Abstract
BackgroundX-linked adrenoleukodystrophy results from mutations in the ABCD1 gene disrupting the metabolism of very-long-chain fatty acids. The most serious form of ALD, cerebral adrenoleukodystrophy (cALD), causes neuroinflammation and demyelination. Neuroimaging in cALD shows inflammatory changes and indicates blood-brain-barrier (BBB) disruption. We hypothesize that disruption may occur through the degradation of the extracellular matrix defining the BBB by matrix metalloproteinases (MMPs). MMPs have not been evaluated in the setting of cALD.Methodology/Principal FindingsWe used a multiplex assay to correlate the concentration of MMPs in cerebrospinal fluid and plasma to the severity of brain inflammation as determined by the ALD MRI (Loes) score and the neurologic function score. There were significant elevations of MMP2, MMP9, MMP10, TIMP1, and total protein in the CSF of boys with cALD compared to controls. Levels of MMP10, TIMP1, and total protein in CSF showed significant correlation [p<0.05 for each with pre-transplant MRI Loes Loes scores (R2 = 0.34, 0.20, 0.55 respectively). Levels of TIMP1 and total protein in CSF significantly correlated with pre-transplant neurologic functional scores (R2 = 0.22 and 0.48 respectively), and levels of MMP10 and total protein in CSF significantly correlated with one-year post-transplant functional scores (R2 = 0.38 and 0.69). There was a significant elevation of MMP9 levels in plasma compared to control, but did not correlate with the MRI or neurologic function scores.Conclusions/SignificanceMMPs were found to be elevated in the CSF of boys with cALD and may mechanistically contribute to the breakdown of the blood-brain-barrier. MMP concentrations directly correlate to radiographic and clinical neurologic severity. Interestingly, increased total protein levels showed superior correlation to MRI score and neurologic function score before and at one year after transplant.
Highlights
X-linked adrenoleukodystrophy (ALD) is a neurometabolic disease that results from mutations in ABCD1, the gene that encodes for a peroxisomal transporter of very long chain fatty acid (VLCFA) and subsequently disrupts their metabolism and results in the accumulation of these compounds in all tissues
We performed a comprehensive examination of matrix metalloproteinases (MMPs), Tissue inhibitors of metalloproteinases (TIMPs), and total protein levels in the CSF of boys with cerebral adrenoleukodystrophy (cALD) prior to HSCT (n = 20) versus control patients (n = 19)
We report that there are significant elevations of CSF total protein, MMP2, MMP9, MMP10, TIMP1 and plasma MMP9 in boys with cALD at the time of transplant compared to controls
Summary
X-linked adrenoleukodystrophy (ALD) is a neurometabolic disease that results from mutations in ABCD1, the gene that encodes for a peroxisomal transporter of very long chain fatty acid (VLCFA) and subsequently disrupts their metabolism and results in the accumulation of these compounds in all tissues. [1]. X-linked adrenoleukodystrophy (ALD) is a neurometabolic disease that results from mutations in ABCD1, the gene that encodes for a peroxisomal transporter of very long chain fatty acid (VLCFA) and subsequently disrupts their metabolism and results in the accumulation of these compounds in all tissues. Cerebral disease is the most common neurologic presentation in childhood. It is important to point out that while ALD is characterized by the accumulation of VLCFA, only 35% of individuals at risk will develop cerebral disease in childhood and no correlation has been observed between the accumulation of the fatty acids in serum and the clinical phenotype for ALD [1]. X-linked adrenoleukodystrophy results from mutations in the ABCD1 gene disrupting the metabolism of verylong-chain fatty acids. The most serious form of ALD, cerebral adrenoleukodystrophy (cALD), causes neuroinflammation and demyelination. MMPs have not been evaluated in the setting of cALD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
