- Unusual Clinical Course and Imaging of D-Bifunctional Protein Deficiency, a Rare Leukodystrophy. [Journal Article]
- PNPediatr Neurol 2018 Sep 21
- Nerve ultrasound characterizes AMN polyneuropathy as inhomogeneous and focal hypertrophic. [Journal Article]
- OJOrphanet J Rare Dis 2018 Nov 03; 13(1):194
- CONCLUSIONS: HRUS reveals significant multifocal regional nerve swellings with reduced echo intensity as the morphological equivalent of electrophysiological peripheral nerve affection in AMN patients. Ultrasound and NCS characteristics in AMN seem to differ from other demyelinating neuropathies like CIDP or CMT1a.
- Intrathecal Adeno-Associated Virus Vector-mediated Gene Delivery for Adrenomyeloneuropathy. [Journal Article]
- HGHum Gene Ther 2018 Oct 25
- Mutations in the gene encoding the peroxisomal ATP binding cassette transporter (ABCD1) cause elevations in very long chain fatty acids (VLCFA) and the neurodegenerative disease adrenoleukodystrophy ...
Mutations in the gene encoding the peroxisomal ATP binding cassette transporter (ABCD1) cause elevations in very long chain fatty acids (VLCFA) and the neurodegenerative disease adrenoleukodystrophy (ALD). In most adults, this manifests as the spinal cord axonopathy, adrenomyeloneuropathy (AMN). A challenge in virus-based gene therapy in AMN is how to achieve functional gene correction to the entire spinal cord while minimizing leakage into the systemic circulation, which could contribute to toxicity. In the present study, we used an osmotic pump to deliver adeno-associated virus (AAV) vector into the lumbar CSF space in mice. We report that slow intrathecal delivery of recombinant AAV serotype 9 (rAAV9) achieves efficient gene transfer across the spinal cord and dorsal root ganglia as demonstrated using two different transgenes, GFP and ABCD1. In the Abcd1-/- mouse, gene correction after rAAV9-CBA-hABCD1 continuous delivery led to a 20% decrease of VLCFA levels in spinal cord compared to controls. The major cell types transduced were astrocytes, vascular endothelial cells and neurons. Importantly, rAAV9 delivered intrathecally by osmotic pump, in contrast to bolus injection, greatly reduced systemic leakage into peripheral organs, particularly liver and heart tissue.
- A novel missense mutation in the ABCD1 gene of a Chinese boy diagnosed with X-linked adrenoleukodystrophy: case report. [Editorial]
- NSNeurol Sci 2018 Oct 20
- Economic impact of screening for X-linked Adrenoleukodystrophy within a newborn blood spot screening programme. [Journal Article]
- OJOrphanet J Rare Dis 2018 Oct 11; 13(1):179
- CONCLUSIONS: Including screening of boys for X-ALD into an existing tandem mass spectrometry based newborn screening programme is projected to reduce lifetime costs and improve outcomes for those with CCALD. The potential disbenefit to those identified with non-CCALD conditions would need to be substantial in order to outweigh the benefit to those with CCALD. Further evidence is required on the potential QALY impact of early diagnosis both for non-CCALD X-ALD and other peroxisomal disorders. The favourable economic results are driven by estimated reductions in the social care and education costs.
- Oxidative Imbalance, Nitrative Stress, and Inflammation in C6 Glial Cells Exposed to Hexacosanoic Acid: Protective Effect of N-acetyl-L-cysteine, Trolox, and Rosuvastatin. [Journal Article]
- CMCell Mol Neurobiol 2018; 38(8):1505-1516
- X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disorder caused by disfunction of the ABCD1 gene, which encodes a peroxisomal protein responsible for the transport of the very lo...
X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disorder caused by disfunction of the ABCD1 gene, which encodes a peroxisomal protein responsible for the transport of the very long-chain fatty acids from the cytosol into the peroxisome, to undergo β-oxidation. The mainly accumulated saturated fatty acids are hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0) in tissues and body fluids. This peroxisomal disorder occurs in at least 1 out of 20,000 births. Considering that pathophysiology of this disease is not well characterized yet, and glial cells are widely used in studies of protective mechanisms against neuronal oxidative stress, we investigated oxidative damages and inflammatory effects of vesicles containing lecithin and C26:0, as well as the protection conferred by N-acetyl-L-cysteine (NAC), trolox (TRO), and rosuvastatin (RSV) was assessed. It was verified that glial cells exposed to C26:0 presented oxidative DNA damage (measured by comet assay and endonuclease III repair enzyme), enzymatic oxidative imbalance (high catalase activity), nitrative stress [increased nitric oxide (NO) levels], inflammation [high Interleukin-1beta (IL-1β) levels], and induced lipid peroxidation (increased isoprostane levels) compared to native glial cells without C26:0 exposure. Furthermore, NAC, TRO, and RSV were capable to mitigate some damages caused by the C26:0 in glial cells. The present work yields experimental evidence that inflammation, oxidative, and nitrative stress may be induced by hexacosanoic acid, the main accumulated metabolite in X-ALD, and that antioxidants might be considered as an adjuvant therapy for this severe neurometabolic disease.
