Abstract
Background & objectives Adrenoleukodystrophy (ALD), caused by a mutation in the ABCD1 gene has a heterogenous clinical spectrum. Very long chain fatty acid (VLCFA) levels, neuroimaging findings and genetic analysis play a role in the final diagnosis. This paper presents a single centre experience on clinical, biochemical and molecular characteristics of ALD. Methods In this cross-sectional study, 35 individuals with ALD were included. Apart from their clinical characterisation, evaluation of their VLCFA levels was done. VLCFA levels and their ratios were also analysed in 383 healthy controls, and ROC curves were prepared to identify suitable cut-offs for the Indian population. Molecular characterisation by ABCD1 gene sequencing was also done. Molecular modelling techniques were used to ascertain the structural effect of mutations in those carrying novel variants in the ABCD1 gene. Results Adolescent ALD (13/35, 37.1%) was the most common subtype identified in our study, and muscle weakness (19/29, 65.5%) was the most common clinical feature. At cut-offs of 0.907 and 0.604 (µmol/3.2mm punch), C24:0 and C26:0 LPCs, respectively, were found to have a sensitivity and specificity of 100 per cent each for the identification of ALD. Sequencing of ABCD1 gene revealed that the mutations were most commonly seen in exon 1. Out of the four novel variations in ABCD1 gene identified in our study, a three-dimensional visualisation of the ABCD-1 gene revealed that three of them resulted in significant alterations in the protein structure, while no changes at the protein level was reported for the g.11476 [G>A] mutation. Interpretation & conclusions This study highlights the importance of considering the ratios of VLCFAs, along with the individual values, for establishing ALD diagnosis. We also identified a mutational hotspot in exon 1 of the ABCD1 gene, which may also help strategize the preliminary screening of the ABCD1 gene.