Sphingomyelin as a myelin biomarker in CSF of acquired demyelinating neuropathies

Fast, accurate and reliable methods to quantify the amount of myelin still lack, both in humans and experimental models. The overall objective of the present study was to demonstrate that sphingomyelin (SM) in the cerebrospinal fluid (CSF) of patients affected by demyelinating neuropathies is a myelin biomarker. We found that SM levels mirror both peripheral myelination during development and small myelin rearrangements in experimental models. As in acquired demyelinating peripheral neuropathies myelin breakdown occurs, SM amount in the CSF of these patients might detect the myelin loss. Indeed, quantification of SM in 262 neurological patients showed a significant increase in patients with peripheral demyelination (p\u2009=\u20093.81\u2009*\u200910\u2009-\u20098) compared to subjects affected by non-demyelinating disorders. Interestingly, SM alone was able to distinguish demyelinating from axonal neuropathies and differs from the principal CSF indexes, confirming the novelty of this potential CSF index. In conclusion, SM is a specific and sensitive biomarker to monitor myelin pathology in the CSF of peripheral neuropathies. Most importantly, SM assay is simple, fast, inexpensive, and promising to be used in clinical practice and drug development

The SPTLC1 p.S331 mutation bridges sensory neuropathy and motor neuron disease and has implications for treatment

Aims SPTLC1-related disorder is a late onset sensory-autonomic neuropathy associated with perturbed sphingolipid homeostasis which can be improved by supplementation with the serine palmitoyl-CoA transferase (SPT) substrate, l-serine. Recently, a juvenile form of motor neuron disease has been linked to SPTLC1 variants. Variants affecting the p.S331 residue of SPTLC1 cause a distinct phenotype, whose pathogenic basis has not been established. This study aims to define the neuropathological and biochemical consequences of the SPTLC1 p.S331 variant, and test response to l-serine in this specific genotype. Methods We report clinical and neurophysiological characterisation of two unrelated children carrying distinct p.S331 SPTLC1 variants. The neuropathology was investigated by analysis of sural nerve and skin innervation. To clarify the biochemical consequences of the p.S331 variant, we performed sphingolipidomic profiling of serum and skin fibroblasts. We also tested the effect of l-serine supplementation in skin fibroblasts of patients with p.S331 mutations. Results In both patients, we recognised an early onset phenotype with prevalent progressive motor neuron disease. Neuropathology showed severe damage to the sensory and autonomic systems. Sphingolipidomic analysis showed the coexistence of neurotoxic deoxy-sphingolipids with an excess of canonical products of the SPT enzyme. l-serine supplementation in patient fibroblasts reduced production of toxic 1-deoxysphingolipids but further increased the overproduction of sphingolipids. Conclusions Our findings suggest that p.S331 SPTLC1 variants lead to an overlap phenotype combining features of sensory and motor neuropathies, thus proposing a continuum in the spectrum of SPTLC1-related disorders. l-serine supplementation in these patients may be detrimental

Magnetic resonance imaging in the evaluation of the gastric emptying and antral motion: feasibility and reproducibility of a fast not invasive technique

PURPOSE:The aim of this study was to evaluate reproducibility of a fast MRI protocol to measure gastric emptying and motility of the gastric antrum. METHODS AND MATERIALS: Gastric emptying and antral speed were measured in 12 type 1 diabetic patients (mean age 43 years) and 9 healthy volunteers (mean age 31 years). Subjects, fasting from 6h, were evaluated in supine position using a 1.5T MR scanner and a eight-channels phased-array body coil after ingestion of 400 ml of a vanillas pudding mixed with 5 ml of Gd-DTPA. Axial 3D T1w sequence at 0 and 30 min for volume evaluation and cine-steady state acquisition every 5 min for a total time of 30 min for gastric wave speed assessing were acquired. Two blinded observers extrapolated T(1/2) from gastric volume assessment and speed of gastric waves. RESULTS: All the patients tolerated the examination. The T(1/2) cut-off was of 115 min with an accuracy in differentiate controls from diabetics of 96% (95% CI 0.766-0.992; p<0.001), while the antral speed cut-off was of 0.15 mm/s with an accuracy of 87% (95% CI 0.628-0.977; p<0.001). The inter-observer agreement for the volumes at time 0 and 30 min was respectively 0.983 (95% CI 0.9628-0.9929; p<0.001) and 0.9933 (95% CI 0.9847-0.9971; p<0.001) with an agreement of 0.9918 (95% CI 0.9853-0.9954; p<0.001), while for antral speed it was of 0.935 (95% CI 0.9097-0.9528; p<0.001). CONCLUSIONS: MRI is a reproducible technique for the evaluation of gastric emptying and antral motility. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved

Soluble Neuregulin1 is strongly up-regulated in the rat model of Charcot-Marie-Tooth 1A disease

Neuregulin1 (NRG1) is a growth factor playing a pivotal role in peripheral nerve development through the activation of the transmembrane co-receptors ErbB2-ErbB3. Soluble NRG1 isoforms, mainly secreted by Schwann cells, are strongly and transiently up-regulated after acute peripheral nerve injury, thus suggesting that they play a crucial role also in the response to nerve damage. Here we show that in the rat experimental model of the peripheral demyelinating neuropathy Charcot-Marie-Tooth 1A (CMT1A) the expression of the different NRG1 isoforms (soluble, type \u3b1 and \u3b2, type a and b) is strongly up-regulated, as well as the expression of NRG1 co-receptors ErbB2-ErbB3, thus showing that CMT1A nerves have a gene expression pattern highly reminiscent of injured nerves. Because it has been shown that high concentrations of soluble NRG1 negatively affect myelination, we suggest that soluble NRG1 over-expression might play a negative role in the pathogenesis of CMT1A disease, and that a therapeutic approach, aimed to interfere with NRG1 activity, might be beneficial for CMT1A patients. Further studies will be necessary to test this hypothesis in animal models and to evaluate NRG1 expression in human patients. Impact statement Charcot-Marie-Tooth1A (CMT1A) is one of the most frequent inherited neurological diseases, characterized by chronic demyelination of peripheral nerves, for which effective therapies are not yet available. It has been recently proposed that the treatment with soluble Neuregulin1 (NRG1), a growth factor released by Schwann cells immediately after acute nerve injury, might be effective in CMT1A treatment. However, the expression of the different isoforms of endogenous NRG1 in CMT1A nerves has not been yet investigated. In this preliminary study, we demonstrate that different isoforms of soluble NRG1 are strongly over-expressed in CMT1A nerves, thus suggesting that a therapeutic approach based on NRG1 treatment should be carefully reconsidered. If soluble NRG1 is over-expressed also in human CMT1A nerves, a therapeutic approach aimed to inhibit (instead of stimulate) the signal transduction pathways driven by NRG1 might be fruitfully developed. Further studies will be necessary to test these hypotheses