Notice NOT-MH-18-034 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-HL-19-024 from the NIH Guide for Grants and Contracts. The NIH Research Education Program (R25) supports research education activities in the mission areas of the NIH. The over-arching goal of this NHLBI R25 program is to support educational activities that enhance the diversity of the biomedical, behavioral and clinical research workforce in the mission areas of importance to NHLBI. To accomplish the stated over-arching goal, this FOA will support creative educational activities with a primary focus on Research Experiences

Funding Opportunity RFA-DK-18-006 from the NIH Guide for Grants and Contracts. The NIH Research Education Program (R25) supports research education activities in the mission areas of the NIH. The over-arching goal of this NIDDK R25 program is to support educational activities that help recruit individuals with specific specialty or disciplinary backgrounds to research careers in biomedical, behavioral and clinical sciences. To accomplish the stated over-arching goal, this FOA will support creative educational activities with a primary focus on Research Experiences. This FOA solicits applications to establish summer research institutes for qualified undergraduates to participate in summer research experiences relevant to the mission of the Division of Kidney, Urologic and Hematologic Diseases/NIDDK (NIDDK/DKUH).

Notice NOT-OD-18-171 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-18-767 from the NIH Guide for Grants and Contracts. Partnerships to Advance Cancer Health Equity (CPACHE) Program. The CPACHE Program develops and maintains comprehensive, long-term, and mutually beneficial partnerships between institutions serving underserved health disparity population and underrepresented students (ISUPSs) and NCI-designated Cancer Centers (CCs). The program aims to achieve a stronger national cancer program and address challenges in cancer and cancer disparities research, education and outreach, as well as their impact on underserved populations. The institutions in each partnership are expected to work collaboratively to: 1) increase the cancer research and cancer research education capacity of the ISUPSs; 2) increase the number of students and investigators from underrepresented populations engaged in cancer research; 3) improve the effectiveness of CCs in developing and sustaining research programs focused on cancer health disparities and increase the number of investigators and students conducting cancer health disparities research; and 4) develop and implement cancer-related activities that benefit the surrounding underserved communities.

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Atypical presentations associated with non-polyalanine repeat PHOX2B mutations.

Am J Med Genet A. 2018 Apr 28;:

Authors: Katwa U, D'Gama AM, Qualls AE, Donovan LM, Heffernan J, Shi J, Agrawal PB

Abstract
Congenital central hypoventilation syndrome (CCHS) is a disorder of ventilatory control and autonomic dysregulation that can be caused by mutations in the paired-like homeobox 2B (PHOX2B) gene. The majority of CCHS cases are caused by polyalanine repeat mutations (PARMs) in PHOX2B; however, in rare cases, non-polyalanine repeat mutations (NPARMs) have been identified. Here, we report two patients with NPARMs in PHOX2B. Patient 1 has a mild CCHS phenotype seen only on polysomnogram, which was performed for desaturations and stridor following a bronchiolitis episode, and characterized by night-time hypoventilation and a history of ganglioneuroblastoma. She carried a novel de novo missense variant, p.R102S (c.304C > A), in exon 2. Patient 2 has an atypical CCHS phenotype including micrognathia, gastroesophageal reflux, stridor, hypopnea, and intermittent desaturations. Sleep study demonstrated that Patient 2 had daytime and night-time hypercarbia with obstructive sleep apnea, requiring tracheostomy. On PHOX2B sequencing, she carried a recently identified nonsense variant, p.Y78* (c.234C > G), in exon 1. In summary, we present two patients with CCHS and identified NPARMs in PHOX2B who have distinct differences in phenotype severity, further elucidating the range of clinical outcomes in CCHS and illustrating the necessity of considering PHOX2B mutations when encountering atypical CCHS presentations.

PMID: 29704303 [PubMed - as supplied by publisher]

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Receptor/gene/protein-mediated signaling connects methylprednisolone exposure to metabolic and immune-related pharmacodynamic actions in liver.

