Systemic lupus erythematosus.

Nat Rev Dis Primers. 2016 06 16;2:16039

Authors: Kaul A, Gordon C, Crow MK, Touma Z, Urowitz MB, van Vollenhoven R, Ruiz-Irastorza G, Hughes G

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs, including the skin, joints, the central nervous system and the kidneys. Women of childbearing age and certain racial groups are typically predisposed to developing the condition. Rare, inherited, single-gene complement deficiencies are strongly associated with SLE, but the disease is inherited in a polygenic manner in most patients. Genetic interactions with environmental factors, particularly UV light exposure, Epstein-Barr virus infection and hormonal factors, might initiate the disease, resulting in immune dysregulation at the level of cytokines, T cells, B cells and macrophages. Diagnosis is primarily clinical and remains challenging because of the heterogeneity of SLE. Classification criteria have aided clinical trials, but, despite this, only one drug (that is, belimumab) has been approved for use in SLE in the past 60 years. The 10-year mortality has improved and toxic adverse effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset by newer drugs such as mycophenolate mofetil and glucocorticoid-sparing regimes. However, further improvements have been hampered by the adverse effects of renal and neuropsychiatric involvement and late diagnosis. Adding to this burden is the increased risk of premature cardiovascular disease in SLE together with the risk of infection made worse by immunosuppressive therapy. Challenges remain with treatment-resistant disease and symptoms such as fatigue. Newer therapies may bring hope of better outcomes, and the refinement to stem cell and genetic techniques might offer a cure in the future.

PMID: 27306639 [PubMed - indexed for MEDLINE]

Stimulation of Intestinal Cl- Secretion Through CFTR by Caffeine Intake in Salt-Sensitive Hypertensive Rats.

Kidney Blood Press Res. 2018 Mar 16;43(2):439-448

Authors: Wei X, Lu Z, Yang T, Gao P, Chen S, Liu D, Zhu Z

Abstract
BACKGROUND/AIMS: High salt consumption is a major risk factor for hypertension, and sodium homeostasis is regulated by both intestinal sodium absorption and urinary sodium excretion. Chronic caffeine intake has been reported to attenuate salt-sensitive hypertension by promoting urinary sodium excretion; however, its exact role in intestinal sodium absorption remains unknown. Here, we investigated whether and how chronic caffeine consumption antagonizes salt-sensitive hypertension by inhibiting intestinal sodium absorption.
METHODS: Dahl salt-sensitive rats were fed 8% NaCl chow and 0.1% caffeine in their drinking water for 15 days. The blood pressure and fecal sodium content were measured. The effect of caffeine on the movement of Cl- in enterocyte cells was determined with the Ussing chamber assay.
RESULTS: Rats that were treated with caffeine displayed significantly lower mean blood pressure and higher fecal sodium content than the controls. Consistent with these findings, caffeine intake decreased fluid absorption by the intestine in the fluid perfusion experiment. Further, the results from the Ussing chamber assay indicated that caffeine promoted Cl- secretion through enterocyte apical cystic fibrosis transmembrane conductance regulator (CFTR), and thus inhibited sodium absorption. Moreover, depletion of cAMP or inhibition of CFTR completely abolished the effect of caffeine on Cl- secretion.
CONCLUSION: The results indicate that chronic caffeine consumption reduces sodium absorption by promoting CFTR-mediated Cl- secretion in the intestine, which contributes to the anti-hypertensive effect of caffeine in salt-sensitive rats.

PMID: 29558753 [PubMed - as supplied by publisher]

Massive hemorrhage: a late complication of replacement percutaneous endoscopic gastrostomy: case report.

Arch Argent Pediatr. 2018 Apr 01;116(2):e315-e318

Authors: Sekmenli T, Gündüz M, Akbulut H, Haldun Emiroglu H, Koplay M, Ciftci I

Abstract
Percutaneous endoscopic gastrostomy (PEG) is used as an alternative to enteral/nasoenteral feeding in situations where long-term oral feeding is ineffective or not tolerated. It is mostly preferred in patients with neurological conditions and also to support nutrition in patients with congenital heart diseases, cystic fibrosis, inflammatory bowel disease, and various oropharyngeal diseases. Although it is easily applicable compared to many invasive procedures, it has complications ranging from wound infection to death. PEG requires experienced medical personnel, appropriate prophylactic antibiotics and exhaustive information to the patients or their families about the procedure and subsequent care. We present a rare but important complication during the replacement of the gastrostomy tube subsequent to the "cut and push" method. The bumper portions, which should move to the distal end of the stomach, moved upwards to the proximal esophagus, caused a deep ulcer in the esophageal mucosa and a massive hemorrhage.

PMID: 29557624 [PubMed - in process]

Palivizumab prophylaxis for respiratory syncytial virus in infants with cystic fibrosis: is there a need?

