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

• Published in: Brain (London, England : 1878) England : 1878), 2014-03, Vol.137 (Pt 3), p.693-706
• Main Authors: ENGELEN, Marc, BARBIER, Mathieu, DE VISSER, Marianne, POLL-THE, Bwee T, KEMP, Stephan, DIJKSTRA, Inge M. E, SCHÜR, Remmelt, DE BIE, Rob M. A, VERHAMME, Camiel, DIJKGRAAF, Marcel G. W, AUBOURG, Patrick A, WANDERS, Ronald J. A, VAN GEEL, Bjorn M
• Format: Article
• Language: English
• Subjects: Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Adrenoleukodystrophy - blood; Adrenoleukodystrophy - complications; Adrenoleukodystrophy - genetics; Adrenoleukodystrophy - physiopathology; Adult; Age Factors; Aged; ATP Binding Cassette Transporter, Sub-Family D, Member 1; ATP-Binding Cassette Transporters - genetics; Biological and medical sciences; Cerebrospinal fluid. Meninges. Spinal cord; Cohort Studies; Cross-Sectional Studies; Endocrinopathies; Errors of metabolism; Evoked Potentials - physiology; Female; Gastroenterology. Liver. Pancreas. Abdomen; Heterozygote; Humans; Lipids (lysosomal enzyme disorders, storage diseases); Medical sciences; Metabolic diseases; Middle Aged; Nervous system (semeiology, syndromes); Neurology; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Other diseases. Semiology; Peripheral Nervous System Diseases - etiology; Peripheral Nervous System Diseases - physiopathology; Prospective Studies; Spinal Cord Diseases - etiology; Spinal Cord Diseases - physiopathology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; X Chromosome Inactivation - genetics; Young Adult
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awt361

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 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.