBS) for ALD, and a few programs have reported on the successes and challenges experienced. However, the overall impact of NBS on early detection of ALD has yet to be fully determined. Here, we conducted a retrospective analysis of VLCFA testing performed by our reference laboratory (ARUP Laboratories, Salt Lake City, UT, USA) over 10 years. Rate of detection, age at diagnosis, and male-to-female ratio were evaluated in patients with abnormal results before and after NBS implementation. After NBS inclusion, a significant increase in abnormal results was observed (471/6930, 6.8% vs. 384/11,670, 3.3%; p < 0.0001). Patients with ALDP deficiency identified via NBS were significantly younger (median age: 30 days vs. 21 years; p < 0.0001), and males and females were equally represented. ALD inclusion in NBS programs has increased pre-symptomatic detection of this disease, which is critical in preventing adrenal crisis as well as the severe cerebral form.

The experiences of parents of children diagnosed with cerebral adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is a rare X-linked neurodegenerative disease, affecting the brain, spinal cord and adrenal cortex. Childhood cerebral ALD (CCALD) is the most severe form of disease, involving rapidly progressive neurological deterioration. The treatment option for CCALD is allogenic haemopoietic stem cell transplant, which is only successful for early-stage disease. Parents' experiences of CCALD can inform healthcare delivery. To detail the experiences of parents of children diagnosed with cerebral ALD. A descriptive qualitative study. Parents were recruited via a UK-based community support organisation. Data collection involved single semi-structured interviews structured around a topic guide and conducted remotely. Data were analysed using the thematic analysis approach. Twelve parents from 11 families with a total of 16 children with ALD contributed to the study. Their 16 children with ALD followed one of three disease pathways, determined by the extent of neurological damage at diagnosis. Three themes, and their respective sub themes, describe the pathways and what they meant for parents. 'No possibility of treatment' concerns situations when CCALD was diagnosed at an advanced stage, the landslide of deterioration parents witnessed and their efforts to maintain normality. 'Close to the treatment threshold' describes situations where a small treatment window required parents to make agonising treatment decisions. 'Watching and waiting' explains the challenges for parents when disease was detected early enabling children to benefit from timely treatment. Parents' experiences were largely defined by the extent of cerebral damage at diagnosis, which determined the availability and success of treatment. There were specific challenges related to the three situations, indicating areas where support from health and care services may help parents deal with this devastating diagnosis. This study indicates support needs of parents across the spectrum of CCALD diagnoses and highlights the critical importance of early diagnosis.

