Adrenoleukodystrophy
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
The cholesterol esters found in the adrenal glands contain large amounts of very long-chain fatty acids (VLCFA) [8]. Moser and colleagues [14, 15] found that these elevated VLCFA could be demonstrated in blood and cultured fibroblasts, and this has become the method of choice for diagnosis. They can be demonstrated by gas chromatography and gas chromatography-mass spectrometry (GCMS). The oxidation of VLCFA takes place in peroxisomes. The enzyme that catalyzes the formation of the CoA esters of these VLCFAs is defective in this disorder (Figure 62.1) [16, 17]. However, the defective gene is that of a peroxisomal membrane transporter protein [18]. The gene was mapped to Xq28 [19]. It was isolated and found to be a member of the ABC transporter family [18, 20]. Of more than 200 mutations identified, approximately 50 percent were missense and 24 percent frameshifts; large deletions, insertions, and splicing defects are uncommon [21–23]. The gene is now referred to as ABCD1 and its product as ALDP.
DTI of Developmental and Pediatric Disorders
Andrei I. Holodny in Functional Neuroimaging, 2019
X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder caused by a defect in ABCD1 gene, leading to the accumulation of saturated very long-chain fatty acids that affect the CNS, adrenal cortex, and testes (34–41). The brain lesions are typically characterized by symmetrical inflammatory demyelination in the cerebral and cerebellar white matter (35). The childhood cerebral form of ALD most commonly presents in boys four- to eight-years old. The initial clinical manifestations are often learning disabilities and behavioral problems, rapidly deteriorating to blindness, quadriparesis, and ultimately death within ten years of diagnosis (36). Bone marrow transplantation during a limited time window is generally considered the most effective treatment.
Metabolic Diseases
Stephan Strobel, Lewis Spitz, Stephen D. Marks in Great Ormond Street Handbook of Paediatrics, 2019
ALD is an X-linked disorder caused by a defect in a peroxisomal transmembrane transporter protein (ABCD1 gene). This leads to defective oxidation of VLCFAs, fatty acids with carbon chains lengths of 24 and 26. The cerebral forms involve a rapidly progressive inflammatory myelinopathy, that usually begins in the parieto-occipital regions and may involve autoimmune mechanisms. Degenerative mechanism are thought to be part of the slower onset AMN. Up to 50% of women who are heterozygous for ALD develop an AMN-like syndrome in adulthood.
Treatment of cerebral adrenoleukodystrophy: allogeneic transplantation and lentiviral gene therapy
Published in Expert Opinion on Biological Therapy, 2022
Ashish O Gupta, Gerald Raymond, Elizabeth I Pierpont, Stephan Kemp, R Scott McIvor, Arpana Rayannavar, Bradley Miller, Troy C Lund, Paul J Orchard
Interestingly, there is evidence that the ability for ABCD1 protein to be incorporated into the peroxisomal membrane is limited, and that increased expression of wild-type ALD protein can influence the relative amount in the membrane as opposed to a defective gene product [109]. Over 75% of ABCD1 pathogenic variants result in unstable and non-detectable ABCD1 protein [110]. However, several missense variants have been reported that do not affect protein stability, but disrupt the protein’s function by decreasing ATP-binding capacity or ATPase activity [110]. The ABCD1 protein forms homodimers, therefore the presence of a nonfunctional ABCD1 protein may result in a dominant negative effect. Indeed, in cells expressing normal ABCD1 protein, in vitro co-expression of a nonfunctional p.Asp194His ABCD1 protein resulted in decreased peroxisomal beta-oxidation capacity and an increase in VLCFA levels [109]. These considerations could prove potentially important in vector design related to necessary ABCD1 gene expression. Additionally, it may influence the choice of gene therapy vs. allogeneic transplantation based on the presence or absence of endogenous expression of aberrant ALDP. This is speculative, and additional information will be required to better assess the importance of these considerations.
Genetic diseases mimicking multiple sclerosis
Published in Postgraduate Medicine, 2021
Chueh Lin Hsu, Piotr Iwanowski, Chueh Hsuan Hsu, Wojciech Kozubski
X-linked adrenoleukodystrophy(X-ALD), a genetic disease that affects both the CNS and adrenal glands, is caused by a mutation in the ABCD1 gene, which encodes essential messages to make X-linked adrenoleukodystrophy protein (ALDP). The role of ALDP is to transport very- long -chain fatty acids (VLCFA) into peroxisomes for breaking down. Insufficient amounts of ALDP result in the building up of VLCFA which overwhelms and damages the adrenal cortex and normal myelin protection of the nerves. X-ALD affects males more than females, as suggested by its name. Three major patterns of X-ALD have been identified, namely a childhood cerebral form, an adrenomyeloneuropathy form, and an adrenal insufficiency-only form. Childhood cerebral form is considered a rapidly fatal disorder with the onset of neurologic symptoms to total disability or death within three years. Almost all male X-ALD patients at some points in their disease course would be affected by myelopathy and peripheral neuropathy, which are collectively named adrenomyeloneuropathy (AMN) [89,90]. In the male, the elevated level of VLCFA is highly sensitive to X-ALD and is thus favorable for diagnosis. However, in women, the genetic test for the ABCD1 gene is required because 15% of female carriers have normal plasma VLCFA levels [91].
An update on gene therapy for lysosomal storage disorders
Published in Expert Opinion on Biological Therapy, 2019
Murtaza S. Nagree, Simone Scalia, William M. McKillop, Jeffrey A. Medin
As correction of most LSDs appears to require systemic delivery of enzyme, autologous HSC-based gene therapy will be most effective for LSDs in which corrective enzyme can be secreted and subsequently taken up by affected ‘bystander’ cells. Conversely, the potential of HSC-directed gene therapy in a disorder without the ability to cross-correct can be seen in the recent success treating X-linked adrenoleukodystrophy, a non-LSD caused by ABCD1 gene dysfunction (NCT01896102) [41]. In that trial, hematopoietic-derived cells migrated into the CNS, persisted, and provided ‘factories’ of functional ABCD1, providing clinical benefit years following transplant [41].
Related Knowledge Centers
- Adrenoleukodystrophy
- Fatty Acid
- Knockout Mouse
- Nervous System
- Peroxisome
- X Chromosome
- Organelle
- Atp-Binding Cassette Transporter
- Very Long Chain Fatty Acid
- Model Organism