- Characteristics of Japanese patients with X-linked adrenoleukodystrophy and concerns of their families from the 1st registry system. [Journal Article]
- BDBrain Dev 2018 Aug 01
- CONCLUSIONS: This is the first study clarifying the clinical characteristics of X-ALD and the concerns of patients' families using the registry system. Investigation of rare diseases using registry systems is very valuable for the understanding of such conditions.
- Dendrimer N-acetylcysteine modulates monophagocytic response in adrenoleukodystrophy. [Journal Article]
- ANAnn Neurol 2018 Aug 01
- CONCLUSIONS: ALD phenotypes display unique inflammatory profiles in response to VLCFA stimulation and therefore ex-vivo monophagocytic cells may provide a novel test-bed for therapeutic agents. Based on our findings, D-NAC may be a viable therapeutic strategy for the treatment of cALD. This article is protected by copyright. All rights reserved.
- [Biogenesis, the Function of Peroxisomes, and Their Role in Genetic Disease: With a Focus on the ABC Transporter]. [Review]
- YZYakugaku Zasshi 2018; 138(8):1067-1083
- Peroxisomes are organelles that are present in almost all eukaryotic cells. These organelles were first described in 1954, in the cytoplasm of the proximal tubule cells in the mouse kidney, using el...
Peroxisomes are organelles that are present in almost all eukaryotic cells. These organelles were first described in 1954, in the cytoplasm of the proximal tubule cells in the mouse kidney, using electron microscopy by Rhodin and referred to as "microbodies". Then, de Duve and Baudhuin isolated microbodies from rat liver using density gradient centrifugation, defined the microbodies as membrane-bound organelles containing several H2O2-producing oxidases and H2O2-degrading catalase, and named them peroxisomes. At present, the biogenesis of peroxisomes in mammals involves three different processes: the formation of pre-peroxisomes from the endoplasmic reticulum, the import of peroxisomal membrane and matrix proteins to the pre-peroxisomes, and the growth and division of the peroxisomes. These organelles are involved in a variety of metabolic processes, including the β-oxidation of very long chain fatty acids, and the synthesis of ether phospholipids and bile acids in mammals. These metabolic pathways require the transport of metabolites in and out of peroxisomes. The transport of such metabolites is facilitated in part by the ATP-binding cassette (ABC) transporter. Impairment of the biogenesis and function of peroxisomes causes severe peroxisomal disorders. Since I began peroxisome research at Professor de Duve's laboratory in 1985, I have studied the biogenesis and function of peroxisomes and peroxisome diseases for more than 30 years, with a focus on ABC transporters. Here, I review the biogenesis of peroxisomes, the targeting of ABC transporters to the peroxisome, and the function of ABC transporters in physiological and pathological processes, including X-linked adrenoleukodystrophy, a neurodegenerative disease.
- [A boy with treatment-resistant psychiatric problems: X-linked adrenoleukodystrophy]. [Journal Article]
- TPTijdschr Psychiatr 2018; 60(7):485-489
- In this case report we describe a 17-year-old boy with severe behavioural disorders, apathy and cognitive decline who was eventually diagnosed with X-linked adrenoleukodystrophy (x-ald). If a patient...
In this case report we describe a 17-year-old boy with severe behavioural disorders, apathy and cognitive decline who was eventually diagnosed with X-linked adrenoleukodystrophy (x-ald). If a patient presents with a combination of psychiatric and neurological problems, metabolic diseases such as x-ald should be included in the differential diagnosis.
- Liquid chromatography-tandem mass spectrometry method for estimation of a panel of lysophosphatidylcholines in dried blood spots for screening of X-linked adrenoleukodystrophy. [Journal Article]
- CCClin Chim Acta 2018 Jul 07; 485:305-310
- CONCLUSIONS: The LC-MS/MS method for estimating LPCs in DBS can be used to identify X-ALD in clinically suspected patients. Further large-scale studies to determine the pre-analytical variables and to define age- and gender-specific reference ranges in various ethnic groups are warranted before introducing this method for high-risk screening in India.
- Aberrant regulation of the GSK-3β/NRF2 axis unveils a novel therapy for adrenoleukodystrophy. [Journal Article]
- EMEMBO Mol Med 2018; 10(8)
- The nuclear factor erythroid 2-like 2 (NRF2) is the master regulator of endogenous antioxidant responses. Oxidative damage is a shared and early-appearing feature in X-linked adrenoleukodystrophy (X-...
