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The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis

Authors Wiesinger C, Eichler F, Berger J

Received 22 January 2015

Accepted for publication 10 March 2015

Published 2 May 2015 Volume 2015:8 Pages 109—121


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 5

Editor who approved publication: Prof. Dr. Martin H. Maurer

Christoph Wiesinger,1 Florian S Eichler,2 Johannes Berger1

1Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria; 2Department for Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Abstract: X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding a peroxisomal ABC transporter. In this review, we compare estimates of incidence derived from different populations in order to provide an overview of the worldwide incidence of X-ALD. X-ALD presents with heterogeneous phenotypes ranging from adrenomyeloneuropathy (AMN) to inflammatory demyelinating cerebral ALD (CALD). A large number of different mutations has been described, providing a unique opportunity for analysis of functional domains within ABC transporters. Yet the molecular basis for the heterogeneity of clinical symptoms is still largely unresolved, as no correlation between genotype and phenotype exists in X-ALD. Beyond ABCD1, environmental triggers and other genetic factors have been suggested as modifiers of the disease course. Here, we summarize the findings of numerous reports that aimed at identifying modifier genes in X-ALD and discuss potential problems and future approaches to address this issue. Different options for prenatal diagnosis are summarized, and potential pitfalls when applying next-generation sequencing approaches are discussed. Recently, the measurement of very long-chain fatty acids in lysophosphatidylcholine for the identification of peroxisomal disorders was included in newborn screening programs.

Keywords: X-ALD, AMN, mutations, incidence, prenatal diagnosis, newborn screening

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