Oral l-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1

Garofalo, Kevin; Penno, Anke; Schmidt, Brian P.; Lee, Ho‐Joon; Frosch, Matthew P.; Eckardstein, Arnold von; Brown, Robert H.; Hornemann, Thorsten; Eichler, Florian

doi:10.1172/jci57549

Cited by 181 publications

(181 citation statements)

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“…Oral L-serine supplementation was demonstrated to efficiently suppress 1-deoxySL formation and is currently being tested as a treatment in HSAN1 (https://clinicaltrials.gov/ct2/show/ NCT01733407). The positive effects of lowering 1-deoxySLs on peripheral nerve function was demonstrated in transgenic HSAN1 mice and HSAN1 patients (11), as well as in a diabetic rat model (12). In all three instances, 1-deoxySL levels decreased while mechanical sensitivity and nerve function improved.…”

Section: The Downstream Metabolism Of 1-deoxyso Is Mediated By Cyp4f mentioning

confidence: 85%

“…The column was first equilibrated using a mixture of 50% mobile phase A and 50% mobile phase B, and then 25 l of sample was injected, which was neuropathic symptoms in a HSAN1 mouse model as well as in a diabetic rat model (11,12). In addition, 1-deoxySLs were shown to be elevated under Taxol treatment and might contribute to Taxol-induced peripheral neuropathy (13).…”

Section: Extraction and Analysis Of Sphingoid And Deoxysphingoid Basesmentioning

confidence: 99%

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Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Alecu¹,

Othman²,

Penno³

et al. 2017

Journal of Lipid Research

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This article is available online at http://www.jlr.org Sphingolipid (SL) de novo synthesis typically starts with the condensation of serine and palmitoyl-CoA, a reaction catalyzed by serine palmitoyltransferase (SPT) (1-3). SPT can also use alanine in certain conditions (4), which results in the formation of the atypical cytotoxic 1-deoxysphingolipids (1-deoxySLs). These lack the C1-hydroxyl group of regular SLs, which is essential for further metabolic steps and degradation (4, 5). As such, 1-deoxySLs are commonly believed to be "dead-end" metabolites that accumulate within cells, tissues, and body fluids.Pathologically elevated 1-deoxySLs have been found in a number of neurological and metabolic disorders. They are a hallmark of hereditary sensory autonomic neuropathy type 1 (HSAN1), a rare autosomal dominant inherited peripheral neuropathy that is caused by various mutations in SPT. Plasma 1-deoxySLs are also elevated in patients with nondiabetic metabolic syndrome (MetS) and T2D (6) and may contribute to the development of diabetic sensory polyneuropathy (DSN), which is clinically very similar to HSAN1 (7,8). Both conditions start in the lower extremities with a loss of sensation often accompanied by positive sensory symptoms such as hyperpathia and neuropathic pain, as well as the development of painless wounds leading to ulcers (9, 10). L-serine supplementation was shown to effectively lower 1-deoxySL levels while improving Abstract The 1-deoxysphingolipids (1-deoxySLs) are atypical sphingolipids (SLs) that are formed when serine palmitoyltransferase condenses palmitoyl-CoA with alanine instead of serine during SL synthesis. The 1-deoxySLs are toxic to neurons and pancreatic -cells. Pathologically elevated 1-deoxySLs cause the inherited neuropathy, hereditary sensory autonomic neuropathy type 1 (HSAN1), and are also found in T2D. Diabetic sensory polyneuropathy (DSN) and HSAN1 are clinically very similar, suggesting that 1-deoxySLs may be implicated in both pathologies. The 1-deoxySLs are considered to be dead-end metabolites, as they lack the C1-hydroxyl group, which is essential for the canonical degradation of SLs. Here, we report a previously unknown metabolic pathway, which is capable of degrading 1-deoxySLs. Using a variety of metabolic labeling approaches and high-resolution high-accuracy MS, we identified eight 1-deoxySL downstream metabolites, which appear to be formed by cytochrome P450 (CYP)4F enzymes. Comprehensive inhibition and induction of CYP4F enzymes blocked and stimulated, respectively, the formation of the downstream metabolites. Consequently, CYP4F enzymes might be novel therapeutic targets for the treatment of HSAN1 and DSN, as well as for the prevention of T2D. (I.A., A.O., T.H., and A.v.E.) Abbreviations: ATRA, all-trans retinoic acid; CYP, cytochrome P450; DB, double bond; 1-deoxySA, 1-deoxysphinganine; 1-deoxySAdiene, deoxysphingadiene; 1-deoxySA-OH, hydroxyl-deoxysphinganine; 1-deoxySA-2OH, dihydroxyl-deoxysphinganine; 1-deoxySL, 1-deoxysphingolipid; 1-deoxySO, 1-deoxysphingosi...