FRI433 Hypogonadism In Males With Adrenoleukodystrophy

Abstract Disclosure: J. Ramirez Alcantara: None. N. Grant: None. T.L. Stanley: Research Investigator; Self; Pfizer, Inc. F. Eichler: Consulting Fee; Self; consultant to Alnylam, Autobahn, Ionis, Minoryx, Orchard, Origen, Poxel, Takeda Therapeutics,and Taysha Gene Therapies, is a consultant to Third Rock Ventures on rare neurological disorders. Grant Recipient; Self; GLIA-CTN from National Institute of Neurological Disorders and Stroke (NINDS). Owner/Co-Owner; Self; founder of SwanBio Therapeutics. Research Investigator; Self; primary investigator (PI) of ex vivo lentiviral gene therapy trial in cerebral adrenoleukodystrophy sponsored by bluebird bio, the site-PI of Minoryx trial of leriglitazone for adrenomyeloneuropathy. N.A. Tritos: None. X-linked adrenoleukodystrophy (ALD) is a rare peroxisomal disorder caused by mutations in the ABCD1 gene. Little is known about the prevalence and characteristics of hypogonadism in ALD.We conducted a retrospective chart review to investigate hypogonadism in adult males with ALD. The presence of hypogonadism was determined by a clinician’s diagnosis and/or a total testosterone (TT) level below 249 ng/dL. Prospectively, we distributed a survey and evaluated serum gonadotropins and TT levels. The survey included the quantitative Saint Louis University Androgen Deficiency in the Aging Male (qADAM) questionnaire, a standardized screening tool for hypogonadism (score range: 10-50, lower scores indicate more symptoms). The normal laboratory ranges were 249-836 ng/dL (TT), 1-12 IU/L (FSH), and 2-12 IU/L (LH).We included 56 patients in the study (median age 36.2 years, range 19.3-72.4 years). Forty-seven (84%) patients had signs of myelopathy and 46 (82%) had adrenal insufficiency. Puberty data were available for 11 (20%) patients; two had documentation of delayed puberty onset, one of whom required testosterone treatment at age 15 years to jumpstart puberty. Thirty-one (55%) patients had erectile dysfunction and 24 (43%) used phosphodiesterase-5 inhibitors. Three patients had low libido and two had anorgasmia. Fifteen (27%) patients, two of whom required fertility treatment, had children. Nine (16%) patients had hypogonadism (median [IQR] age of diagnosis 37.4 [35.7,39.0] years), six of whom were on testosterone replacement. The median [IQR] TT level was 200 [143,240] ng/dL at the time of hypogonadism diagnosis. In patients with normal TT, the median [IQR] TT level was 498 [445,615] ng/dL. Twenty-two patients had LH levels and 18 had FSH levels available from clinical testing. In patients with hypogonadism, the median [IQR] levels for LH and FSH were 8.2 [7.2,8.4] and 8.3 [7.4,8.3] IU/L respectively. In patients with normal TT, the levels were 7.6 [5.7,10.4] and 4.0 [3.0,5.3] IU/L. There were no differences in LH or FSH levels between patients with normal TT and hypogonadism. Eight patients completed the prospective survey (median age 38.1 years). The median age of reported puberty onset was 13 years (range 12-15). Four patients, one of whom required fertility treatment, had children. Two (25%) patients reported low libido and 3 (38%) reported ED. The mean qADAM score was 36.5 (SD 5). We obtained prospective laboratory evaluation in ten patients. Median [IQR] levels were 564 [504,663] ng/dL (TT), 6.9 [5.4,9.8] IU/L (FSH), and 11 [7.2,13.8] IU/L (LH). In contrast to the retrospective clinical cohort, no patients had laboratory evidence of hypogonadism. Our results suggest that males with ALD may be at higher risk of developing central hypogonadism. In addition, ED and low libido may be present in males with ALD without laboratory evidence of hypogonadism. Presentation: Friday, June 16, 2023

SAT315 A Case Of PAI "Do Not Miss This Rare Cause"

Abstract Disclosure: R. Alshantti: None. C. Musurakis: None. U. Rafat: None. W. Akhter: None. J.L. Gilden: None. A. Moid: None. Background: Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a mutation in the ABCD1 gene, located at Xq28. This impairs beta-oxidation and breakdown of very long chain fatty acids (VLCFAs) which then accumulate in the CNS, adrenal cortex, and Leydig cells of the testes, leading to three main phenotypes of X-ALD: childhood cerebral ALD, adrenomyeloneuropathy AMN, and adrenal insufficiency (AI). AI presents in 47% of X-ALD cases by age 10 years. X-ALD represents a spectrum of phenotypes that vary in age of onset, severity, and clinical characteristic. AI may predate, occur simultaneously with, or follow the onset of the neurologic deterioration. While in the majority, it is inherited in an X-linked manner, at least 4.1% of individuals with X-ALD have a de novo pathogenic variant of ABCD1. Case Description: A 30-year-old male, previously healthy, was found to have adrenal nodule on CT renal during the evaluation of a transient episode of acute abdominal pain. Further evaluation of the adrenal nodule with a CT adrenal protocol showed a 1.5 cm x 1.0 cm right adrenal nodule, HU 22, washout of 66.7% consistent with an adrenal adenoma. Evaluation of adrenal hormones failed to show abnormal hypersecretion, but rather suggested insufficiency. Lab tests: RENIN FRZ PLS 45.76 ng/mL/h (0.25 - 5.82), ALDOSTERONE &amp;lt;1 ng/dL, ACTH &amp;gt;1250 pg/mL (0 - 47), SALIV CORT 0.06 mcg/dL, DHEAS 28.19 ug/dL (34.5 - 568.9). The patient was referred to endocrinology. Only reported symptom was poor exercise tolerance. Diagnosis of primary adrenal insufficiency was confirmed by low AM cortisol of 7.91 ug/dL, and very high ACTH of &amp;gt;1250 H pg/mL. He was started on glucocorticoid &amp; mineralocorticoid replacements. An evaluation to determine the etiology of PAI was conducted. The patient was not taking any medications or drugs. Family history was noncontributory. 21 OH Ab was negative. Quantiferron was negative. Our patient had no risk factors or clinical manifestations to suggest TB or fungal infections. No bleeding disorders. CT adrenal findings did not suggest infiltrative, infectious, hemorrhage, or malignant etiologies. Blood tests for VLCFAs showed elevations in phytanic, C22:0, C24:0, C26:0, C24/C22, &amp; C26/C22. These are consistent with X-linked adrenomyeloneuropathy. Genetic testing has confirmed the diagnosis; POSITIVE for a hemizygous pathogenic variant in ABCD1, consistent with a diagnosis of X-linked adrenoleukodystrophy/adrenomyeloneuropathy (ALD/AMN). Conclusion: Our case highlights the importance of a comprehensive evaluation to determine the cause of PAI. When autoimmunity and infectious etiologies are ruled out in male patients, it is crucial to consider X- ALD regardless of age at presentation, family history, or presence/absence of neurologic symptoms. This diagnosis is particularly important not to miss, since X-ALD can have devastating implications not only for the patient but also the family. Presentation: Saturday, June 17, 2023

Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is highly variable, ranging from slowly progressive adrenomyeloneuropathy to severe brain demyelination and inflammation (cerebral ALD, CALD) affecting males with childhood peak onset. Risk models integrating blood-based biomarkers to indicate CALD onset, enabling timely interventions, are lacking. Therefore, we evaluated the prognostic value of blood biomarkers in addition to current neuroimaging predictors for early detection of CALD. We measured blood biomarkers in a retrospective, male CALD risk-assessment cohort consisting of 134 X-ALD patients and 66 controls and in a phenotype-blinded validation set (25 X-ALD boys, 4-13 years) using Simoa®and Luminex® technologies. Among 25 biomarkers indicating axonal damage, astrocye/microglia activation, or immune-cell recruitment, neurofilament light chain (NfL) had the highest prognostic value for early indication of childhood/adolescent CALD. A plasma NfL cut-off level of 8.33pg/mL, determined in the assessment cohort, correctly discriminated CALD with an accuracy of 96% [95% CI: 80-100] in the validation group. Multivariable logistic regression models revealed that combining NfL with GFAP or cytokines/chemokines (IL-15, IL-12p40, CXCL8, CCL11, CCL22, and IL-4) that were significantly elevated in CALD vs healthy controls had no additional benefit for detecting neuroinflammation. Some cytokines/chemokines were elevated only in childhood/adolescent CALD and already upregulated in asymptomatic X-ALD children (IL-15, IL-12p40, and CCL7). In adults, NfL levels distinguished CALD but were lower than in childhood/adolescent CALD patients with similar (MRI) lesion severity. Blood GFAP did not differentiate CALD from non-inflammatory X-ALD. Biomarker-based risk prediction with a plasma NfL cut-off value of 8.33pg/mL, determined by ROC analysis, indicates CALD onset with high sensitivity and specificity in childhood X-ALD patients. A specific pro-inflammatory cytokine/chemokine profile in asymptomatic X-ALD boys may indicate a primed, immanent inflammatory state aligning with peak onset of CALD. Age-related differences in biomarker levels in adult vs childhood CALD patients warrants caution in predicting onset and progression of CALD in adults. Further evaluations are needed to assess clinical utility of the NfL cut-off for risk prognosis of CALD onset. Austrian Science Fund, European Leukodystrophy Association.

System-based integrated metabolomics and microRNA analysis identifies potential molecular alterations in human X-linked cerebral adrenoleukodystrophy brain.

X-linked adrenoleukodystrophy is a severe demyelinating neurodegenerative disease mainly affecting males. The severe cerebral adrenoleukodystrophy (cALD) phenotype has a poor prognosis and underlying mechanism of onset and progression of neuropathology remains poorly understood. In this study we aim to integrate metabolomic and microRNA (miRNA) datasets to identify variances associated with cALD. Postmortem brain tissue samples from five healthy controls (CTL) and five cALD patients were utilized in this study. White matter from ALD patients was obtained from normal-appearing areas, away from lesions (NLA) and from the periphery of lesions- plaque shadow (PLS). Metabolomics was performed by gas chromatography coupled with time-of-flight mass spectrometry and miRNA expression analysis was performed by next generation sequencing (RNAseq). Principal component analysis revealed that among the three sample groups (CTL, NLA and PLS) there were 19 miRNA, including several novel miRNA, of which 17 were increased with disease severity and 2 were decreased. Untargeted metabolomics revealed 13 metabolites with disease severity-related patterns with 7 increased and 6 decreased with disease severity. Ingenuity pathway analysis of differentially altered metabolites and miRNA comparing CTL with NLA and NLA with PLS, identified several hubs of metabolite and signaling molecules and their upstream regulation by miRNA. The transomic approach to map the crosstalk between miRNA and metabolomics suggests involvement of specific molecular and metabolic pathways in cALD and offers opportunity to understand the complex underlying mechanism of disease severity in cALD.