J Pharmacokinet Pharmacodyn. 2018 Apr 27;:

Authors: Ayyar VS, Sukumaran S, DuBois DC, Almon RR, Qu J, Jusko WJ

Abstract
A multiscale pharmacodynamic model was developed to characterize the receptor-mediated, transcriptomic, and proteomic determinants of corticosteroid (CS) effects on clinically relevant hepatic processes following a single dose of methylprednisolone (MPL) given to adrenalectomized (ADX) rats. The enhancement of tyrosine aminotransferase (TAT) mRNA, protein, and enzyme activity were simultaneously described. Mechanisms related to the effects of MPL on glucose homeostasis, including the regulation of CCAAT-enhancer binding protein-beta (C/EBPβ) and phosphoenolpyruvate carboxykinase (PEPCK) as well as insulin dynamics were evaluated. The MPL-induced suppression of circulating lymphocytes was modeled by coupling its effect on cell trafficking with pharmacogenomic effects on cell apoptosis via the hepatic (STAT3-regulated) acute phase response. Transcriptomic and proteomic time-course profiles measured in steroid-treated rat liver were utilized to model the dynamics of mechanistically relevant gene products, which were linked to associated systemic end-points. While time-courses of TAT mRNA, protein, and activity were well described by transcription-mediated changes, additional post-transcriptional processes were included to explain the lack of correlation between PEPCK mRNA and protein. The immune response model quantitatively discerned the relative roles of cell trafficking versus gene-mediated lymphocyte apoptosis by MPL. This systems pharmacodynamic model provides insights into the contributions of selected molecular events occurring in liver and explores mechanistic hypotheses for the multi-factorial control of clinically relevant pharmacodynamic outcomes.

PMID: 29704219 [PubMed - as supplied by publisher]

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A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes.

Diabetes. 2018 Apr 27;:

Authors: van Zuydam NR, Ahlqvist E, Sandholm N, Deshmukh H, Rayner NW, Abdalla M, Ladenvall C, Ziemek D, Fauman E, Robertson NR, McKeigue PM, Valo E, Forsblom C, Harjutsalo V, FINNDIANE Study centres, Perna A, Rurali E, Marcovecchio ML, Igo RP, Salem RM, Perico N, Lajer M, Käräjämäki A, Imamura M, Kubo M, Takahashi A, Sim X, Liu J, van Dam RM, Jiang G, Tam CHT, Luk AOY, Lee HM, Lim CKP, Szeto CC, So WY, Chan JCN, Hong Kong Diabetes Registry TRS Project Group, Ang SF, Dorajoo R, Wang L, Hua Clara TS, McKnight AJ, Duffy S, Warren 3/UK GoKinD Study Group, Pezzolesi MG, Consortium G, Marre M, Gyorgy B, Hadjadj S, Hiraki LT, DCCT/EDIC group, Ahluwalia TS, Almgren P, Schulz CA, Orho-Melander M, Linneberg A, Christensen C, Witte DR, Grarup N, Brandslund I, Melander O, Paterson AD, Tregouet D, Maxwell AP, Lim SC, Ma RCW, Tai ES, Maeda S, Lyssenko V, Tuomi T, Krolewski AS, Rich SS, Hirschhorn JN, Florez JC, Dunger D, Pedersen O, Hansen T, Rossing P, Remuzzi G, SUMMIT Consortium, Brosnan MJ, Palmer CNA, Groop PH, Colhoun HM, Groop LC, McCarthy MI

Abstract
Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined (T1D+T2D) GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 diabetic subjects (and 18,582 DKD cases).Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, p=4.5×10-8) associated with 'microalbuminuria' in European T2D cases. However, no replication of this signal was observed in Asian subjects with T2D, or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously-reported DKD signals, except for those at UMOD and PRKAG2, both associated with 'eGFR'.We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk-variant discovery for DKD.

PMID: 29703844 [PubMed - as supplied by publisher]

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Points-to-consider documents: Scientific information on the evaluation of genetic polymorphisms during non-clinical studies and phase I clinical trials in the Japanese population.