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Section: The Downstream Metabolism Of 1-deoxyso Is Mediated By Cyp4f mentioning

confidence: 85%

Section: Extraction and Analysis Of Sphingoid And Deoxysphingoid Basesmentioning

confidence: 99%

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Alecu¹,

Othman²,

Penno³

et al. 2017

Journal of Lipid Research

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“…Similarly, the patient found to have a SPTLC1 pathogenic mutation with intermediate nerve conduction slowing will need vigilant foot care to avoid mutilating ulcers, and can now consider participation in clinical trials using serine supplementation. 31 One concern among physicians is that large targeted panel sequencing will result in many variants of unclear significance (VUS). We only found 7 VUS in 93 cases (table 2), and some of these VUS may lead to new genetic discoveries with further research investigations.…”

Section: -28mentioning

confidence: 99%

Target-enrichment sequencing and copy number evaluation in inherited polyneuropathy

Wang

Dawson

et al. 2016

Neurology

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Objective: To assess the efficiency of target-enrichment next-generation sequencing (NGS) with copy number assessment in inherited neuropathy diagnosis.Methods: A 197 polyneuropathy gene panel was designed to assess for mutations in 93 patients with inherited or idiopathic neuropathy without known genetic cause. We applied our novel copy number variation algorithm on NGS data, and validated the identified copy number mutations using CytoScan (Affymetrix). Cost and efficacy of this targeted NGS approach was compared to earlier evaluations.Results: Average coverage depth was ;7603 (median 5 600, 99.4% . 1003). Among 93 patients, 18 mutations were identified in 17 cases (18%), including 3 copy number mutations: 2 PMP22 duplications and 1 MPZ duplication. The 2 patients with PMP22 duplication presented with bulbar and respiratory involvement and had absent extremity nerve conductions, leading to axonal diagnosis. Average onset age of these 17 patients was 25 years (2-61 years), vs 45 years for those without genetic discovery. Among those with onset age less than 40 years, the diagnostic yield of targeted NGS approach is high (27%) and cost savings is significant (;20%). However, the cost savings for patients with late onset age and without family history is not demonstrated. Conclusions:Incorporating copy number analysis in target-enrichment NGS approach improved the efficiency of mutation discovery for chronic, inherited, progressive length-dependent polyneuropathy diagnosis. The new technology is facilitating a simplified genetic diagnostic algorithm utilizing targeted NGS, clinical phenotypes, age at onset, and family history to improve diagnosis efficiency. Our findings prompt a need for updating the current practice parameters and payer guidelines. Neurology ® 2016;86:1762-1771 GLOSSARY CIAP 5 chronic idiopathic axonal polyneuropathy; CMT 5 Charcot-Marie-Tooth; CNV 5 copy number variation; DGV 5 Database of Genomic Variants; HMSN 5 hereditary motor and sensory polyneuropathy; MAF 5 minor allele frequency; NGS 5 next-generation sequencing; VUS 5 variants of unclear significance; WES 5 whole exome sequencing.Polyneuropathies are common, with overall prevalence of 1.7%, and 6.6% among persons over 60 years old.1 The high prevalence, multiple impairments, and complicated diagnostic procedures lead to high health care cost.1,2 Separating inherited from acquired causes is often difficult for insidious adult-onset cases, due to overlapping phenotypes.3,4 Furthermore, inherited and acquired polyneuropathies may coexist, resulting in worse severity. [5][6][7][8] One large prospective study indicated that as many as 42% of patients with previously undiagnosed polyneuropathy coming to tertiary care referral had familial occurrence. 9Pragmatic diagnostic strategies have long been sought to improve testing effectiveness and reduce costs in neuropathy diagnosis. [10][11][12] In Charcot-Marie-Tooth clinics, algorithms have been developed for selecting candidate genes.13 This approach is helpful for patients who have c...

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“…In this issue of the JCI, Garofalo et al extend their earlier findings indicating that deoxysphingolipids are toxic for cultured sensory neurons (14) by showing that oral supplementation of l-alanine exacerbated the neuropathy of C133W transgenic mice (16). Mice supplemented with l-alanine between 3 and 9 months of age had higher sensory thresholds than did untreated transgenic mice, and the unmyelinated and myelinated axons in the sciatic nerve tended to have smaller diameters (16).…”

Section: Toxic Lipids Cause Hsan1?mentioning

confidence: 89%

“…Mice supplemented with l-alanine between 3 and 9 months of age had higher sensory thresholds than did untreated transgenic mice, and the unmyelinated and myelinated axons in the sciatic nerve tended to have smaller diameters (16). It remains to be rigorously shown, however, that l-alanine exacerbates axonal loss (which should be age and length dependent).…”

Section: Toxic Lipids Cause Hsan1?mentioning

confidence: 99%

The debut of a rational treatment for an inherited neuropathy?

Scherer¹

2011

J. Clin. Invest.

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Hereditary neuropathies are common neurological conditions characterized by progressive loss of motor and/or sensory function. There are no effective treatments. Among the many causes of hereditary neuropathies are dominant mutations in serine palmitoyltransferase, long chain base subunit 1 (SPTLC1), which cause hereditary sensory and autonomic neuropathy type 1 (HSAN1). By incorporating l-alanine in place of l-serine, the mutant HSAN1-associated serine palmitoyltransferase generates deoxysphingolipids, which are thought to be neurotoxic. In this issue of the JCI, Garofalo and colleagues report that oral l-serine reverses the accumulation of deoxysphingolipids in humans with HSAN1 and in a transgenic mouse model. As oral l-serine reduces the severity of neuropathy in the mouse model of HSAN1, these data suggest a rational candidate therapy for this devastating condition.

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Oral l-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1

Cited by 181 publications

References 31 publications

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Target-enrichment sequencing and copy number evaluation in inherited polyneuropathy

The debut of a rational treatment for an inherited neuropathy?

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