Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously. METHODS Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in SPTLC1 encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT are known to cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), we examined 10 additional persons with HSAN1 for ophthalmologic disease. We assayed serum amino acid and sphingoid base levels, including levels of deoxysphingolipids, in patients who had macular telangiectasia type 2 but did not have HSAN1 or pathogenic variants affecting SPT. We characterized mice with low serine levels and tested the effects of deoxysphingolipids on human retinal organoids. RESULTS Two variants known to cause HSAN1 were identified as causal for macular telangiectasia type 2: of 11 patients with HSAN1, 9 also had macular telangiectasia type 2. Circulating deoxysphingolipid levels were 84.2% higher among 125 patients with macular telangiectasia type 2 who did not have pathogenic variants affecting SPT than among 94 unaffected controls. Deoxysphingolipid levels were negatively correlated with serine levels, which were 20.6% lower than among controls. Reduction of serine levels in mice led to increases in levels of retinal deoxysphingolipids and compromised visual function. Deoxysphingolipids caused photoreceptor-cell death in retinal organoids, but not in the presence of regulators of lipid metabolism. CONCLUSIONS Elevated levels of atypical deoxysphingolipids, caused by variant SPTLC1 or SPTLC2 or by low serine levels, were risk factors for macular telangiectasia type 2, as well as for peripheral neuropathy.

Idiopathic juxtafoveal retinal telangiectasis type 2 (macular telangiectasia type 2; MacTel) is a rare neurovascular degenerative retinal disease. To identify genetic susceptibility loci for MacTel, we performed a genomewide association study (GWAS) with 476 cases and 1733 controls of European ancestry. Genome-wide significant associations (P < 5 × 10 -8 ) were identified at 3 independent loci (rs73171800 at 5q14.3, P = 7.74 × 10 -17 ; rs715 at 2q34, P = 9.97 × 10 -14 ; rs477992 at 1p12, P = 2.60 × 10 -12 ) and then replicated (P < 0.01) in an independent cohort of 172 cases and 1134 controls. The 5q14.3 locus is known to associate with variation in retinal vascular diameter, and the 2q34 and 1p12 loci have been implicated in the glycine/serine metabolic pathway. We subsequently found significant differences of blood serum levels of glycine (P = 4.04 × 10 -6 ) and serine (P = 2.48 × 10 -4 ) between MacTel cases and controls.MacTel cases typically present at 40-60 years with abnormal right-angled juxtafoveolar capillaries and parafoveal telangiectasias. It is an uncommon disease with a 0.0045-0.1% population prevalence and no obvious sex bias [1][2][3] . Retinal lesions typically co-present with MacTel, including retinal transparency, outer retinal and choroidal neovascularization, lamellar holes or foveal cysts, photoreceptor dysfunction, minimal exudation, yellow-white parafoveal crystals, and retinal pigment epithelial (RPE) pigmentation abnormalities and atrophy. Central vision impairment and decreased visual acuity are the usual clinical outcomes. MacTel is a bilateral disease, but asymmetry of the eyes for disease severity and presence of lesions is possible. The lesions also occur in 0.06-1.18% of the general population 2 .Risk factors for MacTel are largely unknown, however associations have been observed with smoking 2,4 , diabetes 5,6 , high BMI 6 , hypertension 6 and obesity 6 .Observations of MacTel affected monozygotic twins 4,[7][8][9] , and multiplex families with vertical transmissions of MacTel 1,5,[9][10][11][12] , suggest a genetic etiology for the disease. The late-age of onset, low penetrance and variable phenotype as exemplified by asymptomatic affected relatives 9 , and positive and negative misdiagnoses, complicate the discovery of genetic variants predisposing to MacTel. We previously screened 27 candidate genes in 8 unrelated MacTel cases but found no causative mutations 13 . Linkage analysis of 17 families with MacTel individuals identified a 15.3Mb locus on chromosome 1q41-42.2 (LOD=3.45), however sequencing of the underlying genes revealed no causative mutations 14 . Results Discovery GWAS stageThe GWAS discovery stage included genotype data for 6,312,048 single nucleotide polymorphisms (SNPs) after quality control and imputation (including 1,093,805 SNPs genotyped on the Illumina Omni SNP chips) in 476 MacTel cases and 1,733 controls (see Table 1 and Online Methods). This sample size was large enough to achieve power of at least 0.90 for risk variants with allele frequencies of 0.10-...

Our data suggest that six is the maximum number of IH episodes that the retina can sustain. Accumulation of H₂O₂ in the choroid may result in high levels being delivered to the entire retina, ultimately resulting in irreversible retinal oxidative damage.

