Chitotriosidase as a biomarker of cerebral adrenoleukodystrophy

Abstract

Background: Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder characterized by the abnormal beta-oxidation of very long chain fatty acids (VLCFA). In 35-40% of children with ALD, an acute inflammatory process occurs in the central nervous system (CNS) leading to demyelination that is rapidly progressive, debilitating and ultimately fatal. Allogeneic hematopoietic stem cell transplantation (HSCT) can halt disease progression in cerebral ALD (C-ALD) if performed early. In contrast, for advanced patients the risk of morbidity and mortality is increased with transplantation. To date there is no means of quantitating neuroinflammation in C-ALD, nor is there an accepted measure to determine prognosis for more advanced patients.

Methods: As cellular infiltration has been observed in C-ALD, including activation of monocytes and macrophages, we evaluated the activity of chitotriosidase in the plasma and spinal fluid of boys with active C-ALD. Due to genotypic variations in the chitotriosidase gene, these were also evaluated.

Results: We document elevations in chitotriosidase activity in the plasma of patients with C-ALD (n = 38; median activity 1,576 ng/mL/hr) vs. controls (n = 16, median 765 ng/mL/hr, p = 0.0004), and in the CSF of C-ALD patients (n = 38; median activity 4,330 ng/mL/hr) vs. controls (n = 16, median 0 ng/mL/hr, p < 0.0001). In addition, activity levels of plasma and CSF chitotriosidase prior to transplant correlated with progression as determined by the Moser/Raymond functional score 1 year following transplantation (p = 0.002 and < 0.0001, respectively).

Conclusions: These findings confirm elevation of chitotriosidase activity in patients with active C-ALD, and suggest that these levels predict prognosis of patients with C-ALD undergoing transplantation.

Figure 1

Chitotriosidase Activity is Elevated in Patients with ALD: Chitotriosidase activity was evaluated in the spinal fluid (Figure 1A) and plasma (Figure 2B) of patients with cerebral ALD or controls. There were 38 ALD patient samples and 16 controls represented in each group

Figure 2

Chitotriosidase Activity Correlates in C-ALD Plasma and Spinal Fluid: . For the 37 patients with cerebral ALD for which both plasma and spinal fluid were available, the relative activity for both are depicted. For each patient, Statistical significance related to correlations of the 2 groups is shown (Pearson two-tailed analysis).

Figure 3

Spinal Fluid Chitotriosidase Determinations Are Associated with MRI and Functional Scores For ALD patients with cerebral disease, the correlation of CSF chitotriosidase activity prior to transplantation and the baseline Loes MRI severity score (Fig 3A), the Loes score 1 year post transplantation (3B) and the relative increases in the Loes score from baseline to 1 year after transplantation (Loes Score; Delta; Fig 3C) are presented. The correlation of CSF chitotriosidase activity to the Moser/Raymond functional score (Table 1) prior to transplantation (Fig 3D), at 1 year after transplantation (Fig 3E) and in regards to the change in the functional score from baseline to 1 year after transplant (Functional Score; Delta; Fig 3F) are shown.

Figure 4

Plasma Chitotriosidase Determinations Are Associated with MRI and Functional Scores: For ALD patients with cerebral disease, the correlation of plasma chitotriosidase activity prior to transplantation and the baseline Loes MRI severity score (Fig 4A), the Loes score 1 year post transplantation (4B) and the relative increases in the Loes score from baseline to 1 year after transplantation (Loes Score; Delta; Fig 4C) are presented. The correlation of plasma chitotriosidase activity to the Moser/Raymond functional score prior to transplantation (Fig 4D), at 1 year after transplantation (Fig 4E) and in regards to the change in the functional score from baseline to 1 year after transplant (Functional Score; Delta; Fig 4F) are shown.