Long-term effects of l-serine supplementation upon a mouse model of diabetic neuropathy.

Deoxysphingolipids (1-deoxySLs) are neurotoxic sphingolipids associated with obesity and diabetic neuropathy (DN) and have been linked to severity of functional peripheral neuropathies. While l-serine supplementation can reduce 1-deoxySL accumulation and improve insulin sensitivity and sensory nerve velocity, long-term outcomes have not yet been examined. To assess this, we treated 2 month old db/db mice, a model of DN, with 5-20 % oral l-serine for 6 months and longitudinally quantified the extent of functional neuropathy progression.

Development of MRC Centre MRI calf muscle fat fraction protocol as a sensitive outcome measure in Hereditary Sensory Neuropathy Type 1.

Objectives: Hereditary sensory neuropathy type 1 (HSN1) is a rare, slowly progressive neuropathy causing profound sensory deficits and often severe motor loss. L-serine supplementation is a possible candidate therapy but the lack of responsive outcome measures is a barrier for undertaking clinical trials in HSN1. We performed a 12-month natural history study to characterise the phenotype of HSN1 and to identify responsive outcome measures.

A Novel Variant (Asn177Asp) in SPTLC2 Causing Hereditary Sensory Autonomic Neuropathy Type 1C.

Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is a rare, autosomal dominantly inherited, slowly progressive and length-dependent axonal peripheral neuropathy. HSAN1 is associated with several mutations in serine-palmitoyltransferase (SPT), the first enzyme in the de novo sphingolipid biosynthetic pathway. HSAN1 mutations alter the substrate specificity of SPT, which leads to the formation of 1-deoxysphingolipids, an atypical and neurotoxic subclass of sphingolipids.

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.

DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans.

Background: Sphingolipids are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling, and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids leads to various neurological pathologies; however, the entire spectrum of sphingolipid metabolism disorders remains elusive.

Methods: A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder.

Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C.

Hereditary sensory neuropathy type 1 (HSAN1) may be the first genetic neuropathy amenable to a specific mechanism-based treatment, as L-serine supplementation can be used to lower the neurotoxic levels of 1-deoxysphingolipids (1-deoxySL) that cause the neurodegeneration. The treatment is so far untested in HSAN1C caused by variants in the serine palmitoyl transferase subunit 2 () gene. The aim of this study was to establish whether oral L-serine lowers 1-deoxySL in a patient with HSAN1C, to perform a dose escalation to find the minimal effective dose, and to assess the safety profile and global metabolic effects of the treatment.

Frequent genes in rare diseases: panel-based next generation sequencing to disclose causal mutations in hereditary neuropathies.

Hereditary neuropathies comprise a wide variety of chronic diseases associated to more than 80 genes identified to date. We herein examined 612 index patients with either a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generation sequencing technique. In 121 cases (19.

1-Deoxysphingolipid-induced neurotoxicity involves N-methyl-d-aspartate receptor signaling.

1-Deoxysphingolipids (1-deoxySL) are atypical and neurotoxic sphingolipids formed by alternate substrate usage of the enzyme serine-palmitoyltransferase. Pathologically increased 1-deoxySL formation causes hereditary sensory and autosomal neuropathy type 1 (HSAN1) - a progressive peripheral axonopathy. However, the underlying molecular mechanisms by which 1-deoxySL acts are unknown.

The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory Neuropathy.

Hereditary sensory and autonomic neuropathy 1 (HSAN1) is an autosomal dominant disorder that can be caused by variants in SPTLC1 or SPTLC2, encoding subunits of serine palmitoyl-CoA transferase. Disease variants alter the enzyme's substrate specificity and lead to accumulation of neurotoxic 1-deoxysphingolipids. We describe two families with autosomal dominant HSAN1C caused by a new variant in SPTLC2, c.

Influence of self-assembling peptide nanofibre scaffolds on retinal differentiation potential of stem/progenitor cells derived from ciliary pigment epithelial cells.

Aim of the study was to investigate the influence of the self-assembling peptide nanofibre scaffolds (SAPNs) on the growth, proliferation and retinal neuronal differentiation of the stem/progenitor cells (SCs) derived from the ciliary pigment epithelium (CPE) of human cadaveric eye. Here SAPNs (RADA16-I, PM), which is well described in previous studies, commercially available and xeno-free. The CPE cells isolated were cultured in DMEM/F12 supplemented with N2 and growth factors such as basic fibroblast growth factor and epidermal growth factor, encapsulated in the scaffolds.