Eur J Clin Microbiol Infect Dis. 2018 Mar 19;:

Authors: Bjornson C, Chan P, Li A, Paes B, Lanctôt KL, Mitchell I

Abstract
Respiratory syncytial virus (RSV) infection in cystic fibrosis (CF) infants is associated with significant morbidities. This study's objective is to evaluate the effectiveness and adverse events related to palivizumab (PVZ) in CF infants. Data on respiratory-related illness (RIH) and RSV hospitalizations (RSVH) were collected retrospectively in CF infants aged < 2 years in Alberta, Canada, from 2000 to 2017. Logistic regression models were used to compare the odds of RSVH or RIH in PVZ infants from the Canadian registry of palivizumab (CARESS) versus untreated (UPVZ) infants from Alberta, after adjusting for potential confounders. Illness severity was compared between cohorts using χ2 and t tests. A total of 267 CF infants were included: 183 (PVZ) and 84 (UPVZ). A total of 53.3% were tested for RSV. Fifty-five infants experienced a RIH and 10 had a RSVH. The PVZ cohort experienced similar odds of RSVH but decreased odds of RIH versus UPVZ, adjusting for gestational age, birth weight, birth during RSV peak months, and presence of siblings (Exp(B) = 0.23 [0.11-0.49], p < 0.0005). In RSVH-related subjects, PVZ subjects experienced shorter length of overall stay (LOS; t = 2.39 [df = 7], p = 0.048). In those with a RIH, the PVZ group had shorter overall intensive care unit (t = 3.52 [df = 15], p = 0.003) and hospital LOS (t = 2.11 [df = 52], p = 0.04). No serious adverse events were related to PVZ. The odds of RSVH were similar between groups, but PVZ subjects had decreased odds of RIH. The low number of RSV tests performed may explain the similarity in RSVH rates. Significant differences in LOS may indicate decreased RSVH and RIH illness severity in the PVZ versus UPVZ groups.

PMID: 29557081 [PubMed - as supplied by publisher]

[Specific characteristics of chest X‑ray in childhood : Basics for radiologists].

Radiologe. 2018 Mar 19;:

Authors: Schneider K

Abstract
The radiographic technique of pediatric chest X‑rays is substantially different from that in adults. In nearly all cases ap/pa X‑rays are sufficient and lateral radiographs are rarely needed. In the first years of life the thymus may overshadow the heart, the great vessels and the lung hila. The most important anatomical structures essential for diagnosing pathological findings of the lungs and mediastinum are the trachea with the bifurcation and the main bronchi with the adjacent great vessels. For the assessment of distended lungs and intrathoracic consolidations, fundamental knowledge of the anatomy in childhood and malformations which can involve the airways, the lungs, the heart, as well as systemic and pulmonary vessels are indispensable. Diseases of the pleura and the chest wall should always be investigated by ultrasound. Malignant disorders are rare in children, except for lymphomas. Optimized computed tomography (CT) and/or magnetic resonance imaging (MRI) are crucial in the diagnostic workflow of complex congenital heart diseases, complex lung and airway malformations, pulmonary complications in cystic fibrosis and the diagnostics of all tumors in order to make the right treatment decisions.

PMID: 29556698 [PubMed - as supplied by publisher]

Host-Microbe Interactions in Airway Disease: toward Disease Mechanisms and Novel Therapeutic Strategies.

mSystems. 2018 Mar-Apr;3(2):

Authors: Cope EK

Abstract
Despite growing efforts to understand the role of the microbiota in airway disease, mechanisms that link microbial community dysbiosis to chronic inflammation remain elusive. Our laboratory is interested in how altered microbiota composition or function influences airway inflammatory diseases, including chronic rhinosinusitis, asthma, and cystic fibrosis. Given the tight interplay between host-associated microbes and host immunity, the potential for translational microbiome research to guide clinical decisions and novel therapeutics is becoming better appreciated. We hope to advance our understanding of the ecology of airway disease through integrating multiple omics assays and in vitro and in vivo experimental validation. An increased understanding of the role of the microbiota in chronic airway inflammation will ultimately lead to the rational development of therapeutics aimed at manipulation of microbiota composition or activity to treat these important and costly diseases. In this perspective, I discuss our current research investigating the microbiology and ecology of the airway microbiome.

PMID: 29556535 [PubMed]

Dissection of the Role of VIMP in Endoplasmic Reticulum-Associated Degradation of CFTRΔF508.

