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Adrenoleukodystrophy
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
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.
Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
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.
DTI of Developmental and Pediatric Disorders
Published in Andrei I. Holodny, Functional Neuroimaging, 2019
Michael J. J. Kim, James M. Provenzale
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.
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
Adrenoleukodystrophy (ALD) is an X-linked disorder with an estimated incidence of approximately one in 14–17,000 births [1–3]. The gene associated with ALD is ABCD1, which encodes for a peroxisomal membrane protein responsible for transportation of very long-chain fatty acids (VLCFA) into the peroxisome, where they are subsequently degraded via β-oxidation. The gene consists of 10 exons, encoding for a protein of 745 amino acids. Over 900 pathogenic variants have been described, and a listing of ABCD1 variants known to be disease-causing and variants of uncertain significance are maintained in a database (https://adrenoleukodystrophy.info) [4]. Due to impaired degradation within the peroxisome, and through the action of elongases such as ELOVL1, increased concentrations of saturated VLCFA >C22:0 are observed [5,6]. These accumulate in the tissues as well as the blood, and elevations of VLCFA in plasma or serum are important in diagnosis of ALD [7,8]. In females, the use of VLCFA analysis in blood is insufficient to definitively establish the presence of a heterozygous state, as there may be a false-negative rate up to 20% using VLCFA testing alone. Recently, it has been demonstrated that C26:0-lysophosphatidylcholine (C26-lysoPC) has a superior diagnostic performance with a sensitivity of >99% in diagnosing women with ALD, including those with normal plasma VLCFA levels [9]. However, because VLCFA and C26:0-lysoPC are not specific for ALD, sequencing of the ABCD1 gene is done to make this determination [10].
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].