The nuclear factor erythroid 2-like 2 (NRF2) is the master regulator of endogenous antioxidant responses. Oxidative damage is a shared and early-appearing feature in X-linked adrenoleukodystrophy (X-ALD) patients and the mouse model (Abcd1 null mouse). This rare neurometabolic disease is caused by the loss of function of the peroxisomal transporter ABCD1, leading to an accumulation of very long-chain fatty acids and the induction of reactive oxygen species of mitochondrial origin. Here, we identify an impaired NRF2 response caused by aberrant activity of GSK-3β. We find that GSK-3β inhibitors can significantly reactivate the blunted NRF2 response in patients' fibroblasts. In the mouse models (Abcd1- and Abcd1-/Abcd2-/- mice), oral administration of dimethyl fumarate (DMF/BG12/Tecfidera), an NRF2 activator in use for multiple sclerosis, normalized (i) mitochondrial depletion, (ii) bioenergetic failure, (iii) oxidative damage, and (iv) inflammation, highlighting an intricate cross-talk governing energetic and redox homeostasis in X-ALD Importantly, DMF halted axonal degeneration and locomotor disability suggesting that therapies activating NRF2 hold therapeutic potential for X-ALD and other axonopathies with impaired GSK-3β/NRF2 axis.
- Novel ABCD1 Gene Mutation in Adrenomyeloneuropathy with Hypoplasia and Agenesis of the Corpus Callosum. [Journal Article]
- NDNeurodegener Dis 2018; 18(2-3):156-164
- CONCLUSIONS: In addition to the typical symptoms such as spastic myelopathy, cognitive impairment, mixed neuropathy, and alopecia, AMN patients can also display hypoplasia and agenesis of the CC, which was not described in the other AMN patients reported before.
- Rare variability in adrenoleukodystrophy: a case report. [Journal Article]
- JMJ Med Case Rep 2018 Jun 28; 12(1):182
- CONCLUSIONS: We report a rare case of adult-onset cerebral X-linked leukodystrophy with a clinical phenotype of adrenomyeloneuropathy, and the diagnosis was confounded by a history of alcohol abuse.
- Newborn Screening and Emerging Therapies for X-Linked Adrenoleukodystrophy. [Journal Article]
- JNJAMA Neurol 2018 Jun 25
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- Stability of the ABCD1 Protein with a Missense Mutation: A Novel Approach to Finding Therapeutic Compounds for X-Linked Adrenoleukodystrophy. [Journal Article]
- JRJIMD Rep 2018 Jun 21
- Mutations in the ABCD1 gene that encodes peroxisomal ABCD1 protein cause X-linked adrenoleukodystrophy (X-ALD), a rare neurodegenerative disorder. More than 70% of the patient fibroblasts with this m...
Mutations in the ABCD1 gene that encodes peroxisomal ABCD1 protein cause X-linked adrenoleukodystrophy (X-ALD), a rare neurodegenerative disorder. More than 70% of the patient fibroblasts with this missense mutation display either a lack or reduction of the ABCD1 protein because of posttranslational degradation. In this study, we analyzed the stability of the missense mutant ABCD1 proteins (p.A616T, p.R617H, and p.R660W) in X-ALD fibroblasts and found that the mutant ABCD1 protein p.A616T has the capacity to recover its function by incubating at low temperature. In the case of such a mutation, chemical compounds that stabilize mutant ABCD1 proteins could be therapeutic candidates. Here, we prepared CHO cell lines stably expressing ABCD1 proteins with a missense mutation in fusion with green fluorescent protein (GFP) at the C-terminal. The stability of each mutant ABCD1-GFP in CHO cells was similar to the corresponding mutant ABCD1 protein in X-ALD fibroblasts. Furthermore, it is of interest that the GFP at the C-terminal was degraded together with the mutant ABCD1 protein. These findings prompted us to use CHO cells expressing mutant ABCD1-GFP for a screening of chemical compounds that can stabilize the mutant ABCD1 protein. We established a fluorescence-based assay method for the screening of chemical libraries in an effort to find compounds that stabilize mutant ABCD1 proteins. The work presented here provides a novel approach to finding therapeutic compounds for X-ALD patients with missense mutations.