Abstract
X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disease associated with mutations in the ABCD1 gene that encodes an ATP-binding cassette transporter protein, ALDP. The disease is characterized by increased concentrations of very long-chain fatty acids (VLCFAs) in plasma and in adrenal, testicular and nervous tissues, due to a defect in peroxisomal VLCFA β-oxidation. In the present study, we analyzed 10 male patients and 17 female carriers from 10 unrelated pedigrees with X-ALD from Argentina. By sequencing the ABCD1 we detected 9 different mutations, 8 of which were novel. These new mutations were verified by a combination of methods that included both functional (western blot and peroxisomal VLCFA β-oxidation) and bioinformatics analysis. The spectrum of novel mutations consists of 3 frameshift (p.Ser284fs*16, p.Glu380Argfs*21 and p.Thr254Argfs*82); a deletion (p.Ser572_Asp575del); a splicing mutation (c.1081+5G>C) and 3 missense mutations (p.Ala341Asp, p.His420Pro and p.Tyr547Cys). In one patient 2 changes were found: a known missense (p.His669Arg) and an unpublished amino acid substitution (p.Ala19Ser). In vitro studies suggest that p.Ala19Ser is a polymorphism. Moreover, we identified two novel intronic polymorphisms and two amino acid polymorphisms. In conclusion, this study extends the spectrum of mutation in X-ALD and facilitates the identification of heterozygous females.
Highlights
X-linked adrenoleukodystrophy [(X-ALD), MIM 300100] is the most common inherited peroxisomal disorder with an estimated birth incidence of 1 in 17,000 newborns [1]
Clinical phenotypes are characterized by impaired peroxisomal b-oxidation [4] which results in elevated levels of saturated very longchain fatty acids (VLCFA) in blood plasma and tissues [5]
The patients came from different regions of Argentina; the clinical data were evaluated in the Centro de Estudio de las Metabolopatıas Congenitas (CEMECO), Universidad Nacional de Cordoba, Hospital de Ninos de Cordoba
Summary
X-linked adrenoleukodystrophy [(X-ALD), MIM 300100] is the most common inherited peroxisomal disorder with an estimated birth incidence of 1 in 17,000 newborns (male and female) [1]. Clinical manifestations of X-ALD are highly variable even in the same family [2]. The major forms are childhood cerebral ALD (CCALD) and adrenomyeloneuropathy (AMN). Children affected by the cerebral variant show inflammatory demyelination and usually die within 3–5 years after onset of neurologic symptoms [3]. Clinical phenotypes are characterized by impaired peroxisomal b-oxidation [4] which results in elevated levels of saturated very longchain fatty acids (VLCFA) in blood plasma and tissues [5]. Biochemical diagnosis of X-ALD is based on the measurement of plasma VLCFAs [6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
