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A patient with mitochondrial disorder due to a novel mutation in MRPS22.

Metab Brain Dis. 2017 Oct;32(5):1389-1393

Authors: Kılıç M, Oğuz KK, Kılıç E, Yüksel D, Demirci H, Sağıroğlu MŞ, Yücel-Yılmaz D, Özgül RK

Abstract
MRPS22 gene defect is a very rare newly discovered mitochondrial disorder. We report a 4-month-old severely affected male infant with MRPS22 mutation. Whole exome sequencing revealed a novel homozygous splicing mutation c.339 + 5 G > A in MRPS22 gene. He has mild dysmorphism, hypotonia, developmental delay but not hypertrophic cardiomyopathy and tubulopathy which differ from other majority of reported patients. Therefore, hypertrophic cardiomyopathy and tubulopathy may not be considered as constant features of MRPS22. With this case report, we also present first symmetrical bilateral brainstem and medial thalamic lesions, and cerebellar and cerebral atrophy on a brain MR imaging follow-up of ten months.

PMID: 28752220 [PubMed - indexed for MEDLINE]

Funding Opportunity PAR-18-866 from the NIH Guide for Grants and Contracts. The NIAMS Research Innovation for Scientific Knowledge (RISK) for Skin and Rheumatic Diseases initiative focuses on innovative research within the NIAMS mission by encouraging applicants to pursue unusual observations, test imaginative hypotheses, investigate creative concepts, and build ground-breaking paradigms, all of which deviate significantly from the current prevailing theories or practice. This FOA is particularly designed to encourage the submission of projects that are considered too risky, premature, controversial, or unconventional for other NIH mechanisms. This FOA intends to support disease-focused translational studies. We invite research studies aimed at understanding the mechanisms of diseases or conditions relevant to the NIAMS mission, as well as studies aimed at developing or testing diagnostics, therapeutic agents, or preventive interventions up to, but not including, first in human studies. The RISK R61/R33 FOAs are not intended to support clinical trials.

Funding Opportunity RFA-AR-19-012 from the NIH Guide for Grants and Contracts. The NIAMS Research Innovation for Scientific Knowledge (RISK) for Skin and Rheumatic Diseases (R61/R33) initiative focuses on innovative research within the NIAMS mission by encouraging applicants to pursue unusual observations, test imaginative hypotheses, investigate creative concepts, and build ground-breaking paradigms, all of which deviate significantly from the current prevailing theories or practice. This FOA is particularly designed to encourage the submission of projects that are considered too risky, premature, controversial, or unconventional for other NIH mechanisms. This FOA intends to support disease-focused translational studies. We invite research studies aimed at understanding the mechanisms of diseases or conditions relevant to the NIAMS mission, as well as studies aimed at developing or testing diagnostics, therapeutic agents, or preventive interventions up to, but not including, first in human studies. The RISK R61/R33 FOAs are not intended to support clinical trials.

Funding Opportunity PA-18-867 from the NIH Guide for Grants and Contracts. Genome-wide association studies and other disease studies have identified many variants that are statistically associated with disease risk, disease protection, or other traits. However, such studies do not generally show which specific variants in genomic elements cause these effects, or how they result in differences in function. Similarly, genomic sequencing studies in clinical settings have identified many variants in healthy and diseased individuals. However, the pathogenicity of such variants is often unknown, leading to their classification as variants of uncertain significance (VUS), which makes clinical implementation difficult. This Program Announcement and the companion R21 Program Announcement aim to support the development of novel and generalizable approaches to study how genetic variants lead to differences in function and to study how such functional differences affect human health and disease processes or how this knowledge can be used clinically.

Funding Opportunity PA-18-868 from the NIH Guide for Grants and Contracts. Genome-wide association studies have found many variants associated with disease risk, disease protection, or other traits. However, these studies generally identify many variants that are statistically associated with the trait, but do not show which variants in genomic elements cause these effects, or how they result in differences in function. Similarly, clinical genomic sequencing studies have identified many variants in healthy and diseased individuals, but the pathogenicity of such variants is usually unknown, leading to their classification as variants of uncertain significance (VUSs), which makes clinical implementation difficult. This program aims to support the development of generalizable approaches to study how genetic variants lead to differences in function, how such functional differences lead to disease processes, and how this knowledge can be used clinically.

Notice NOT-NR-18-013 from the NIH Guide for Grants and Contracts

Notice NOT-NR-18-014 from the NIH Guide for Grants and Contracts

Notice NOT-NR-18-015 from the NIH Guide for Grants and Contracts

Notice NOT-CA-18-095 from the NIH Guide for Grants and Contracts

Notice NOT-MH-18-037 from the NIH Guide for Grants and Contracts

Notice NOT-MH-18-038 from the NIH Guide for Grants and Contracts

Notice NOT-GM-18-039 from the NIH Guide for Grants and Contracts

Notice NOT-HL-18-639 from the NIH Guide for Grants and Contracts

Notice NOT-NS-18-075 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-RM-18-030 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to establish one or two centers that can rapidly generate high quality whole genome sequence and variant data from a large number of human specimens representing two types of pediatric conditions - childhood cancers and structural birth defects. All sequence data generated under this FOA will be re-processed and harmonized by the Gabriella Miller Kids First Pediatric Data Resource Center (Kids First DRC), which is also charged with building a public-facing, web-based portal that will allow researchers to search, access, aggregate, analyze, and share annotated genomic sequence, variant, and phenotypic datasets. Together these resources will promote comprehensive and cross-cutting research and collaboration within the pediatric research community.

Notice NOT-AG-18-023 from the NIH Guide for Grants and Contracts

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Orbitofrontal pseudotumour in young adult.

