The two most common forms of X-linked adrenoleukodystrophy (X-ALD), the childhood cerebral form (CCER) and the adult form, adrenomyeloneuropathy (AMN), arise from the same mutations in the X-ALD gene at Xq28.
X-linked adrenoleukodystrophy in Spain. Identification of 26 novel mutations in the ABCD1 gene in 80 patients. Improvement of genetic counseling in 162 relative females.
ABCD1 mutations lead to a variety of phenotypes, including cerebral X-ALD and adrenomyeloneuropathy (AMN) in affected males and 80% of carrier females.
The nearly complete novel spectrum of ALD gene mutations identified has revealed no obvious correlation between the type of mutation and age of AMN onset in this small series.
In mice, ABCD1 loss causes late onset axonal degeneration in the spinal cord in association with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy.
X-adrenoleukodystrophy (X-ALD) is a complex disease where inactivation of ABCD1 gene results in clinically diverse phenotypes, the fatal disorder of cerebral ALD (cALD) or a milder disorder of adrenomyeloneuropathy (AMN).
We assessed spinal cord microglia in humans and mice with AMN and investigated the role of ABCD1 in microglial activity toward neuronal phagocytosis in cell culture.
The default manifestation of mutations in ABCD1 is adrenomyeloneuropathy, a slowly progressive dying-back axonopathy affecting both ascending and descending spinal cord tracts as well as in some cases, a peripheral neuropathy.
X-Adrenoleukodystrophy (X-ALD) and its adult-onset, most prevalent variant adrenomyeloneuropathy (AMN) are caused by mutations in the peroxisomal transporter of the very long-chain fatty acid ABCD1.
We combined an untargeted metabolome assay of plasma and peripheral blood mononuclear cells (PBMC) of AMN patients, which used liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (LC-Q-TOF), with a functional genomics analysis of spinal cords of Abcd1(-) mouse.
Pipecolic acid was elevated, often markedly, in most of the patients with NALD but in none of those with X-linked ALD or adrenomyeloneuropathy, or in normal adults and children, or children with cirrhosis or other neurodegenerative disorders.
To elucidate the mechanisms underlying the phenotypic variability of ALD, we studied the expression of ABCD1, three other peroxisomal transporter genes of the same family (ABCD2, ABCD3 and ABCD4) and two VLCFA synthetase genes (VLCS and BG1) involved in VLCFA metabolism, as well as the VLCFA concentrations in the normal white matter (WM) from ALD patients with CCER, AMN-C and AMN phenotypes.
In the mouse, Abcd1 loss causes late onset axonal degeneration in the spinal cord, associated with locomotor disability resembling the most common phenotype in patients, adrenomyeloneuropathy.
Both CCALD and AMN iPSCs normally differentiated into oligodendrocytes, the cell type primarily affected in the X-ALD brain, indicating no developmental defect due to the ABCD1 mutations.