A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, DELAYED-START TRIAL TO EVALUATE THE SAFETY AND EFFICACY OF L-SERINE IN SUBJECTS WITH HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY TYPE 1 (HSAN1)
Vera Fridman1, Peter Novak2, William David3, Anne Louise Oaklander3, Eric Macklin3, Diane McKenna-Yasek2, Kailey Walsh3, Robert Brown2, Thorsten Hornemann4, Florian Eichler3 1University of Colorado Medical Center, Denver, US., 2University of Massachusetts Medical School, Worcester, US.,3 Massachusetts General Hospital (MGH), Boston, US., 4University Hospital Zurich, Clinical Chemistry, Zurich, Switzerland.
Introduction: Hereditary Sensory Autonomic Neuropathy Type 1 (HSAN1) is a severe, autosomal dominant, axonal neuropathy that manifests with marked, small fiber predominant sensory loss, variable degrees of limb weakness, and skin ulceration. HSAN1 is caused by mutations in the SPTLC1 and SPTLC2 genes, which encode two of the three subunits of the enzyme serine palmitoyltransferase (SPT). Mutations in SPT induce a permanent shift in the substrate preference from serine to alanine thereby forming a class of neurotoxic deoxysphingolipids (dSL). Supplementation with L-serine reduces dSL levels in transgenic HSAN1 mice and results in clinical improvement of neuropathy. We report a two-year, delayed-start, placebo-controlled clinical trial evaluating the safety and efficacy of oral L-serine (400 mg/kg/d) in human subjects with HSAN1.
Results: All but 2 subjects (both of whom were in the placebo group) completed the study. At 1 year, participants randomized to L-serine experienced a significant decline in CMTNSv2 (Charcot-Marie-Tooth Neuropathy Scale version 2) relative to placebo (-1.8 units, 95% CI -3.3 to -0.3, p = 0.02). Both groups experienced improvement in the second year of the study, and the difference in CMTNSv2 diminished. (-1.45 units, 95% CI -3.7 to 0.81, p=0.20). The three items that contributed most heavily to benefit from L-Serine supplementation at 48 weeks included sensory symptoms, arm strength and leg strength. dSL levels declined significantly among subjects on L-Serine vs. those on placebo after one year of treatment: 41% decrease in 1-deoxy-sphingosine vs. 9.2% increase on placebo (p=0.001); and 59% decrease in 1-deoxy-sphinganine vs. 11% increase on placebo, (p < 0.001). Skin biopsy in the majority of subjects showed no detectable nerve fibers in the distal calf. IENFD (intraepidermal nerve fiber density) findings in the thigh were highly variable and preliminary analysis did not show a significant difference between the two treatment groups. AFT (autonomic function testing) showed only minimal change over time with no significant difference between the two groups.
Conclusions: L-serine is a safe and potentially efficacious treatment option for patients with HSAN1. L-Serine supplementation suppresses dSL levels in subjects with HSAN1 to near normal levels. IENFD on skin biopsy does not reliably capture progression in HSAN1.
Excerpts from the Poster Presentation given at the American Neurological Association