Childhood cerebral adrenoleukodystrophy (CCALD) in France: epidemiology, natural history, and burden of disease - A population-based study

BackgroundX-linked adrenoleukodystrophy (ALD) is a rare metabolic and neurodegenerative disorder belonging to the group of leukodystrophies, with an estimated incidence around 1:25 000 newborns worldwide, mostly among men. Childhood Cerebral ALD (CCALD) is the most severe form with a poor prognosis if not properly treated during the first years of life. Currently, only allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely available for CCALD treatment. To date, there is a lack of data regarding CCALD epidemiology, natural history, and current management in France. This knowledge is crucial for the development of new therapies such as gene therapies. In this context, the French National Health Data System (SNDS) is a particularly indicated database to collect information meeting these needs. A non-interventional, national, real-life, retrospective study was performed using secondary data from the national ALD registry (LEUKOFRANCE) and SNDS. CCALD patients detected between 2009 and 2018 and successfully matched between LEUKOFRANCE and SNDS were included in this study. Index date was defined as the first CCALD event detected during study period. Subgroups of patients with sufficient follow-up (6 months) and history (1 year) available around index date were analyzed to assess CCALD burden and natural history.Results52 patients were included into the matched cohort. Median annual incidence of CCALD was estimated at 4 patients. Median age at CCALD diagnosis was 7.0 years. Among patients without allo-HSCT, five-year overall survival was 66.6%, with 93.3% of them presenting at least one CCALD symptom and 62.1% presenting a least one major functional disability (MFD). Among patients with allo-HSCT, five-year overall survival was 94.4%, with only 11.1% of patients presenting CCALD symptoms, and 16.7% of presenting a MFD. Mean annualized costs were almost twice as important among patients without allo-HSCT, with 49,211€, 23,117€, respectively. Costs were almost exclusively represented by hospitalizations.ConclusionsTo the best of our knowledge, this is the most up to date study analyzing CCALD epidemiology, clinical and economic burden in France. The necessity of a precocious management with HSCT highlight the potential benefits of including an expanded screening program among newborns, coupled with family screenings when a mutation is detected.

Exploratory study of autophagy inducer sirolimus for childhood cerebral adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is a peroxisomal disease caused by mutations in the ABCD1 gene. Childhood cerebral ALD (CCALD) is characterized by inflammatory demyelination, rapidly progressing, often fatal. Hematopoietic stem cell transplant only delays disease progression in patients with early-stage cerebral ALD. Based on emergency humanitarianism, this study aims to investigate the safety and efficacy of sirolimus in the treatment of patients with CCALD. This was a prospective, single-center, one-arm clinical trial. We enrolled patients with CCALD, and all enrolled patients received sirolimus treatment for three months. Adverse events were monitored and recorded to evaluate the safety. The efficacy was evaluated using the neurologic function scale (NFS), Loes score, and white matter hyperintensities. A total of 12 patients were included and all presented with CCALD. Four patients dropped out and a total of eight patients in the advanced stage completed a 3-month follow-up. There were no serious adverse events, and the common adverse events were hypertonia and oral ulcers. After sirolimus treatment, three of the four patients with an initial NFS > 10 showed improvements in their clinical symptoms. Loes scores decreased by 0.5-1 point in two of eight patients and remained unchanged in one patient. Analysis of white matter hyperintensities revealed a significant decrease in signal intensity (n = 7, p = 0.0156). Our study suggested that autophagy inducer sirolimus is safe for CCALD. Sirolimus did not improve clinical symptoms of patients with advanced CCALD significantly. Further study with larger sample size and longer follow-up is needed to confirm the drug efficacy.Clinical Trial registration: https://www.chictr.org.cn/historyversionpuben.aspx, identifier ChiCTR1900021288.