Macular telangiectasia type 2 (MacTel) is a progressive, late-onset retinal degenerative disease linked to decreased serum levels of serine that elevate circulating levels of a toxic ceramide species, deoxysphingolipids (deoxySLs); however, causal genetic variants that reduce serine levels in patients have not been identified. Here, we identify rare, functional variants in the gene encoding the rate-limiting serine biosynthetic enzyme, phosphoglycerate dehydrogenase (PHGDH), as the single locus accounting for a significant fraction of MacTel. Under a dominant collapsing analysis model of a genome-wide enrichment analysis of rare variants predicted to impact protein function in 793 MacTel cases and 17,610 matched controls, the PHGDH gene achieves genome-wide significance (p=1.2×10 −13 ) with variants explaining ~3.2% of the affected

Background:Caffeine or ketorolac decrease the risk of retinopathy of prematurity and may act synergistically to improve beneficial effect. Combination of caffeine (Caff) and ketorolac (Keto) to prevent oxygen-induced retinopathy was studied.Methods:Newborn rats exposed to room air (RA) or intermittent hypoxia (IH) consisting of 12% O2 during hyperoxia (50% O2) from birth (P0) had single daily IP injections of Caff from P0-P13 or saline; and/or ocular Keto (Acuvail, 0.45% ophthalmic solution) administered subcutaneously over the eyes from P5-P7. Pups were studied at P14 or placed in RA for recovery from IH (IHR) until P21. Eyes were examined for neovascularization, histopathology, growth factors, and VEGF-signaling genes.Results:Severe retinal damage noted during IHR in the untreated groups evidenced by hemorrhage, neovascularization, and oxygen-induced retinopathy (OIR) pathologies were prevented with Keto/Caff treatment. Keto and/or Caff treatment in IH also promoted retinal neural development evidenced by eye opening (92%, P < 0.001 vs. 31% in the placebo-treated IH group). No corneal pathologies were noted with Keto.Conclusion.Caff or Keto given individually reduced retinal neovascularization, but the two drugs given together prevented severe OIR.

Necrotizing enterocolitis (NEC) afflicts extremely low birth weight neonates, and probiotics reduces its incidence and severity. NO is involved in the pathogenesis of NEC, and caveolin-1 regulates NO signaling. We tested the hypothesis that intestinal caveolin-1 and NOS are deficient in formula-fed neonatal rats and that supplementation with "Florastar Kids" and/or galactooligosaccharides and fructo-oligosaccharides preserves caveolin-1 and NOS. At birth (P0), neonatal rat pups were maternally fed or hand-gavaged with or without supplemented formula. Samples from the terminal ileum were analyzed for total NO metabolites, growth factors, and gene expression of caveolin-1, NOS isoforms, and antioxidants. Our data showed that formula feeding with and without supplementation resulted in significant growth restriction. Despite suboptimal nutrition, growth factors involved in intestinal repair and regeneration were increased in the neonatal rat ileum. Caveolin-1, endothelial NOS, and neuronal NOS were simultaneously downregulated with formula feeding while inducible NOS was upregulated. Superoxide dismutase and glutathione peroxidase were up-regulated with supplementation. These data provide a probable mechanism for the benefits of supplemented formula for decreasing the severity of NEC by preserving the antioxidant systems. (Pediatr Res 67: 526-531, 2010)

Autosomal recessive Stargardt disease (STGD1) is caused by hundreds of mutations in the ABCA4 gene, which are often specific to racial and ethnic groups. Here, we investigated the ABCA4 variation and their phenotypic expression in a cohort of 44 patients of African American descent, a previously under-characterized racial group. Patients were screened for mutations in ABCA4 by next-generation sequencing and array-comparative genomic hybridization (aCGH), followed by analyses for pathogenicity by in silico programs. Thorough ophthalmic examination was performed on all patients. At least two (expected) disease-causing alleles in the ABCA4 gene were identified in 27 (61.4%) patients, one allele in 11 (25%) patients, and no ABCA4 mutations were found in six (13.6%) patients. Altogether, 39 different disease-causing ABCA4 variants, including seven new, were identified on 65 (74%) chromosomes, most of which were unique for this racial group. The most frequent ABCA4 mutation in this cohort was c.6320G>A (p.(R2107H)), representing 19.3% of all disease-associated alleles. No large copy number variants were identified in any patient. Most patients reported later onset of symptoms. In summary, the ABCA4 mutation spectrum in patients of West African descent differs significantly from that in patients of European descent, resulting in a later onset and “milder” disease.

The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49–8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9–8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1–7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.