Cerebral adrenoleukodystrophy is associated with loss of tolerance to profilin.

Abstract

Childhood cerebral adrenoleukodystrophy (cALD) is a devastating manifestation of ALD accompanied by demyelination, inflammation, and blood brain barrier (BBB) disruption with shared characteristics of an auto-immune disease. We utilized plasma samples pre- and postdevelopment of cALD to determine the presence of specific auto-antibodies. Mass spectrometry of protein specifically bound with post-cALD plasma antibody identified Profilin1 (PFN1) as the target. In a screen of 94 boys with cALD 48 (51%) had anti-PFN1 antibodies, whereas only 2/29 boys with ALD but without cerebral disease, and 0/30 healthy controls showed anti-PFN1 immunoreactivity. Cerebral spinal fluid from those with cALD showed higher levels of PFN1 protein compared with non-cALD samples (324±634 versus 42±23 pg/mL, p=0.04). Boys that were anti-PFN positive had a significant increase in the amount of gadolinium signal observed on MRI when compared to boys that were anti-PFN1 negative (p=0.04) possibly indicating increased BBB disruption. Anti-PFN1 positivity was also associated with elevated levels of very long chain fatty acids (C26 of 1.12±0.41 versus 0.97±0.30mg/dL, p=0.03) and increased plasma BAFF (973±277 versus 733±269 pg/mL, p=0.03). In conclusion, anti-PFN may be a novel biomarker associated with the development of cALD in boys with ALD.