Neurophysiological abnormalities in adrenoleukodystrophy carriers. Evidence of different degrees of central nervous system involvement

Abstract

We studied 19 women, heterozygous for adrenoleukodystrophy (ALD) in whom the carrier status was demonstrated by abnormally high plasma levels of very-long-chain fatty acids. Clinical examination revealed slight neurological signs in two patients. Clear-cut neurological deficits in three, and it was fully normal in the remaining 14. All subjects underwent motor evoked potential (MEP) and somatosensory evoked potential (SEP) studies. Seventeen out of 19 subjects underwent brain MRI which demonstrated various degrees of abnormality in one asymptomatic and five symptomatic subjects; SEPs and MEPs revealed CNS involvement in 12 and 8 out of the 19 subjects, respectively. Symptomatic patients showed severe neurophysiological abnormalities, whereas milder but unequivocal EP abnormalities were found in seven of the 14 patients with normal clinical examination. Our data thus suggest CNS involvement in the majority of the ALD carriers, evident also in preclinical stages and progressively severe. The possibility of assessing different degrees of neurological involvement could be relevant for therapeutical purposes. Moreover, neurophysiological studies could provide the only objective marker of functional nervous system involvement, e.g. in order to monitor the efficacy of treatment, and in clinically and radiologically silent cases.

Therapy of X-linked adrenoleukodystrophy

“…10,47 It is of later onset and milder than the AMN that affects males, but a small proportion of neurologically symptomatic women require a wheelchair. Overt adrenal insufficiency and the inflammatory cerebral phenotype occur in approximately 1% of heterozygotes.…”

ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations

“…Cerebral involvement and adrenocortical insufficiency are rare [Moser, 1997;Restuccia et al, 1997;el Deiry et al, 1997].…”

“…Among 616 kindreds studied, the proband was female in only 16. It is nevertheless important to estimate the frequency of women heterozygous for X-ALD because at least half of the heterozygous women develop an AMN-like syndrome which can cause considerable disability in middle age or later in life [Moser, 1997;Restuccia et al, 1997]. We recommend that women who are at risk of being heterozygous for X-ALD be informed about the availability of genetic testing when they reach reproductive age.…”

Adrenoleukodystrophy: Incidence, new mutation rate, and results of extended family screening

“…12 It is therefore appropriate that they be included in the estimate of disease frequency. Assuming that 37% of X-ALD hemizygotes (the proportion who have the childhood cerebral phenotype) 13 fail to reach reproductive age and that reproductive fitness of heterozygotes is unimpaired, we used standard population genetics arguments to calculate the ratio of female heterozygotes to hemizygous males under modified Hardy-Weinberg conditions and determined that it is about 1.5.…”