Drug Metab Pharmacokinet. 2018 Mar 15;:

Authors: Hiratsuka M, Hirasawa N, Oshima Y, Kodama S, Miyata T, Dan T, Takatoku H, Kuribayashi H, Nakamura R, Saito Y

Abstract
Pharmacotherapy shows striking individual differences in pharmacokinetics and pharmacodynamics, involving drug efficacy and adverse reactions. Recent genetic research has revealed that genetic polymorphisms are important intrinsic factors for these inter-individual differences. This pharmacogenomic information could help develop safer and more effective precision pharmacotherapies and thus, regulatory guidance/guidelines were developed in this area, especially in the EU and US. The Project for the Promotion of Progressive Medicine, Medical Devices, and Regenerative Medicine by the Ministry of Health, Labour and Welfare, performed by Tohoku University, reported scientific information on the evaluation of genetic polymorphisms, mainly on drug metabolizing enzymes and transporters, during non-clinical studies and phase I clinical trials in Japanese subjects/patients. We anticipate that this paper will be helpful in drug development for the regulatory usage of pharmacogenomic information, most notably pharmacokinetics.

PMID: 29703433 [PubMed - as supplied by publisher]

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PXR as a mediator of herb-drug interaction.

J Food Drug Anal. 2018 Apr;26(2S):S26-S31

Authors: Hogle BC, Guan X, Folan MM, Xie W

Abstract
Medicinal herbs have been a part of human medicine for thousands of years. The herb-drug interaction is an extension of drug-drug interaction, in which the consumptions of herbs cause alterations in the metabolism of drugs the patients happen to take at the same time. The pregnane X receptor (PXR) has been established as one of the most important transcriptional factors that regulate the expression of phase I enzymes, phase II enzymes, and drug transporters in the xenobiotic responses. Since its initial discovery, PXR has been implicated in multiple herb-drug interactions that can lead to alterations of the drug's pharmacokinetic properties and cause fluctuating therapeutic efficacies, possibly leading to complications. Regions of the world that heavily incorporate herbalism into their primary health care and people turning to alternative medicines as a personal choice could be at risk for adverse reactions or unintended results from these interactions. This article is intended to highlight our understanding of the PXR-mediated herb-drug interactions.

PMID: 29703383 [PubMed - in process]

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Genetic polymorphisms in very important pharmacogenomic variants in the Zhuang ethnic group of Southwestern China: A cohort study in the Zhuang population.

Medicine (Baltimore). 2018 Apr;97(17):e0559

Authors: Li J, Guo C, Yan M, Niu F, Chen P, Li B, Jin T

Abstract
Pharmacogenomics, the study of the role of genetics in drug response, has recently become a focal point of research. Previous studies showed that genes associated with drug detoxification vary among different populations. However, pharmacogenomic information of the Zhuang ethnic group is scarce. The aim of the present study was to screen members of the Zhuang ethnicity in southwestern China for genotype frequencies of very important pharmacogenomic (VIP) variants and to determine the differences between the Zhuang ethnicity and other human populations.We genotyped 80 variants of VIP genes in 100 unrelated healthy Zhuang adults from the Yunnan province of China. Next, we analyzed the genotyping data with Structure and F-statistics (Fst).We compared our data with those of other populations using the HapMap data set, and observed that the frequency distribution of Zhuang population in Yunnan closely resembles that of JPT. Furthermore, population structure and Fst analysis showed that the Zhuang population is closely related to the Shaanxi Han population with respect to genetic background.Our study supplements existing information on Zhuang population pharmacogenomics and provides an extensive overview for developing personalized medicine.

PMID: 29703042 [PubMed - in process]

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Implication of sulfonylurea derivatives as prospective inhibitors of human carbonic anhydrase II.