- Application of machine learning algorithms for the differential diagnosis of peroxisomal disorders. [Journal Article]
- JBJ Biochem 2018 Oct 08
- We have established diagnostic thresholds of very long-chain fatty acids (VLCFA) for the differential diagnosis of peroxisomal disorders using the machine learning tools. The plasma samples of 131 co...
We have established diagnostic thresholds of very long-chain fatty acids (VLCFA) for the differential diagnosis of peroxisomal disorders using the machine learning tools. The plasma samples of 131 controls and 90 cases were tested for VLCFA using Gas chromatography-Mass spectrometry following stable isotope dilution. This data was used to construct association rules and for recursive partitioning. The C26/22 in healthy controls ranged between 0.008 - 0.01. The C26 levels between 1.61 - 3.34 µmol/L and C26/C22 between 0.05 - 0.10 are diagnostic of X-linked adrenoleukodystrophy (X-ALD). Very high levels of C26 (> 3.34 µmol/L) and C26/C22 ratio (>0.10) are diagnostic of Zellweger syndrome (ZS). Significant elevation of phytanic acid was observed in Refsum (t = 6.14, p < 0.0001) and Rhizomelic chondrodysplasia punctata (RCDP) (t = 16.72, p < 0.0001). The C26/C22 ratio is slightly elevated in RCDP (t = 2.58, p = 0.01) while no such elevation was observed in Refsum disease (t = 0.86, p = 0.39). The developed algorithm exhibited greater clinical utility (AUC: 0.99 - 1.00) in differentiating X-ALD, ZS, and healthy controls. The algorithm has greater clinical utility in the differential diagnosis of peroxisomal disorders based on VLCFA pattern. Plasmalogens will add additional value in differentiating RCDP and Refsum disease.
- Natural history of a cohort of ABCD1 variant female carriers. [Journal Article]
- EJEur J Neurol 2018 Oct 08
- CONCLUSIONS: This study provides data on the natural disease progression of untreated ABCD1 heterozygous female carriers, demonstrating the relevance of aging. The estimated annual increase of the AACS will be useful for future interventional studies.
- Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation. [Journal Article]
- BBBiol Blood Marrow Transplant 2018 Oct 04
- Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit ha...
Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a large multicenter retrospective chart review to characterize the natural history of CALD, to describe outcomes after HSCT, and to identify predictors of treatment outcomes. Major functional disabilities (MFDs) were identified as having the most significant impact on patients' abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes magnetic resonance imaging score were assessed. Data were collected on 72 patients with CALD who did not undergo HSCT (untreated cohort) and on 65 patients who underwent transplantation (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) from the time of CALD diagnosis were 55% (95% confidence interval [CI], 42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HSCT cohort overall (P = .01). KM estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE+) were 29% (95% CI, 11.7% to 48.2%) for untreated patients (n = 21). For patients who underwent HSCT with GdE+ at baseline, with an NFS ≤1 and Loes score of 0.5 to ≤9 (n = 27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%). Mortality rates post-HSCT were 8% (5 of 65) at 100 days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor-recipient HLA matching and lack of GVHD, and early disease treatment was predictive of MFD-free survival. GdE+ status is a strong predictor of disease progression in untreated patients. This study confirms HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than solely assessing OS as an indicator of treatment success.
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- Late Mortality after Allogeneic Blood or Marrow Transplantation for Inborn Errors of Metabolism: A Report from the Blood or Marrow Transplant Survivor Study-2 (BMTSS-2). [Journal Article]
- BBBiol Blood Marrow Transplant 2018 Oct 04
- Allogeneic blood or marrow transplantation (BMT) is currently considered the standard of care for patients with specific inborn errors of metabolism (IEM). However, there is a paucity of studies desc...
Allogeneic blood or marrow transplantation (BMT) is currently considered the standard of care for patients with specific inborn errors of metabolism (IEM). However, there is a paucity of studies describing long-term survival and cause-specific late mortality after BMT in these patients with individual types of IEM. We studied 273 patients who had survived ≥2 years after allogeneic BMT for IEM performed between 1974 and 2014. The most prevalent IEM in our cohort were X-linked adrenoleukodystrophy (ALD; 37.3%), Hurler syndrome (35.1%), and metachromatic leukodystrophy (MLD; 10.2%). Conditional on surviving ≥2 years after BMT, the overall survival for the entire cohort was 85.5 ± 2.4% at 10 years and 73.5 ± 3.7% at 20 years. The cohort had a 29-fold increased risk of late death compared with an age- and sex-matched cohort from the general US population (95% CI, 22- to 38-fold). The increased relative mortality was highest in the 2- to 5-year period after BMT (standardized mortality ratio [SMR], 207; 95% confidence interval [CI], 130 to 308) and declined with increasing time from BMT, but remained elevated for ≥21 years after BMT (SMR, 9; 95% CI, 4 to 18). Sequelae from the progression of primary disease were the most common causes of late mortality in this cohort (76%). The use of T cell-depleted grafts in patients with ALD and Hurler syndrome was a risk factor for late mortality. Younger age at BMT and use of busulfan and cyclosporine were protective in patients with Hurler syndrome. Our findings demonstrate relatively favorable overall survival in ≥2-year survivors of allogeneic BMT for IEM, although primary disease progression continues to be responsible for the majority of late deaths.