Neurofilament light chain levels in cerebrospinal fluid as a sensitive biomarker for cerebral adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) has a poor prognosis when it progresses to the cerebral form (CALD). The aim of this study is to investigate whether cerebrospinal fluid (CSF) neurofilament light chain (cNfL) is a sensitive biomarker for detecting CALD and assessing response to hematopoietic stem cell transplantation (HSCT). We conducted a cross-sectional study of 41 male ALD patients. The cNfL levels in patients with the cerebral form of ALD (CALD) or the cerebello-brainstem form of ALD were compared with those in patients with adrenomyeloneuropathy (AMN). The correlation between cNfL levels and MRI-based Loes severity scores was investigated. A longitudinal analysis was performed on patients who underwent multiple CSF examinations. The cNfL levels in 22 patients with CALD were significantly higher than those in 14 patients with AMN (median, 5545 vs. 1490 pg/mL; p < 0.001). The cutoff cNfL level of 1930 pg/mL showed good sensitivity (95.5%) and specificity (85.7%) for distinguishing CALD from AMN. The cNfL levels were positively correlated with Loes scores (p < 0.001). The cNfL levels in three AMN patients who later converted to CALD increased above the cutoff level during the conversion period, while the cNfL levels in four patients who remained in AMN were consistently below the cutoff. In 10 ALD patients who underwent HSCT, their cNfL levels decreased 3-24 months after HSCT. Two patients whose cNfL increased after HSCT showed deterioration in cognitive functions. The cNfL level is useful for evaluating the disease activities of ALD and the response to HSCT.

Initial frontal lobe involvement in adult cerebral X-linked adrenoleukodystrophy.

Adult cerebral X-linked adrenoleukodystrophy (ACALD) with initial frontal lobe involvement is a rare genetic disease that is easily misdiagnosed and underdiagnosed. We sought to improve the early identification of such diseases. We present three cases of adult X-linked adrenoleukodystrophy (ALD) with initial frontal lobe involvement and identify an additional 13 cases from the database. The clinical and imaging characteristics of the overall sixteen cases were analyzed. The average age of onset was 37years, with 15 male and 1 female patient. A total of 12 patients (75%) developed a decline in cerebral executive and cognitive functions. Brain trauma is the possible trigger for the onset of ALD in five patients (31%). An elevated level of very-long-chain fatty acids (VLCFA) was observed in all 15 patients on whom a plasma VLCFA was performed.10 patients with gene tests showed different mutation sites in the ABCD1 gene. Brain MRI of six patients (46%) were characterized by frontal lobe "butterfly wings"-like lesions with peripheral rim enhancement. Four patients underwent brain biopsies (patients 1, 3, 15, and 13), and five patients (31%) were initially misdiagnosed (patients 1, 2, 3, 11, and 15). Nine of the patients with follow-up records experienced poor prognoses, and five of them, unfortunately, died (56%). ACALD patients with anterior patterns tend to be misdiagnosed. The early clinical manifestation is a decline in cerebral executive and cognitive function. Brain trauma may be a trigger for this pattern. Brain MRI findings are characterized by frontal lobe "butterfly wing"-like lesions with peripheral rim enhancement. The determination of the VLCFA levels and the genetic detection of the causative mutations are required to confirm the diagnosis.

Vitamin D status and latitude predict brain lesions in adrenoleukodystrophy

AbstractObjectivesApproximately 40% of boys with X‐linked adrenoleukodystrophy (ALD) develop inflammatory demyelinating brain lesions (cerebral ALD, cALD) and are at risk for death or severe disability. Risk factors for cALD are poorly understood. Our objective was to evaluate whether vitamin D status, which influences immune function, is associated with risk for cALD.MethodsWe used two independent cohorts to assess whether low vitamin D status is correlated with cALD. We used complementary proxies for vitamin D status: plasma 25‐hydroxyvitamin D levels and latitude. In our first cohort, we measured 25‐hydroxyvitamin D in biobanked plasma samples from ALD boys with initially normal brain MRIs followed at two expert centers. In a second cohort, we measured latitude (using home ZIP code) among ALD boys identified in a national administrative database (PHIS) covering 51 US pediatric hospitals. We used logistic regression models to estimate the odds of developing cALD in each cohort.ResultsIn the first cohort, we identified 20 ALD boys with a total of 53 plasma sample timepoints who met inclusion criteria; 50% (n = 10) subsequently developed cALD. Average 25‐hydroxyvitamin D levels were lower among boys who developed cALD than those who did not (median 28.9 vs 36.6 ng/ml); p = 0.019. For each 10 ng/mL decrease in 25‐hydroxyvitamin D, the odds ratio for developing cALD was 6.94; p = 0.044. In the second cohort, we identified 230 ALD boys across 28 states; 57% of boys (n = 132) developed cALD. Each 2° increase in latitude conferred an odds ratio of 1.17 (95% confidence interval, 1.01, 1.35); p = 0.036 for developing cALD.ConclusionsUsing independent cohorts, we found that ALD boys with lower pre‐morbid plasma levels of 25‐hydroxyvitamin D, or more northerly latitude of residence, were more likely to develop cALD. These findings offer complementary lines of evidence that vitamin D and/or ultraviolet light exposure influence cALD risk.

Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy

Blood-brain barrier disruption marks the onset of cerebral adrenoleukodystrophy (CALD), a devastating cerebral demyelinating disease caused by loss of ABCD1 gene function. The underlying mechanism are not well understood, but evidence suggests that microvascular dysfunction is involved. We analyzed cerebral perfusion imaging in boys with CALD treated with autologous hematopoietic stem-cells transduced with the Lenti-D lentiviral vector that contains ABCD1 cDNA as part of a single group, open-label phase 2-3 safety and efficacy study (NCT01896102) and patients treated with allogeneic hematopoietic stem cell transplantation. We found widespread and sustained normalization of white matter permeability and microvascular flow. We demonstrate that ABCD1 functional bone marrow-derived cells can engraft in the cerebral vascular and perivascular space. Inverse correlation between gene dosage and lesion growth suggests that corrected cells contribute long-term to remodeling of brain microvascular function. Further studies are needed to explore the longevity of these effects.

Two Single Nucleotide Deletions in the ABCD1 Gene Causing Distinct Phenotypes of X-Linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is a rare inborn error of the peroxisomal metabolism caused by pathologic variants in the ATP-binding cassette transporter type D, member 1 (ABCD1) gene located on the X-chromosome. ABCD1 protein, also known as adrenoleukodystrophy protein, is responsible for transport of the very long chain fatty acids (VLCFA) from cytoplasm into the peroxisomes. Therefore, altered function or lack of the ABCD1 protein leads to accumulation of VLCFA in various tissues and blood plasma leading to either rapidly progressive leukodystrophy (cerebral ALD), progressive adrenomyeloneuropathy (AMN), or isolated primary adrenal insufficiency (Addison's disease). We report two distinct single nucleotide deletions in the ABCD1 gene, c.253delC [p.Arg85Glyfs*18] in exon 1, leading to both cerebral ALD and to AMN phenotype in one family, and c.1275delA [p.Phe426Leufs*15] in exon 4, leading to AMN and primary adrenal insufficiency in a second family. For the latter variant, we demonstrate reduced mRNA expression and a complete absence of the ABCD1 protein in PBMC. Distinct mRNA and protein expression in the index patient and heterozygous carriers does not associate with VLCFA concentration in plasma, which is in line with the absence of genotype-phenotype correlation in X-ALD.

Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2–3 trial

Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy. ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2-3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18-65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing. Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: -27·7 [41·4] m; placebo: -30·3 [60·5] m; least-squares mean difference -1·2 m; 95% CI -22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group. The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy. Minoryx Therapeutics.

Newborn screening for X-linked adrenoleukodystrophy in Italy: Diagnostic algorithm and disease monitoring.

X-linked adrenoleukodystrophy (X-ALD) is the most common inherited peroxisomal disorder caused by variants in the ABCD1 gene. The main phenotypes observed in men with X-ALD are primary adrenal insufficiency, adrenomyeloneuropathy, and cerebral ALD (cALD). Cerebral ALD consists of a demyelinating progressive cerebral white matter (WM) disease associated with rapid clinical decline and is fatal if left untreated. Hematopoietic stem cell transplantation is the standard treatment for cALD as it stabilizes WM degeneration when performed early in the disease. For this reason, early diagnosis is crucial, and several countries have already implemented their newborn screening programs (NBS) with the assessment of C26:0-lysophosphatidylcholine (C26:0-LPC) values as screening for X-ALD. In June 2021, an Italian group in Lombardy launched a pilot study for the implementation of X-ALD in the Italian NBS program. A three-tiered approach was adopted, and it involved quantifying the values of C26:0-LPC and other metabolites in dried blood spots with FIA-MS/MS first, followed by the more specific ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) technique and, finally, the genetic confirmation via focused NGS. Genetically confirmed patients are set to undergo a follow-up protocol and are periodically evaluated to promptly start a specific treatment if and when the first signs of brain damage appear, as suggested by international guidelines. A specific disease monitoring protocol has been created based on literature data and personal direct experience. The primary aim of this study was to develop a model able to improve the early diagnosis and subsequent follow-up and timely treatment of X-ALD. The study was approved by the local ethics committee. The research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.