Natural history of a cohort of ABCD1 variant female carriers

Abstract

Background and purpose The therapeutic scenario of X‐linked adrenoleukodystrophy (X‐ALD) is rapidly changing. Whereas the disease is well characterized in men, the condition remains to be fully clarified in women carrying ATP binding cassette subfamily D member 1 (ABCD1) variants. Specifically, data on clinical progression are needed, in order to recommend any appropriate management. The objective of this study was to outline the natural history of a cohort of untreated ABCD1 heterozygous female carriers. Methods Longitudinal data from a single‐center population of 60 carriers were retrospectively reviewed. Demographics, anthropometrics, serum very long chain fatty acid (VLCFA) levels, clinical parameters and the Adult ALD Clinical Score (AACS) were collected from every recorded visit in a 7‐year period and analyzed to define the phenotype modifications, to determine factors associated with clinical features, and to estimate the annual progression rate and the subsequent sample size for interventional trials. Results Thirty‐two patients were eligible for the study, and 59.4% were symptomatic at baseline. Clinical severity worsens with age which increases risk of symptom onset, the cut‐off of 41 years being crucial for phenoconversion. VLCFA levels were not predictive and did not change over time. Symptomatic carriers were followed up for 3.45 ± 2.1 years. The AACS increased at an annual rate of 0.24 points. The estimated sample size for 30% reduction in annual progression at 80% power was 272. Conclusions This study provides data on the natural disease progression of untreated ABCD1 heterozygous female carriers, demonstrating the relevance of aging. The estimated annual increase of the AACS will be useful for future interventional studies.

Young-onset and late-onset Parkinson's disease exhibit a different profile of fluid biomarkers and clinical features

“…In fact, serum UA is a circulating antioxidant, whose levels have been inversely associated with the risk of PD and other neurodegenerative disorders (Bakshi et al, 2019;Schirinzi et al, 2017). In general, it is well established that the systemic oxidative stress aggravates with aging (Schirinzi et al, 2019b). Therefore, if healthy subjects maintain the neuroprotection mediated by UA, those subjects developing PD at later age lack this defense, being more vulnerable to oxidative stress.…”

Unusual early‐onset and severe adrenomyeloneuropathy in women

“…We read with interest the article 'Natural history of a cohort of ABCD1 variant female carriers' [1]. In this cohort of 32 women with adrenomyeloneuropathy (AMN), the adult form of X-linked adrenoleukodystrophy causing spastic paraparesis, the youngest with pyramidal signs and mild spasticity was 29 years old and the others aged 13-39 years were mostly asymptomatic.…”

A Large Family with p.Arg554His Mutation in ABCD1: Clinical Features and Genotype/Phenotype Correlation in Female Carriers

“…This paper describes a five-generation family in which two main phenotypes of X-ALD are segregated (Figure 1). The affected male died in the first decade (III:4; III:8; III:13; and III: 14), and all affected females present with gait disturbance and different neurological features (Figure 1, Table 1). The genetic evaluation included nine people, including eight females and one male.…”

“…Moreover, these female patients, even in the early asymptomatic stage, already carry some abnormalities, which can be detected by instrumental neurophysiology [5]. Sometimes, at this stage also adrenal failure and cerebral adrenoleukodystrophy may appear [5,[14][15][16][17].…”