This report describes adrenoleukodystrophy, which shows X-linked inheritance. The human gene implicated in this disease is ABCD1. There is a high-ranking ortholog of ABCD1 in Drosophila, Abcd1. Several alleles of Dmel\Abcd1 have been generated, including RNAi targeting constructs and insertion lines. Dmel\Abcd1 is also orthologous to human ABCD2.
The human gene ABCD1 has not been introduced into flies.
Flies expressing RNAi knocking down Abcd1 survive to adulthood, but have neurodegenerative phenotypes including an age-dependent retinal disorganization, characterized by retinal holes and pigment cell loss. (The eye is a neuron-rich organ commonly used to quantify neurodegenerative phenotypes in Drosophila). This phenotype is seen when RNAi is driven in neurons or ubiquitously, but not seen when Abcd1 is knocked down in non-neuronal cells. It is very similar to the phenotype caused by amorphic alleles of bgm and hll, two acyl-CoA synthetases (FBgg0000835) that function upstream of ABC transporters (such as Abcd1) in fatty acid metabolism, and are also linked to adrenoleukodystrophy (see FBhh0000762).
[updated Aug. 2021 by FlyBase; FBrf0222196]
[ADRENOLEUKODYSTROPHY; ALD](https://omim.org/entry/300100)
[ATP-BINDING CASSETTE, SUBFAMILY D, MEMBER 1; ABCD1](https://omim.org/entry/300371)
X-ALD patients have mutations in the ABCD1 gene and accumulate very long chain fatty acids in all tissues. Virtually all male X-ALD patients develop adrenocortical insufficiency in childhood and progressive myelopathy and peripheral neuropathy in adulthood. A subset of male patients, however, develops a fatal cerebral demyelinating disease, cerebral adrenoleukodystrophy. Diagnosed in boys usually between the ages of 4 and 8 years, cerebral X-ALD symptoms progress rapidly (in as little as 2 years) through declines in cognition, learning and behavior, to paralysis and ultimately to a vegetative state and death. (adapted from Engelen et al. 2014, pubmed:25115486; Gordon et al. 2018, FBrf0239245.)
Adrenoleukodystrophy can present at a variety of ages and with different manifestations depending on the presence and type of neurologic findings. Moser et al. (pubmed:11204280) stated that there are 7 phenotypes, which include the childhood cerebral form, adrenomyeloneuropathy (AMN), adult cerebral, adolescent, adrenal insufficiency without neurologic disease, asymptomatic, and heterozygotes. The manifestations of the disorder occur primarily in the adrenal cortex, the myelin of the central nervous system, and the Leydig cells of the testes. [from MIM:300100, 2019.05.28]
Adrenoleukodystrophy is an X-linked disorder which is associated with a mutation in the ABCD1 gene and results in the apparent defect in peroxisomal beta oxidation and the accumulation of the saturated very long chain fatty acids (VLCFA) in all tissues of the body. [from MIM:300100, 2019.05.28]
The fundamental biochemical defect in adrenoleukodystrophy is impaired degradation of very long chain fatty acids (VLCFAs) by peroxisomal beta-oxidation. This is caused by mutations in the ABCD1 gene, which encodes a peroxisomal transmembrane protein that is a member of the ATP-binding cassette transporter superfamily. (adapted from Engelen et al. 2014, pubmed:25115486; Moser et al. 2007, pubmed:17342190)
Singh et al. (PMCID:1715420) and Lazo et al. (pubmed:3174658) presented data demonstrating that the accumulation of very long chain fatty acids in ALD is the result of deficient peroxisomal lignoceroyl-CoA ligase activity. Igarashi et al. (pubmed:965973) found that cholesterol esters in the brain and adrenals of these patients had an unusually high proportion of fatty acids with a chain length of 24-30 carbon atoms, rather than the usual length of less than 20. This might interfere with myelin formation in the CNS and steroidogenesis in the adrenal. [from MIM:300100, 2019.05.28]
Many human to one Drosophila (2 human genes to 1 Drosophila gene).
High-ranking ortholog of human ABCD1 and ABCD2.