Int J Biol Macromol. 2018 Apr 25;:

Authors: Idrees D, Hadianawala M, Mahapatra AD, Datta B, Roy S, Ahamad S, Khan P, Imtiyaz Hassan M

Abstract
Selective carbonic anhydrase (CA) inhibitors have gained a lot of importance owing to the implication of specific isoforms of CA in certain diseases like glaucoma, leukemia, cystic fibrosis, and epilepsy. A novel class of sulfonylurea derivatives was synthesized from corresponding sulfonyl chlorides and amines. Compounds with different pendant moieties in the sulfonylurea derivatives show significant interactions with human carbonic anhydrase II (CAII). In vitro evaluation of the sulfonylurea derivatives revealed three compounds possessing admirable inhibitory activity against CAII. Compounds containing methyl (G2), isopropyl (G4) and o-tosyl (G5) groups displayed IC50 (109-137 μm) for CAII. Fluorescence binding and cytotoxicity studies revealed that these compounds are showing good binding affinity (18-34 μM) to CAII and non- toxic to cells. Further, molecular docking studies of G2, G4 and G5 with CAII showed these compounds fit nicely in the active site of CAII. Molecular dynamics simulation studies of these compounds complexed with CAII also showed essential interactions which were maintained up to 50 ns of simulation. These results indicate the promising nature of the sulfonylurea scaffold towards CAII inhibition and opens scope of hit to-lead optimization for discovery of effective drugs against CAII-associated disorders.

PMID: 29704602 [PubMed - as supplied by publisher]

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Peribronchial tertiary lymphoid structures persist after rituximab therapy in patients with cystic fibrosis.

J Clin Pathol. 2018 Apr 27;:

Authors: Regard L, Martin C, Zemoura L, Geolier V, Sage E, Burgel PR

PMID: 29703760 [PubMed - as supplied by publisher]

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Hypersensitivity reactions to intravenous antibiotics in cystic fibrosis.

Paediatr Respir Rev. 2018 Apr 05;:

Authors: Wright MFA, Bush A, Carr SB

Abstract
Hypersensitivity reactions to intravenous antibiotics are common in cystic fibrosis (CF). As well as causing immediate morbidity, the need for future avoidance of the causative antibiotic can have a long-term negative impact on CF management. This paper reviews the epidemiology and clinical presentation of hypersensitivity reactions in CF patients, and using an illustrative case describes a rare but severe form of delayed drug reaction for which a high index of suspicion is required.

PMID: 29703693 [PubMed - as supplied by publisher]

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Influence of SNPs in Genes that Modulate Lung Disease Severity in a Group of Mexican Patients with Cystic Fibrosis.

Arch Med Res. 2018 Apr 24;:

Authors: Yokoyama E, Chávez-Saldaña M, Orozco L, Cuevas F, Lezana JL, Vigueras-Villaseñor RM, Rojas-Castañeda JC, Landero DA

Abstract
BACKGROUND: The variation in cystic fibrosis (CF) lung disease not always is explained by the CFTR genotype, so it has become apparent that modifier genes must play a considerable role in the phenotypic heterogeneity of CF, so we investigated the association of allelic variants in modifier genes that modulate the severity of lung function in a group of Mexican patients diagnosed with CF.
METHODS: We included 140 CF patients classified according to lung phenotype and analyzed 17 single nucleotide polymorphisms (SNPs) by TaqMan® allelic discrimination.
RESULTS: We demonstrated that patients with GG or GC genotype of the allelic variant rs11003125 (MBL2-550) of the MBL2 gene exhibit most of the lung manifestations at an earlier age; and the rs1042713 allelic variant of ADRB2 gene, showed statistical difference only with the age of first spirometry. When we used the dominant model, the MBL2 allele rs11003125 (MBL2-550; p = 0.022, Odds Ratio (OR) 2.87, 95% CI 1.14-7.27) was significantly associated with CF patients as risk factor, and the ADRB2 allele rs1042713 (p.Arg16Gly; p = 0.005, Odds Ratio (OR) 0.37, 95% CI 0.19-0.75) was significantly associated with CF patients as protect factor.
CONCLUSIONS: Our findings suggest that the MBL2 and ADRB2 genes exerts an important genetic influence on the lung disease in our patients. Taking into account our results, we insist on not leaving aside this type of studies, since having techniques such as GWAS or WES will be able to advance in achieving a better quality of life for CF patients with severe lung disease.

