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Introduction
ALD is an X-linked disorder caused by mutations in the ABCD1 gene that encodes an ABC class very long chain fatty acid (VLFCA) transporter known as ALD protein (ALDP). ALDP transports VLCFA from the cytoplasm to the peroxisome for breakdown. Lack of function of this transport activity leads to VLCFA buildup at the cellular and tissue levels, eventually resulting in cell death and organ dysfunction1. The most sensitive organ is the adrenal gland which results in adrenal insufficiency (AI) in boys often between ages four and seven with a rate of 50% or greater by age 18 years2. Approximately 40% of boys develop a devastating inflammatory cerebral demyelination process known as cerebral ALD. Once initiated, this process rarely self-arrests, and the best known current medical treatment is either a hematopoietic stem cell transplant (HSCT) from a sufficiently matched donor or ex-vivo lentiviral gene therapy3,4. Given the substantial incidence of cerebral ALD, international guidelines have been established for longitudinal monitoring of boys with an ALD diagnosis5. Cerebral disease surveillance consists of initiation of MRIs at about age 2 years, which are then performed every six months until age 12, whereafter they occur annually for the remainder of the patient’s life. In young children and toddlers, the MRIs are often performed with sedation and may include the use of gadolinium contrast enhancement to identify inflammatory lesions. While MRI screening is generally safe, there are still some risks associated with pediatric sedation, and there is ongoing debate regarding long term effects of gadolinium contrast infusion6, 7, 8, 9, 10–11.
The search for a biomarker to predict the onset of cerebral ALD has been ongoing for the better part of two decades. Numerous biomarkers have been reported including metalloproteinase levels12, profilin13, chitotriosidase14, and others which have been associated with cerebral ALD. Recently there’s been more focus on the use of neurofilament light chain (NfL) as a biomarker given the newfound ability to detect it in the blood at subfemtomolar levels due to the development of the highly sensitive single-molecule enzyme-linked immunosorbent assay (Simoa) methodology15. NfL has been utilized in numerous neurologic disorders to monitor disease progression and response to therapy