X-linked adrenoleukodystrophy in women: a cross-sectional cohort study.
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.
1 Department of Neurology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
Marc
M
Engelen
Mathieu
M
Barbier
Inge M E
IM
Dijkstra
Remmelt
R
Schür
Rob M A
RM
de Bie
Camiel
C
Verhamme
Marcel G W
MG
Dijkgraaf
Patrick A
PA
Aubourg
Ronald J A
RJ
Wanders
Bjorn M
BM
van Geel
Marianne
M
de Visser
Bwee T
BT
Poll-The
Stephan
S
Kemp
D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000326:Adrenoleukodystrophy / Q000097:blood / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D000328:Adult; D000367:Age Factors; D000368:Aged; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005071:Evoked Potentials / Q000502:physiology; D005260:Female; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases / Q000209:etiology / Q000503:physiopathology*; D011446:Prospective Studies; D013118:Spinal Cord Diseases / Q000209:etiology / Q000503:physiopathology*; D049951:X Chromosome Inactivation / Q000235:genetics; D055815:Young Adult
C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters
X-inactivation; adrenoleukodystrophy; carriers; faecal incontinence; myelopathy