PMID: 29703608 [PubMed - as supplied by publisher]

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Increased GPNMB, phospho-ERK1/2, and MMP-9 in cystic fibrosis in association with reduced arylsulfatase B.

Mol Genet Metab. 2018 Feb 20;:

Authors: Bhattacharyya S, Feferman L, Sharma G, Tobacman JK

Abstract
BACKGROUND: GPNMB was increased in a CF gene array and in Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase)-null mice, consistent with previous reports that ARSB is reduced in cystic fibrosis (CF). Implications of GPNMB increase in CF are unknown.
METHODS: GPNMB levels were determined in serum and circulating leukocytes from CF patients and healthy controls. GPNMB binding with β-1 integrin and measurements of phospho-ERK1/2 and MMP-9 in CFTR-uncorrected, CFTR-corrected, and normal human bronchial epithelial cells (BEC) were determined, following ARSB and GPNMB knockdown, and treatment with RGD peptide, and ERK phosphorylation inhibitor.
RESULTS: GPNMB was markedly increased in CF patients compared to controls (p < 0.0001, unpaired t-test, two-tailed). Silencing GPNMB, treatment with excess RGD peptide, and treatment with ERK phosphorylation inhibitor blocked ARSB silencing-induced increases in MMP-9 in the normal BEC.
CONCLUSIONS: Findings suggest that decline in ARSB activity caused by decline in CFTR function leads to increased GPNMB, which may contribute to organ dysfunction in CF by increased MMP-9 expression.

PMID: 29703589 [PubMed - as supplied by publisher]

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Machine learning in schizophrenia genomics, a case-control study using 5,090 exomes.

Am J Med Genet B Neuropsychiatr Genet. 2018 Apr 28;:

Authors: Trakadis YJ, Sardaar S, Chen A, Fulginiti V, Krishnan A

Abstract
Our hypothesis is that machine learning (ML) analysis of whole exome sequencing (WES) data can be used to identify individuals at high risk for schizophrenia (SCZ). This study applies ML to WES data from 2,545 individuals with SCZ and 2,545 unaffected individuals, accessed via the database of genotypes and phenotypes (dbGaP). Single nucleotide variants and small insertions and deletions were annotated by ANNOVAR using the reference genome hg19/GRCh37. Rare (predicted functional) variants with a minor allele frequency ≤1% and genotype quality ≥90 including missense, frameshift, stop gain, stop loss, intronic, and exonic splicing variants were selected. A file containing all cases and controls, the names of genes with variants meeting our criteria, and the number of variants per gene for each individual, was used for ML analysis. The supervised machine-learning algorithm used the patterns of variants observed in the different genes to determine which subset of genes can best predict that an individual is affected. Seventy percent of the data was used to train the algorithm and the remaining 30% of data (n = 1,526) was used to evaluate its efficiency. The supervised ML algorithm, gradient boosted trees with regularization (eXtreme Gradient Boosting implementation) was the best performing algorithm yielding promising results (accuracy: 85.7%, specificity: 86.6%, sensitivity: 84.9%, area under the receiver-operator characteristic curve: 0.95). The top 50 features (genes) of the algorithm were analyzed using bioinformatics resources for new insights about the pathophysiology of SCZ. This manuscript presents a novel predictor which could potentially enable studies exploring disease-modifying intervention in the early stages of the disease.

PMID: 29704323 [PubMed - as supplied by publisher]

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Epigenetics and autism spectrum disorder: A report of an autism case with mutation in H1 linker histone HIST1H1e and literature review.

Am J Med Genet B Neuropsychiatr Genet. 2018 Apr 27;:

Authors: Duffney LJ, Valdez P, Tremblay MW, Cao X, Montgomery S, McConkie-Rosell A, Jiang YH

