Identification of Two Novel Mutations of ABCD1 Gene in Pedigrees with X-Linked Adrenoleukodystrophy and Review of the Literature

Abstract

Background: X-linked adrenoleukodystrophy (ALD) is an inherited peroxisomal metabolism disorder, resulting from the loss-of-function mutation of ATP-binding cassette protein subfamily D1 (ABCD1) gene. The dysfunction of ALD protein, a peroxisomal ATP-binding cassette transporter, results in the excessive saturated very long-chain fatty acids (VLCFAs) accumulation in organs including the brain, spine, and adrenal cortex. X-ALD is characterized as the childhood, adolescent, adult cerebral ALD, adrenomyeloneuropathy (AMN), adrenal insufficiency, and asymptomatic phenotypes, exhibiting a high variety of clinical neurological manifestations with or without adrenocortical insufficiency.

Results: In this study, we reported two cases of X-ALD, which were first diagnosed as adrenal insufficiency (Addison's disease) and treated with adrenocortical supplement. However, both of the cases progressed as neurological symptoms and signs after decades. Elevated VLCFAs level, brain MRI scan, and genetic analysis confirmed final diagnosis. In addition, we identified two novel mutations of ABCD1 gene, NM_000033.3 (ABCD1): c.874_876delGAG (p.Glu292del) and NM_000033.3 (ABCD1): c.96_97delCT (p.Tyr33Profs∗161), in exon 1 of ABCD1 gene. Sanger sequencing confirmed that the proband's mother of the first case was heterozygous carrying the same variant. Adrenal insufficiency-only type is very rare; however, it may be the starting performance of X-ALD. In addition, we summarized reported mutation sites and clinical manifestations to investigate the correlationship of phenotype-genotype of X-ALD.

Conclusions: The early warning manifestations should be noticed, and the probability of X-ALD should be considered. This report could be beneficial for the early diagnosis and genetic counseling for patients with X-ALD.

Figure 1

Brain magnetic resonance imaging (MRI) scan of patients. (a) Symmetric bands with high T2 low T1 abnormal signal in bilateral genu of the corpus callosum detected in case one. (b) MRI scan of case two revealed long T1 and long T2 signals in white matter of bilateral frontal lobes, around the anterior of lateral ventricle, and splenium of the corpus callosum. (c) Computed tomography (CT) scan of the adrenal gland of case one to show bilateral adrenal atrophy. Red arrow shows lesions.

Figure 2

Pedigree diagrams and genetic analysis of two cases. (a), (c) Pedigree diagrams of the case one and case two with X-linked ALD, respectively. Empty square and circle show healthy male and female. Dark square represents patients with X-ALD. Diagonal stripes show heterozygous carrier. Arrow represents hemizygous proband. (b) Genetic analysis revealing novel mutation of c.874_876delGAG (p.Glu292del) of ABCD1 gene in patient one (proband III-7) and his mother (II-10). (d) Novel mutation c.96_97delCT (p.Tyr33Profs^∗161) detected in patient two (proband III-4).

Figure 3

Three-dimensional structure prediction of adrenoleukodystrophy (ALD) protein. (a) The modeled structure of health control. The visible alteration of ALD protein structure induced by mutations (b) c.874_876delGAG (p.Glu292del) and (c) c.96_97delCT (p.Tyr33Profs∗161) are indicated in circles. It indicates that those mutations might lead to alteration of the protein structure and potential dysfunction.

Figure 4

ABCD1 gene reported from the ALD mutation database. (a) Mutation sites types of variants of ABCD1 gene among reported nonrecurrent and other mutation sites, including pathogenic, synonymous, benign, variants of undetermined significance (VUS), and screening of newborns state of unknown (UN). (b) The content of ABCD1 mutations, including points mutations, deletion, del-insertion, insertion, and duplication (http://www.x-ald.nl/). (c) The distribution of mutations, including point mutation, deletion, del-insertion, insertion, and duplication. Most of the mutations harboring in exon 1. The lower panel shows the mutation rate in each exon. Bold shows the location of two novel mutations indicated in this study.

Figure 5

Summary of the reported mutation sites and clinical manifestations from the database of UniProt (https://www.uniprot.org/uniprot/) and reported references [–35]. The clinical types include childhood and adolescent cerebral ALD (CCALD and adoles ALD), adult ALD, AMN (adrenomyeloneuropathy), adrenal insufficiency-only (AIO), complicated ALD which cannot be classified, and asymptomatic or presymptomatic types.