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.

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

“…Most frequently, adult patients show mainly a slowly progressive spastic paraparesis without cerebral inflammatory demyelination, peripheral neuropathy and sphincter disturbances, the disease manifestations typical of adrenomyeloneuropathy (AMN) of male, and many women carriers. 11,12 In all its variants, the disease is caused by the loss of function of the ABCD1 gene in Xq2.8, which encodes a transmembrane transporter involved in the import of VLCFA and VLCFACoenzyme A esters into the peroxisome for their breakdown by beta-oxidation. 13 Lack of phenotype-genotype correlations within the same nuclear family contribute to the enigmatic nature of the disease.…”

Bladder and Bowel Dysfunction Is Common in Both Men and Women with Mutation of the ABCD1 Gene for X-Linked Adrenoleukodystrophy

“…However, it is now recognised that female carriers of the mutation also manifest with symptoms (O'Neill et al 1984;Jangouk et al 2012;Engelen et al 2014). Females may develop a range of neurological deficits including hyperreflexia, impaired vibration sense and also spastic paraparesis, deficits reported also in our cohort, and may erroneously be diagnosed initially as having some other neurological condition such as multiple sclerosis before being found to be carrying the ABCD1 gene mutation (Dooley and Wright 1985;Stockler et al 1993;Krenn et al 2001;Di Filippo et al 2011).…”

“…To some extent, urinary and faecal incontinence have recently been reported in female X-ALD carriers (Engelen et al 2014) but have not been evaluated in greater detail using validated questionnaires. The early identification of the carrier status because of better availability of screening facilities for family members has uncovered a wide spectrum of symptoms and signs amongst female carriers (Jangouk et al 2012).…”

Genetics of Hereditary Spastic Paraplegias (HSP)

“…With adult onset especially AMN, Krabbe disease and Alexander disease present with prominent spasticity (Table 16.5 ) [ 5 ]. Most female carriers of X-ALD/AMN mutations develop signs and symptoms of myelopathy and/or peripheral neuropathy between 40 and 60 years of age [ 70 ]. Although most of them show some abnormality in very long-chain acid metabolism, the only reliable diagnostic tool in females with suspected AMN is genetic testing of the ABCD1 gene.…”