Abstract
Genetic mutations in genes encoding proteins involved in epigenetic machinery have been reported in individuals with autism spectrum disorder (ASD), intellectual disability, congenital heart disease, and other disorders. H1 histone linker protein, the basic component in nucleosome packaging and chromatin organization, has not been implicated in human disease until recently. We report a de novo deleterious mutation of histone cluster 1 H1 family member e (HIST1H1E; c.435dupC; p.Thr146Hisfs*50), encoding H1 histone linker protein H1.4, in a 10-year-old boy with autism and intellectual disability diagnosed through clinical whole exome sequencing. The c.435dupC at the 3' end of the mRNA leads to a frameshift and truncation of the positive charge in the carboxy-terminus of the protein. An expression study demonstrates the mutation leads to reduced protein expression, supporting haploinsufficiency of HIST1H1E protein and loss of function as an underlying mechanism of dysfunction in the brain. Taken together with other recent cases with mutations of HIST1H1E in intellectual disability, the evidence supporting the link to causality in disease is strong. Our finding implicates the deficiency of H1 linker histone protein in autism. The systematic review of candidate genes implicated in ASD revealed that 42 of 215 (19.5%) genes are directly involved in epigenetic regulations and the majority of these genes belong to histone writers, readers, and erasers. While the mechanism of how haploinsufficiency of HIST1H1E causes autism is entirely unknown, our report underscores the importance of further study of the function of this protein and other histone linker proteins in brain development.

PMID: 29704315 [PubMed - as supplied by publisher]

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A missense mutation in EBF2 was segregated with imperforate anus in a family across three generations.

Am J Med Genet A. 2018 Apr 28;:

Authors: Kim SY, Ko HS, Kim N, Yim SH, Jung SH, Kim J, Lee MD, Chung YJ

Abstract
The etiology of imperforate anus, a major phenotype of anorectal malformation (ARM), is still unknown and not a single gene has been reported to be associated with it. We studied a Korean family with six affected members with imperforate anus across three generations by whole exome sequencing and identified a missense mutation in the EBF2 gene (c.215C > T; p.Ala72Val). This mutation is completely segregated with the disease phenotype in the family and is evolutionarily highly conserved among diverse vertebrates. Also, this mutation was predicted to be functionally damaging. These results support that missense mutation in the EBF2 c.215C > T (p.Ala72Val) is very likely to contribute to the pathogenesis of ARM in this family.

PMID: 29704291 [PubMed - as supplied by publisher]

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Clinical and molecular characterization and response to Acitretin in three Families with Sjögren-Larsson Syndrome.

Int J Dermatol. 2018 Apr 27;:

Authors: Vural S, Vural A, Akçimen F, Bağci IS, Tunca C, Gündoğdu Eken A, Ruzicka T, Başak AN

Abstract
INTRODUCTION: Sjögren-Larsson syndrome (SLS) is a rare congenital disorder characterized by the triad of ichthyosis, spasticity, and mental retardation. Patients are usually referred to dermatology clinics during infancy. As paraplegia becomes the most debilitating symptom of the disease within a few years, ichthyosis, although a major burden for the patient, takes a back seat. Optimum treatment of ichthyosis in these children and the effect of treatment on different aspects such as severity of the ichthyosis, pruritus, or quality of life of the patients' and their caregivers is not well established.
MATERIALS AND METHODS: Genetic background of eight patients from three families diagnosed clinically with SLS was determined with whole-exome and Sanger sequencing. Clinical phenotypes, laboratory findings, magnetic resonance imaging (MRI), and treatment of the ichthyosis with acitretin were assessed.
RESULTS: All patients had the classical triad of Sjögren-Larsson syndrome. Genetic analysis revealed that one patient had a novel c.799-1 (+/+) homozygous splicing mutation in the ALDH3A2 gene. Other patients had the c.683G>A p.R228H (NM_000382.2) mutation in the same gene. Other manifestations included skeletal anomalies, enamel hypoplasia, bilateral T2-hyperintensities in white matter, and moderate-severe pruritus. Acitretin treatment in a maintenance dose of 0.25 mg/kg/day decreased the severity of ichthyosis in all children. It increased quality of life significantly in all of the children and their caregivers.
CONCLUSION: We conclude that ichthyosis can be treated effectively with low-dose acitretin in children with Sjögren-Larsson syndrome, and this treatment is associated with a significant improvement in the quality of life.

PMID: 29704247 [PubMed - as supplied by publisher]