Glycoprotein nonmetastatic melanoma protein B (GNMPB) as a novel biomarker for cerebral adrenoleukodystrophy

Abstract

Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disease caused by a mutation in the ABCD1 gene, producing mutations in the very long chain fatty acid transporter, ALD protein. Cerebral ALD (cALD) is a severe phenotype of ALD with neuroinflammation and neurodegeneration. Elevated levels of Glycoprotein Nonmetastatic Melanoma Protein B (GNMPB) have been recently documented in neurodegenerative diseases such as Alzheimer's disease, Multiple Sclerosis and Amyotrophic Lateral Sclerosis. Our objective was to measure the levels cerebral spinal fluid (CSF) GNMPB in cALD patients to determine if GNMPB could be a potential biomarker in tracking cALD disease progression. CSF GNMPB levels were significantly higher in cALD patients versus controls (2407 ± 1672 pg/mL vs. 639.5 ± 404 pg/mL, p = 0.0009). We found a positive correlation between CSF GNMPB and MRI disease severity score levels (R² = 0.3225, p < 0.0001) as well as the gadolinium intensity score (p = 0.0204). Boys with more severe neurologic deficits also had higher levels of CSF GNMPB (p < 0.0001). A positive correlation was shown between CSF GNMPB and another biomarker, chitotriosidase (R² = 0.2512, p = 0.0244). These data show that GNMPB could be a potential biomarker of cALD disease state and further studies should evaluate it as a predictor of the disease progression.

Figure 1

CSF GNMPB levels are elevated in boys with cALD. (A) shows levels of CSF GNMPB. (B) shows the difference between low risk and high-risk boys based on a Loes score cutoff of ≥ 10. (C) shows Loes score as a continuous variable and p-value derived from a linear regression analysis. (D) shows the comparison of CSF GNMPB amongst cALD patients categorized by GIS. Two-comparisons shows p-values derived from a Student’s t-test. P-value in (D) was derived from an ANOVA and Tukey post-hoc test. The main effect p-value was p = 0.0204.

Figure 2

CSF GNMPB correlates with neurologic function and chitotriosidase. (A) The cerebral adrenoleukodystrophy neurologic function score (NFS), which was used to evaluate gross clinical neurologic severity for the cALD cohort pre-transplantation. Note that a score of zero denotes absence of clinical signs of cerebral disease. Maximal signs within a domain score the total of all grades within that domain (for example, a patient with “total urinary or fecal incontinency” scores 3, for the sum of “Episodes of incontinency” [1 point] and “Total Incontinency” [2 additional points]). (B) The difference between neurologically affected boys (NFS ≥ 2) versus those with NFS ≤ 1 is depicted. (C) Use of the NFS as a continuous variable and p-value derived from a linear regression analysis. (D) The correlation between CSF GNMBP and CSF chitotriosidase and p-value derived from a linear regression analysis. (D) shows the comparison of CSF Two-comparisons shows p-values derived from a Student’s t-test.