J Stomatol Oral Maxillofac Surg. 2018 Jul 19;:

Authors: Kulker D, Queiros C, Kun-Darbois JD, François P, Goga D, Paré A

Abstract
INTRODUCTION: Langerhans Cell Histiocytosis is an orphan disease of clonal dendritic cells that affect the facial skeleton in majority of cases. Actual management for unique and small lesion with easy access is surgical resection. Biggest lesion, with surgical risk is treated by association of vinblastine and corticotherapy. There is no case reported of corticotherapy as neoadjuvant treatment before the surgery for Langerhans Cell disease.
OBSERVATION: In this case, a man age of 18 presented a unifocal frontal bone injury, occasioning pain and skin inflammation in front of orbital lateral superior wall. The CT scan showed an important inflammation of soft tissues, and a heterogeneous osteolysis of the right frontal bone in contact with dura mater. A short corticotherapy was administered followed by a surgical curettage, with parietal bone graft reconstruction. During surgery, soft tissue inflammation wasn't found, and dura matter wasn't invaded. Histological examination confirmed the diagnostic of Histiocytosis. The treatment allowed symptoms resolve.
CONCLUSION: This case shows that corticotherapy doesn't negative histological examination in Langerhans Cell Histiocytosis and could facilitate its dissection and resection.

PMID: 30031893 [PubMed - as supplied by publisher]

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5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination.

Mol Genet Metab. 2018 Jun 15;:

Authors: Rodan LH, Qi W, Ducker GS, Demirbas D, Laine R, Yang E, Walker MA, Eichler F, Rabinowitz JD, Anselm I, Berry GT, Undiagnosed Diseases Network (UDN)

Abstract
Folate metabolism in the brain is critically important and serves a number of vital roles in nucleotide synthesis, single carbon metabolism/methylation, amino acid metabolism, and mitochondrial translation. Genetic defects in almost every enzyme of folate metabolism have been reported to date, and most have neurological sequelae. We report 2 patients presenting with a neurometabolic disorder associated with biallelic variants in the MTHFS gene, encoding 5,10-methenyltetrahydrofolate synthetase. Both patients presented with microcephaly, short stature, severe global developmental delay, progressive spasticity, epilepsy, and cerebral hypomyelination. Baseline CSF 5-methyltetrahydrolate (5-MTHF) levels were in the low-normal range. The first patient was treated with folinic acid, which resulted in worsening cerebral folate deficiency. Treatment in this patient with a combination of oral L-5-methyltetrahydrofolate and intramuscular methylcobalamin was able to increase CSF 5-MTHF levels, was well tolerated over a 4 month period, and resulted in subjective mild improvements in functioning. Measurement of MTHFS enzyme activity in fibroblasts confirmed reduced activity. The direct substrate of the MTHFS reaction, 5-formyl-THF, was elevated 30-fold in patient fibroblasts compared to control, supporting the hypothesis that the pathophysiology of this disorder is a manifestation of toxicity from this metabolite.

PMID: 30031689 [PubMed - as supplied by publisher]

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Metformin protects bone mass in ultra-high-molecular-weight polyethylene particle-induced osteolysis by regulating osteocyte secretion.

J Bone Miner Metab. 2018 Jul 21;:

Authors: Yan Z, Zhu S, Tian X, Ye Z, Zhai D, Zhu Z, Wei D, Zhu Q, Lu Z, Cao X

Abstract
Metformin, an anti-hyperglycemic agent used for type 2 diabetes, has recently been found to have more effects apart from glucose regulation. We found that, in ultra-high-molecular-weight polyethylene particle-induced osteolysis mouse models, metformin had bone protect property and reduced the negative regulator of bone formation sclerostin (SOST) and Dickkopf-related protein 1 (DKK1), and increased osteoprotegerin (OPG) secretion and the ratio of OPG/Receptor Activator for Nuclear Factor-κB Ligand (RANKL). In vitro, we established a 3D co-culture system in which metformin affects osteoblasts and osteoclasts through mature osteocytes secretion. Metformin (50 μM) significantly decreased SOST and DKK1 mRNA expression, stimulating alkaline phosphatase activity and proliferation of osteoblast, and increased OPG secretion and the ratio of OPG/RANKL, inhibiting osteoclastogenesis. Moreover, the effect on OPG was reversed by adenosine 5'-monophosphate-activated protein kinase inhibitor, Compound C. Our finding suggests that metformin induces differentiation and mineralization of osteoblasts, while inhibits osteoclastogenesis via mature osteocytes secretion. Therefore, the drug might be beneficial for not only diabetes but also in other bone disorders by acting on mature osteocytes.

PMID: 30032440 [PubMed - as supplied by publisher]

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Variation within voltage-gated calcium channel genes and antipsychotic treatment response in a South African first episode schizophrenia cohort.

Pharmacogenomics J. 2018 Jul 22;:

Authors: O'Connell KS, McGregor NW, Malhotra A, Lencz T, Emsley R, Warnich L

Abstract
Voltage-gated calcium channels have been implicated in schizophrenia aetiology; however, little is known about their involvement in antipsychotic treatment response. This study investigated variants within the calcium channel subunit genes for association with antipsychotic treatment response in a first episode schizophrenia cohort. Twelve regulatory variants within seven genes were shown to be significantly associated with treatment outcome. Most notably, the CACNA1B rs2229949 CC genotype was associated with improved negative symptomology, where the C allele was predicted to abolish a miRNA-binding site (has-mir-5002-3p), suggesting a possible mechanism of action through which this variant may have an effect. These results implicate the calcium channel subunits in antipsychotic treatment response and suggest that increased activation of these channels may be explored to enhance or predict antipsychotic treatment outcome.

PMID: 30032160 [PubMed - as supplied by publisher]