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

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 \u3c 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

Optical Stimulation of Zebrafish Hair Cells Expressing Channelrhodopsin-2

<div><p>Vertebrate hair cells are responsible for the high fidelity encoding of mechanical stimuli into trains of action potentials (spikes) in afferent neurons. Here, we generated a transgenic zebrafish line expressing Channelrhodopsin-2 (ChR2) under the control of the hair-cell specific <i>myo6b</i> promoter, in order to examine the role of the mechanoelectrical transduction (MET) channel in sensory encoding in afferent neurons. We performed <i>in vivo</i> recordings from afferent neurons of the zebrafish lateral line while activating hair cells with either mechanical stimuli from a waterjet or optical stimuli from flashes of ∼470-nm light. Comparison of the patterns of encoded spikes during 100-ms stimuli revealed no difference in mean first spike latency between the two modes of activation. However, there was a significant increase in the variability of first spike latency during optical stimulation as well as an increase in the mean number of spikes per stimulus. Next, we compared encoding of spikes during hair-cell stimulation at 10, 20, and 40-Hz. Consistent with the increased variability of first spike latency, we saw a significant decrease in the vector strength of phase-locked spiking during optical stimulation. These <i>in vivo</i> results support a physiological role for the MET channel in the high fidelity of first spike latency seen during encoding of mechanical sensory stimuli. Finally, we examined whether remote activation of hair cells via ChR2 activation was sufficient to elicit escape responses in free-swimming larvae. In transgenic larvae, 100-ms flashes of ∼470-nm light resulted in escape responses that occurred concomitantly with field recordings indicating Mauthner cell activity. Altogether, the <i>myo6b</i>:ChR2 transgenic line provides a platform to investigate hair-cell function and sensory encoding, hair-cell sensory input to the Mauthner cell, and the ability to remotely evoke behavior in free-swimming zebrafish.</p></div

Mechanical stimulation is required for the temporal fidelity of phase-locked spiking.

<p>(<b>A</b>) <i>Top</i>: Phase-locked spiking for a mechanical 20-Hz stimulus. <i>Middle</i>: Phase-locked spiking for an optical 20-Hz stimulus. <i>Bottom</i>: 20-Hz stimulus protocol (scale bar 25 ms). Note that stimuli were 25-ms in length and delivered at a 20-Hz rate. (<b>B</b>) Polar plots from 60 sweeps of mechanical (upper) and optical (lower) stimulation. Plots constructed from all spikes elicited by 20-Hz stimulation of the cell shown in A. (<b>C</b>) The vector strength of phase-locked spiking for multiple cells recorded during 60 sweeps of 10, 20, and 40 Hz mechanical and optical stimulation. The bars represent the mean of the vector strength from all cells.</p

Comparison of spike encoding following mechanical and optical activation of hair cells.

<p>(<b>A</b>) Mechanical stimulation of neuromast hair cells with a waterjet and optical stimulation with ∼470-nm light produced similar patterns of spiking in the afferent neuron. Stimulus protocol is below the traces (scale bar 100 ms). (<b>B</b>) Plots of all spikes in response to 60 repeated sweeps for the cell recorded in A, using either a mechanical (upper) or optical (lower) 100-ms stimulus. Each successive spike is represented by circles of incrementing color: first spike of each sweep is dark blue, the second light blue, the third green, the fourth brown, with subsequent spikes fading from brown to white. (<b>C</b>) The mean number of spikes per sweep for cells (n = 9) recorded with both mechanical (black) and optical (grey) stimuli. The overall mean plus SEM across all recorded cells are represented by the bars. The cell labeled red in C, D, and E corresponds to the cell shown in A and B. (<b>D</b>) The mean first spike latency for all cells recorded with either mechanical or optical stimuli. Symbols and bars are as in C. (<b>E</b>) The coefficient of variation (C.V.) of the first spike latency for all cells recorded with both mechanical and optical stimuli. Symbols and bars are as in C and D.</p

The natural history of adrenal insufficiency in X-linked adrenoleukodystrophy: An international collaboration

Context: Primary adrenal insufficiency is an important clinical manifestation of X-linked adrenoleukodystrophy (ALD). Other manifestations include spinal cord disease and/or inflammatory demyelinating cerebral disease. Implementation of newborn screening requires natural history data to develop follow-up recommendations. Objective: To delineate the natural history of adrenal insufficiency in male patients with ALD and to assess associations between the risk for developing adrenal insufficiency, spinal cord disease, or cerebral disease and plasma C26:0/C22:0 and C24:0/C22:0 ratios, which are diagnostic biomarkers for ALD. Design: Retrospective review of medical records. Setting: Two international tertiary referral centers of expertise for ALD. Patients: Male patients with ALD followed at the centers between 2002 and 2016. Main Outcome Measures: The primary endpoint was adrenal insufficiency; secondary endpoints were spinal cord and cerebral disease. Results: Data on 159 male patients was available. The probability of developing adrenal insufficiency was described with survival analysis. Median time until adrenal insufficiency was 14 years (95% CI, 9.70 to 18.30 years). The cumulative proportion of patients who developed adrenal insufficiency was age-dependent and highest in early childhood [0 to 10 years, 46.8% (SEM 0.041%); 11 to 40 years, 28.6% (SEM, 0.037%); >40 years, 5.6% (SEM, 0.038%)]. No association between clinical manifestations and plasma ratios was detected with Cox model or Spearman correlation. Conclusions: Lifetime prevalence of adrenal insufficiency in male patients with ALD is ~80%. Adrenal insufficiency risk is time-dependent and warrants age-dependent follow-up. Besides ondemand testing if symptoms manifest, we suggest a minimum of adrenal testing every 4 to 6 months for patients age ≤10 years, annual testing for those age 11 to 40 years, and solely on-demand testing for those age >40 years