X-linked adrenoleukodystrophy in women: a cross-sectional cohort study.

Abstract

X-linked adrenoleukodystrophy is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal transporter of very long-chain fatty acids. A defect in the ABCD1 protein results in elevated levels of very long-chain fatty acids in plasma and tissues. The clinical spectrum in males with X-linked adrenoleukodystrophy has been well described and ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. As in many X-linked diseases, it was assumed that female carriers remain asymptomatic and only a few studies addressed the phenotype of X-linked adrenoleukodystrophy carriers. These studies, however, provided no information on the prevalence of neurological symptoms in the entire population of X-linked adrenoleukodystrophy carriers, since data were acquired in small groups and may be biased towards women with symptoms. Our primary goal was to investigate the symptoms and their frequency in X-linked adrenoleukodystrophy carriers. The secondary goal was to determine if the X-inactivation pattern of the ABCD1 gene was associated with symptomatic status. We included 46 X-linked adrenoleukodystrophy carriers in a prospective cross-sectional cohort study. Our data show that X-linked adrenoleukodystrophy carriers develop signs and symptoms of myelopathy (29/46, 63%) and/or peripheral neuropathy (26/46, 57%). Especially striking was the occurrence of faecal incontinence (13/46, 28%). The frequency of symptomatic women increased sharply with age (from 18% in women <40 years to 88% in women >60 years of age). Virtually all (44/45, 98%) X-linked adrenoleukodystrophy carriers had increased very long-chain fatty acids in plasma and/or fibroblasts, and/or decreased very long-chain fatty acids beta-oxidation in fibroblasts. We did not find an association between the X-inactivation pattern and symptomatic status. We conclude that X-linked adrenoleukodystrophy carriers develop an adrenomyeloneuropathy-like phenotype and there is a strong association between symptomatic status and age. X-linked adrenoleukodystrophy should be considered in the differential diagnosis in women with chronic myelopathy and/or peripheral neuropathy (especially with early faecal incontinence). ABCD1 mutation analysis deserves a place in diagnostic protocols for chronic non-compressive myelopathy.

• Authors: Marc Engelen, Mathieu Barbier, Inge M E Dijkstra, Remmelt Schür, Rob M A de Bie, Camiel Verhamme, Marcel G W Dijkgraaf, Patrick A Aubourg, Ronald J A Wanders, Bjorn M van Geel, Marianne de Visser, Bwee T Poll-The, Stephan Kemp
• Journal: Brain : a journal of neurology (Brain) Vol. 137 Issue Pt 3 Pg. 693-706 (Mar 2014) ISSN: 1460-2156 [Electronic] England
• PMID: 24480483 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCD1 protein, human
• ATP Binding Cassette Transporter, Subfamily D, Member 1
• ATP-Binding Cassette Transporters

Topics

• ATP Binding Cassette Transporter, Subfamily D, Member 1
• ATP-Binding Cassette Transporters (genetics)
• Adrenoleukodystrophy (blood, complications, genetics, physiopathology)
• Adult
• Age Factors
• Aged
• Cohort Studies
• Cross-Sectional Studies
• Evoked Potentials (physiology)
• Female
• Heterozygote
• Humans
• Middle Aged
• Peripheral Nervous System Diseases (etiology, physiopathology)
• Prospective Studies
• Spinal Cord Diseases (etiology, physiopathology)
• X Chromosome Inactivation (genetics)
• Young Adult