Adrenoleukodystrophy (X-ALD) is the most common genetic disorder of the brain white matter
with an incidence of 1:14,700 births. It is caused by mutations in the ABCD1 gene, which
encodes a transporter of very long-chain fatty acids (VCLFA) into the peroxisome for
degradation. As a consequence VLCFA accumulate in tissues and plasma being the pathognomonic
biomarker for diagnosis. The excess of VLCFA produces mitochondrial ROS and oxidative damage,
a major factor driving X-ALD pathogenesis. Other key dysregulated pathways are energy
production, mitochondrial biogenesis and respiration, proteostasis, and ER stress. Current
therapeutic options are unsatisfactory, restricted to bone marrow transplant and gene
therapy, for which most patients do not qualify. The encouraging results of plasma exchange
(PE) with albumin replacement for Alzheimer's Disease prompted us to start this study. Our
rationale is the following: In plasma, VLCFA are transported by lipoproteins and albumin.
Albumin is the major transporter of fatty acids (FA) to the brain. ABCD1 deficiency induces
inflammation and increases blood-brain barrier leakage, which could facilitate increased
permeability to albumin. We posit that replacement of albumin would lower VLCFA levels in
plasma through peripheral sink mechanisms, diminishing the quantity of VLCFA reaching the
brain, and would prevent lipid peroxidation. A pilot proof-of-concept study in 5 X-ALD
patients will be carried out to replace endogenous albumin through PE applied, once a week
the first month and monthly for 5 months. A 6 months follow-up after the end of the treatment
will be carried out.