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

Molecular analysis of sequence variants in the Fcepsilon receptor I beta gene and IL-4 gene promoter in Italian atopic families

The genetic variants in the Fcepsilon receptor I beta gene (Glu237Gly) and the T allele of the (C590T) polymorphism of interleukin (IL)-4 gene promoter were reported to be associated with atopy. But the data of the studies in different populations are contrasting with one another

Helicobacter pylori infection and atopic diseases: Is there a relationship? A systematic review and meta-analysis

AIM: To review and conduct a meta-analysis of the existing literature on the relationship between Helicobacter pylori (H. pylori), atopy and allergic diseases. METHODS: Studies published in English assessing the prevalence of atopy and/or allergic diseases in patients with H. pylori infection and the prevalence of H. pylori infection in patients with atopy and/or allergic diseases were identified through a MEDLINE search (1950-2014). Random-effect model was used for the meta-analysis. RESULTS: Pooled results of case-control studies showed a significant inverse association of H. pylori infection with atopy/allergic disease or with exclusively atopy, but not with allergic disease, whereas pooled results of cross-sectional studies showed only a significant association between allergic disease and H. pylori infection. CONCLUSION: There is some evidence of an inverse association between atopy/allergic diseases and H. pylori infection, although further studied are needed

Molecular epidemiology of HIV-1 infection in immigrant population in northern Italy

Human immunodeficiency virus-1 (HIV-1) is characterised by a vast genetic diversity classified into distinct phylogenetic strains and recombinant forms. We describe the HIV-1 molecular epidemiology and evolution of 129 consecutive HIV-1 positive migrants living in Milan (northern Italy). Polymerase gene sequences of 116 HIV-1 subtype-B positive patients were aligned with HIV-1 reference sequences (https://www.ncbi.nlm.nih.gov/) by using MAFFT alignment and edited by using Bioedit software. A maximum likelihood (ML) phylogenetic tree was performed by MEGA7 and was visualised by using FigTree v1.4.3. Of 129 migrants, 35 were born in Europe (28 in Eastern Europe), 70 in the Americas (67 in South America), 15 in Africa and nine in Asia; 76.4% were men who have sex with men (MSM). The serotype HIV-1-B prevailed (89.9%), followed by -C, -F1, -D and -A. Compared with 116 HIV-B patients, the 13 with HIV-non-B showed lower Nadir of CD4+ cell/mmc (P = 0.043), more frequently had sub Saharan origin (38.5 vs. 1.72%, P = 0.0001) and less frequently were MSM (40 vs. 74.5%, P = 0.02). The ML phylogenetic tree of the 116 HIV-1 subtype-B positive patients showed 13 statistically supported nodes (bootstrap > 70%). Most of the sequences included in these nodes have been isolated from male patients from the Americas and the most common risk factor was MSM. The low number of HIV-1 non-B subtype patients did not allow to perform this analysis. These results suggest a shift of HIV-1 prevention projects' focus and a continuous monitoring of HIV-1 molecular epidemiology among entry populations. Prevention efforts based on HIV molecular epidemiology may improve public health surveillance setting

TM6SF2 E167K variant predicts severe liver fibrosis for human immunodeficiency/hepatitis C virus co-infected patients, and severe steatosis only for a non-3 hepatitis C virus genotype

AIM To evaluate the impact of the Glu167Lys (E167K) transmembrane 6 superfamily member 2 (TM6SF2) variant on the biochemical and morphologic expression of liver lesions in human immunodeficiency virus (HIV)/ hepatitis C virus (HCV) co-infected patients. METHODS The study comprised 167 consecutive patients with HIV/ HCV coinfection and biopsy-proven chronic hepatitis. A pathologist graded liver fibrosis and necroinflammation using the Ishak scoring system, and steatosis using Kleiner's scoring system. Patients were genotyped for TM6SF2 E167K (rs58542926) by real-time Polymerase chain reaction. The 167 patients, 35 therapy-naive and 132 receiving ART, were prevalently males (73.6%), the median age was 40.7 years and the immunological condition good (median CD4+ cells/mm3 = 505.5). RESULTS The 17 patients with the TM6SF2 E167K variant, compared with the 150 with TM6SF2-E/E, showed higher AST (P = 0.02) and alanine aminotransferase (P = 0.02) and higher fibrosis score (3.1 ± 2.0 vs 2.3 ± 1.5, P = 0.05). In a multivariate analysis, TM6SF2 E167K was independently associated with severe fibrosis. The same analysis showed that HCV-genotype 3, present in 42.2% of patients was an independent predictor of severe steatosis. The association of TM6SF2 E167K with severe steatosis, absent for the whole group of 167 patients, was re-evaluated separately for HCVgenotype 3 and non-3 patients: No factor was independently associated with severe steatosis in the HCV-genotype-3 subgroup, whereas an independent association was observed between severe steatosis and TM6SF2 E167K in non-3 HCV genotypes. No association between the TM6SF2 E167K variant and severe liver necroinflammation was observed. CONCLUSION In HIV/HCV coinfection the TM6SF2 E167K variant is an independent predictor of severe fibrosis, but appears to be independently associated with severe steatosis only for patients with a non-3 HCV genotype

Additional file 2: Table S1. of Associations of statins and antiretroviral drugs with the onset of type 2 diabetes among HIV-1-infected patients

Exposure to antiretroviral drugs during follow-up according to occurrence of type 2 diabetes. (DOCX 15 kb

Demographic, biochemical and histological characteristics of the 166 HIV/HCV coinfected patients according to necroinflammation (HAI score).

<p>Demographic, biochemical and histological characteristics of the 166 HIV/HCV coinfected patients according to necroinflammation (HAI score).</p

Logistic regression for HAI score ≥9 for the 166 HIV/HCV coinfected patients.

<p>Logistic regression for HAI score ≥9 for the 166 HIV/HCV coinfected patients.</p

Demographic, biochemical and histological characteristics of the 166 HIV/HCV coinfected patients according to the CB2 63 genotype variants.

<p>Demographic, biochemical and histological characteristics of the 166 HIV/HCV coinfected patients according to the CB2 63 genotype variants.</p