Pearls & Oy-sters: Adolescent-onset adrenomyeloneuropathy and arrested cerebral adrenoleukodystrophy.
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ABSTRACT:
SUBMITTER: Lin JE
PROVIDER: S-EPMC6656648 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
Publications
Pearls & Oy-sters: Adolescent-onset adrenomyeloneuropathy and arrested cerebral adrenoleukodystrophy.
Lin Jieru E JE Armour Eric A EA Heshmati Arezou A Umandap Christine C Couto Julia J JJ Iglesias Alejandro D AD Mallack Eric J EJ Bain Jennifer M JM
Neurology 20190701 2
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Project description:ObjectiveTo gain insight into the natural history of arrested cerebral adrenoleukodystrophy (CALD) by quantifying the change in Neurologic Function Score (NFS) and Loes Score (LS) over time in patients whose cerebral lesions spontaneously stopped progressing.MethodsWe retrospectively reviewed a series of 22 patients with arrested CALD followed longitudinally over a median time of 2.4 years (0.7-17.0 years). Primary outcomes were change in radiographic disease burden (measured by LS) and clinical symptoms (measured by NFS) between patients who never developed a contrast-enhancing lesion (gadolinium enhancement (GdE)- subgroup) and those who did (GdE+ subgroup). Secondary analyses comparing patterns of neuroanatomic involvement and lesion number, and prevalence estimates, were performed.ResultsCerebral lesions were first detected at a median age of 23.3 years (8.0-67.6 years) with an initial LS of 4 (0.5-9). NFS was 0.5 (0-6). Overall change in NFS or LS per year did not differ between subgroups. No patients who remained GdE- converted to a progressive CALD phenotype. The presence of contrast enhancement was associated with disease progression (r s = 0.559, p < 0.001). Four patients (18.2%) underwent step-wise progression, followed by spontaneous resolution of contrast enhancement and rearrest of disease. Three patients (13.6%) converted to progressive CALD. Nineteen patients (86.4%) had arrested CALD at the most recent follow-up. The prevalence of arrested CALD is 12.4%.ConclusionArrested CALD lesions can begin in childhood, and patients are often asymptomatic early in disease. The majority of patients remain stable. However, clinical and MRI surveillance is recommended because a minority of patients undergo step-wise progression or conversion to progressive CALD.
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Project description:X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene, leading to a defect in the peroxisomal adrenoleukodystrophy protein (ALDP), which inhibits the β-oxidation of very long chain fatty acids (VLCFAs). It is a complex disease where the same mutation in the peroxisomal ABCD1 can lead to clinically diverse phenotypes ranging from the fatal disorder of cerebral ALD (cALD) to mild adult disorder of adrenomyeloneuropathy (AMN). This suggests a role of epigenetic factors/modifier genes in disease progression of X-ALD which is not understood at present. To examine the possible role of microRNA (miRNA) in X-ALD disease mechanisms for differences in cALD and AMN phenotype, we profiled 1008 known miRNA in cALD, AMN, and normal human skin fibroblasts using miScript miRNA PCR array (Qiagen) and selected miRNAs which had differential expression in cALD and AMN fibroblasts. Eleven miRNA which were differentially regulated in cALD and AMN fibroblasts were identified. miR-196a showed a significant differential expression between cALD and AMN and is further characterized for target gene regulation. The predicted role of miR-196a in inhibition of inflammatory signaling factors (IKKα and IKKβ) and ELOVL1 expression suggests the pathological role of altered expression of miR-196a. This study indicates that miR-196a participated in differential regulation of ELOVL1 and inflammatory response between cALD as compared to AMN and may be a possible biomarker to differentiate between cALD and AMN.
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Project description:BACKGROUND:In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation. METHODS:We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion. RESULTS:A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications. CONCLUSIONS:Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).
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