Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1

Abstract

Objective: To evaluate the safety and efficacy of l-serine in humans with hereditary sensory autonomic neuropathy type I (HSAN1).

Methods: In this randomized, placebo-controlled, parallel-group trial with open-label extension, patients aged 18-70 years with symptomatic HSAN1 were randomized to l-serine (400 mg/kg/day) or placebo for 1 year. All participants received l-serine during the second year. The primary outcome measure was the Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNS). Secondary outcomes included plasma sphingolipid levels, epidermal nerve fiber density, electrophysiologic measurements, patient-reported measures, and adverse events.

Results: Between August 2013 and April 2014, we enrolled and randomized 18 participants, 16 of whom completed the study. After 1 year, the l-serine group experienced improvement in CMTNS relative to the placebo group (-1.5 units, 95% CI -2.8 to -0.1, p = 0.03), with evidence of continued improvement in the second year of treatment (-0.77, 95% CI -1.67 to 0.13, p = 0.09). Concomitantly, deoxysphinganine levels dropped in l-serine-treated but not placebo-treated participants (59% decrease vs 11% increase; p < 0.001). There were no serious adverse effects related to l-serine.

Conclusion: High-dose oral l-serine supplementation appears safe in patients with HSAN1 and is potentially effective at slowing disease progression.

Clinicaltrialsgov identifier: NCT01733407.

Classification of evidence: This study provides Class I evidence that high-dose oral l-serine supplementation significantly slows disease progression in patients with HSAN1.

Figure 1. Trial profile

Figure 2. Change in primary endpoints

Charcot-Marie-Tooth Neuropathy Score (CMTNS) and Charcot-Marie-Tooth Examination Score (CMTES) in patients taking l-serine vs placebo during the trial period. Baseline values were normalized to zero, and data represent the mean change from baseline. At week 48, patients on placebo crossed over to l-serine (red arrows). I bars indicate 95% confidence bounds.

Figure 3. Change in plasma sphingolipid levels

Change in plasma levels of canonical sphingolipids (A, B) and neurotoxic 1-deoxysphingolipids (C, D) over the course of the study. Baseline values were normalized to zero. Data represent the mean change from baseline. The correlation between the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and deoxysphingosine levels is plotted for baseline (E) and change at 48-week follow-up (F). I bars indicate 95% confidence bounds.

Figure 4. Change in epidermal nerve fiber density (ENFD)

Skin biopsies from the standard distal leg site (lower calf) were largely devoid of epidermal nerve fibers and demonstrated an increase in ENFD at 1 year (p = 0.014) (A). Skin biopsies from the upper thigh revealed no significant change in ENFD in participants taking placebo vs serine (B). Correlation between changes in ENFD in the lower calf and changes in plasma deoxysphingosine levels is shown in (C).