Molecular Biomarkers for Adrenoleukodystrophy: An Unmet Need

Abstract

X-linked adrenoleukodystrophy (ALD) is an inherited progressive neurometabolic disease caused by mutations in the ABCD1 gene and the accumulation of very long-chain fatty acids in plasma and tissues. Patients present with heterogeneous clinical manifestations which can include adrenal insufficiency, myelopathy, and/or cerebral demyelination. In the absence of a genotype-phenotype correlation, the clinical outcome of an individual cannot be predicted and currently there are no molecular markers available to quantify disease severity. Therefore, there is an unmet clinical need for sensitive biomarkers to monitor and/or predict disease progression and evaluate therapy efficacy. The increasing amount of biological sample repositories (‘biobanking’) as well as the introduction of newborn screening creates a unique opportunity for identification and evaluation of new or existing biomarkers. Here we summarize and review the many studies that have been performed to identify and improve knowledge surrounding candidate molecular biomarkers for ALD. We also highlight several shortcomings of ALD biomarker studies, which often include a limited sample size, no collection of longitudinal data, and no validation of findings in an external cohort. Nonetheless, these studies have generated a list of interesting biomarker candidates and this review aspires to direct future biomarker research.

High incidence of null variants identified from newborn screening of X-linked adrenoleukodystrophy in Taiwan

“…Hemizygous males with severe variants have been shown to develop cerebral ALD more frequently than those with less detrimental variants [ 31 ]. Although a direct correlation between genotype and phenotype has not been established, and the prognostic value of C26:0-LPC level to predict ALD disease severity is unknown [ 32 ], overproduction of C26:0-LPC has been correlated with the development of neurodegeneration [ 33 ]. Inflammation has been suggested as an important factor for ALD pathogenesis [ 34 ], and increased inflammatory and low anti-inflammatory cytokines levels were found in symptomatic ALD patients compared with asymptomatic hemizygous individuals [ 35 ].…”

An update on the diagnosis and treatment of adrenoleukodystrophy

“…Elevated fasting plasma levels of VLCFA are diagnostic of X-linked ALD but can be elevated in other peroxisomal disorders [14]. VLCFA levels do not predict the prognosis of the condition or progression to cerebral ALD [15]. In females, there is a 20% false negative rate using VLCFA testing only but the use of C26-lysoPC has a sensitivity of >99% including even those with normal VLCFA levels [16].…”

Newborn Screening for X-Linked Adrenoleukodystrophy in Nebraska: Initial Experiences and Challenges

“…Further, up to 88% of heterozygous females for the X-ALD gene develop mild AMN-like symptoms of myelopathy and/or peripheral neuropathy by the 6th decade of life, but rarely exhibit adrenal dysfunction or cerebral demyelination [ 8 ]. This striking clinical variation has led to unsuccessful searches for modifier genes or other biomarkers to predict X-ALD phenotype [ 9 , 10 ].…”