X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management

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Abstract

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal membrane protein ALDP which is involved in the transmembrane transport of very long-chain fatty acids (VLCFA; ≥C22). A defect in ALDP results in elevated levels of VLCFA in plasma and tissues. The clinical spectrum in males with X-ALD ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. The majority of heterozygous females will develop symptoms by the age of 60 years. In individual patients the disease course remains unpredictable. This review focuses on the diagnosis and management of patients with X-ALD and provides a guideline for clinicians that encounter patients with this highly complex disorder.

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Most cited references 76

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Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters.

J Mosser, A Douar, C O Sarde … (1993)

Adrenoleukodystrophy (ALD) is an X-linked disease affecting 1/20,000 males either as cerebral ALD in childhood or as adrenomyeloneuropathy (AMN) in adults. Childhood ALD is the more severe form, with onset of neurological symptoms between 5-12 years of age. Central nervous system demyelination progresses rapidly and death occurs within a few years. AMN is a milder form of the disease with onset at 15-30 years of age and a more progressive course. Adrenal insufficiency (Addison's disease) may remain the only clinical manifestation of ALD. The principal biochemical abnormality of ALD is the accumulation of very-long-chain fatty acids (VLCFA) because of impaired beta-oxidation in peroxisomes. The normal oxidation of VLCFA-CoA in patients' fibroblasts suggested that the gene coding for the VLCFA-CoA synthetase could be a candidate gene for ALD. Here we use positional cloning to identify a gene partially deleted in 6 of 85 independent patients with ALD. In familial cases, the deletions segregated with the disease. An identical deletion was detected in two brothers presenting with different clinical ALD phenotypes. Candidate exons were identified by computer analysis of genomic sequences and used to isolate complementary DNAs by exon connection and screening of cDNA libraries. The deduced protein sequence shows significant sequence identity to a peroxisomal membrane protein of M(r) 70K that is involved in peroxisome biogenesis and belongs to the 'ATP-binding cassette' superfamily of transporters.

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Invited article: an MRI-based approach to the diagnosis of white matter disorders.

R Schiffmann, M S van der Knaap (2009)

There are many different white matter disorders, both inherited and acquired, and consequently the diagnostic process is difficult. Establishing a specific diagnosis is often delayed at great emotional and financial costs. The pattern of brain structures involved, as visualized by MRI, has proven to often have a high diagnostic specificity. We developed a comprehensive practical algorithm that relies mainly on the characteristics of brain MRI. The initial decision point defines a hypomyelination pattern, in which the cerebral white matter is hyperintense (normal), isointense, or slightly hypointense relative to the cortex on T1-weighted images, vs other pathologies with more prominent hypointensity of the cerebral white matter on T1-weighted images. In all types of pathology, the affected white matter is hyperintense on T2-weighted images, but, as a rule, the T2 hyperintensity is less marked in hypomyelination than in other pathologies. Some hypomyelinating disorders are typically associated with peripheral nerve involvement, while others are not. Lesions in patients with pathologies other than hypomyelination can be either confluent or isolated and multifocal. Among the diseases with confluent lesions, the distribution of the abnormalities is of high diagnostic value. Additional MRI features, such as white matter rarefaction, the presence of cysts, contrast enhancement, and the presence of calcifications, further narrow the diagnostic possibilities. Application of a systematic decision tree in MRI of white matter disorders facilitates the diagnosis of specific etiologic entities.

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X-linked adrenoleukodystrophy.

Gerald V. Raymond, Asif Mahmood, Hugo W Moser (2007)

X-linked adrenoleukodystrophy (X-ALD) is caused by a defect in the gene ABCD1, which maps to Xq28 and codes for a peroxisomal membrane protein that is a member of the ATP-binding cassette transporter superfamily. X-ALD is panethnic and affects approximately 1:20,000 males. Phenotypes include the rapidly progressive childhood, adolescent, and adult cerebral forms; adrenomyeloneuropathy, which presents as slowly progressive paraparesis in adults; and Addison disease without neurologic manifestations. These phenotypes are frequently misdiagnosed, respectively, as attention-deficit hyperactivity disorder (ADHD), multiple sclerosis, or idiopathic Addison disease. Approximately 50% of female carriers develop a spastic paraparesis secondary to myelopathic changes similar to adrenomyeloneuropathy. Assays of very long chain fatty acids in plasma, cultured chorion villus cells and amniocytes, and mutation analysis permit presymptomatic and prenatal diagnosis, as well as carrier identification. The timely use of these assays is essential for genetic counseling and therapy. Early diagnosis and treatment can prevent overt Addison disease, and significantly reduce the frequency of the severe childhood cerebral phenotype. A promising new method for mass newborn screening has been developed, the implementation of which will have a profound effect on the diagnosis and therapy of X-ALD.

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Author and article information

Journal

Journal ID (nlm-ta): Orphanet J Rare Dis

Journal ID (iso-abbrev): Orphanet J Rare Dis

Title: Orphanet Journal of Rare Diseases

Publisher: BioMed Central

ISSN (Electronic): 1750-1172

Publication date Collection: 2012

Publication date (Electronic): 13 August 2012

Volume: 7

Page: 51

Affiliations

[1 ]Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

[2 ]Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

[3 ]Department of Pediatric Neurology/Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

[4 ]Department of Neurology, Medical Center Alkmaar, Alkmaar, The Netherlands

[5 ]Department of Pediatric Neurology, Hospital Kremlin-Bicêtre, Assistance Publique des Hôpitaux de Paris, Paris, France

[6 ]INSERM UMR745, University Paris-Descartes, Paris, France

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Publisher ID: 1750-1172-7-51

DOI: 10.1186/1750-1172-7-51

PMC ID: 3503704

PubMed ID: 22889154

SO-VID: ab96c22a-4889-41cc-9829-54af3ca93b5d

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management

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Most cited references 76

Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters.

Invited article: an MRI-based approach to the diagnosis of white matter disorders.

X-linked adrenoleukodystrophy.

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