Abstract Details

Title The Vitamin D Activator, CYP27B1, is a Novel Muscle Biomarker of ALS Disease Progression

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P1 - Poster Session 1 (5:30 PM-6:30 PM)

Poster/Presentation
Number 12-002

Objective To validate CYP27B1 as a novel muscle biomarker in amyotrophic lateral sclerosis (ALS).

Background Pathological changes in skeletal muscle, including the neuromuscular junction, occur at the earliest stages of ALS and progress in parallel with clinical disease. Molecular changes that underlie skeletal muscle pathology in ALS may therefore serve as biomarkers that can assist with diagnosis and/or monitoring of disease progression. We previously performed RNA sequencing on muscle biopsies from ALS patients and identified an elevation of the vitamin D activator, CYP27B1.

Design/Methods RNA was extracted from muscle biopsy samples from patients with definite or probable ALS (n = 29), myopathy (n = 8), neuropathy (n = 12), or no neuromuscular disease (n = 10) and assessed by qPCR for CYP27B1. For some of the biopsies, CYP27B1 protein expression was assessed by western blot and immunohistochemistry. To evaluate disease progression, muscle samples from the SOD1^G93A ALS mouse were collected at different ages and assayed for CYP27B1 expression.

Results CYP27B1mRNA and protein levels were significantly increased in human ALS muscle samples versus control and myopathy samples. Neuropathy-associated samples also had increased levels, but to a lesser extent than the ALS group. In the SOD1^G93A mouse, mRNA and protein levels were similarly elevated and showed progressive increases with clinical progression, beginning in the pre-symptomatic stage up to end-stage. Immunohistochemistry showed intense CYP27B1 staining of atrophied muscle fibers in both human and mouse ALS muscle.

Conclusions These data validate CYP27B1 as a muscle biomarker in ALS and indicate its potential as a marker of ALS disease progression. These findings also suggest a perturbation of vitamin D signaling in the denervated myofiber. Further characterization of this pathway may provide insight into underlying molecular processes linked to muscle denervation.

Authors/Disclosures
PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
Mohamed Kazamel, MD (UAB)	Dr. Kazamel has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alnylam Pharamceuticals. Dr. Kazamel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Akcea Therapeutics.
Ikjae Lee, MD (Columbia University)	Dr. Lee has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Regeneron. The institution of Dr. Lee has received research support from NIH. The institution of Dr. Lee has received research support from Spastic Paraplegia Foundation.
	No disclosure on file
Peter H. King, MD	The institution of Dr. King has received research support from Department of Veterans Affairs. The institution of Dr. King has received research support from NIH.

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