Sci Rep. 2018 Mar 19;8(1):4764

Authors: Hou X, Wei H, Rajagopalan C, Jiang H, Wu Q, Zaman K, Xie Y, Sun F

Abstract
Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is an important quality control mechanism that eliminates misfolded proteins from the ER. The Derlin-1/VCP/VIMP protein complex plays an essential role in ERAD. Although the roles of Derlin-1 and VCP are relatively clear, the functional activity of VIMP in ERAD remains to be understood. Here we investigate the role of VIMP in the degradation of CFTRΔF508, a cystic fibrosis transmembrane conductance regulator (CFTR) mutant known to be a substrate of ERAD. Overexpression of VIMP markedly enhances the degradation of CFTRΔF508, whereas knockdown of VIMP increases its half-life. We demonstrate that VIMP is associated with CFTRΔF508 and the RNF5 E3 ubiquitin ligase (also known as RMA1). Thus, VIMP not only forms a complex with Derlin-1 and VCP, but may also participate in recruiting substrates and E3 ubiquitin ligases. We further show that blocking CFTRΔF508 degradation by knockdown of VIMP substantially augments the effect of VX809, a drug that allows a fraction of CFTRΔF508 to fold properly and mobilize from ER to cell surface for normal functioning. This study provides insight into the role of VIMP in ERAD and presents a potential target for the treatment of cystic fibrosis patients carrying the CFTRΔF508 mutation.

PMID: 29555962 [PubMed - in process]

Real-time exhaled breath analysis in patients with cystic fibrosis and controls.

J Breath Res. 2018 Mar 20;:

Authors: Gaisl T, Bregy L, Stebler N, Gaugg MT, Bruderer T, García-Gómez D, Moeller A, Singer F, Schwarz EI, Benden C, Sinues PM, Zenobi R, Kohler M

Abstract
We aimed at defining profiles of volatile organic compounds in exhaled breath from patients with cystic fibrosis (CF) using a novel real-time mass spectrometry technique.&#13; In this prospective matched case-control study, 30 patients with CF, and 30 healthy control subjects were matched one-to-one according to age, gender, and smoking state. We performed exhaled breath analysis by untargeted secondary electrospray ionization-high resolution mass spectrometry (SESI-HRMS). &#13; Patients with CF (mean age 26.0±13.0 years) and controls (mean age 27.9±14.0 years) were analysed using SESI-HRMS. 49 exhaled breath features were found to be altered (p-value &lt; 0.05 / q-value &lt; 0.1) in CF patients, in comparison to healthy controls. The two most discriminating features showed a prediction AUROC of 77.1% (95% CI 62.2% - 87.8%) with a specificity of 80.0% and a sensitivity of 63.3%. Levels of oxidative stress metabolites such as fatty acids were found to differ significantly between patients with CF and healthy controls. Furthermore, in patients with CF, 11 features correlated with the mucus concentration of Stenotrophomonas maltophilia bacteria.&#13; Exhaled Breath analysis with SESI-HRMS allows to identify CF specific compounds in real-time and may trace bacterial strains in affected patients with CF.

PMID: 29555894 [PubMed - as supplied by publisher]

Identification and Characterization of Novel Receptor Interacting Serine/threonine-Protein Kinase 2 (RIPK2) Inhibitors Using Structural Similarity Analysis.

J Pharmacol Exp Ther. 2018 Mar 19;:

Authors: Salla M, Aguayo-Ortiz R, Gaddafi Ibrahim D, Zare A, Said A, Moore J, Pandya V, Manaloor R, Fong S, Blankstein AR, Gibson S, Garcia LR, Meier P, Bhullar KS, Hubbard BP, Fiteh Y, Vliagoftis H, Goping IS, Brocks D, Hwang P, Martinez Velazquez JCA, Baksh S

Abstract
Receptor interacting protein kinase 2 (RIP2 or RICK herein referred to as RIPK2) is linked to the pathogen pathway that activates NFkB and autophagic activation. Using molecular modeling (docking) and chemoinformatics analyses we utilized the RIPK2/ponatinib crystal structure and searched in chemical databases for small molecules exerting binding interactions similar to those exerted by ponatinib. The identified RIPK2 inhibitors potently inhibited the proliferation of cancer cells by > 70% as well as inhibition of NFkB activity. More importantly, in vivo inhibition of intestinal and lung inflammation rodent models suggest effectiveness to resolve inflammation with low toxicity to the animals. Thus, our identified RIPK2 inhibitor may offer a possible therapeutic control of inflammation in diseases such as inflammatory bowel disease, asthma, cystic fibrosis, primary sclerosing cholangitis and pancreatitis.

PMID: 29555876 [PubMed - as supplied by publisher]

Design of a broad-range bacteriophage cocktail that reduces Pseudomonas aeruginosa biofilms and treats acute infections in two animal models.

Antimicrob Agents Chemother. 2018 Mar 19;:

Authors: Forti F, Roach DR, Cafora M, Pasini ME, Horner DS, Fiscarelli EV, Rossitto M, Cariani L, Briani F, Debarbieux L, Ghisotti D

Abstract
The alarming diffusion of multidrug resistant (MDR) bacterial strains requires investigations on non-antibiotic therapies. Amongst them, the use of bacteriophages (phages) as antimicrobial agents, namely phage therapy, is a promising treatment strategy with support by recent successful compassionate treatments in Europe and the U.S.A. In this work, we combined host range and genomic information to design a 6-phage cocktail killing several clinical strains of P. aeruginosa, including those collected from Italian cystic fibrosis (CF) patients, and analyzed the cocktail performance. We demonstrated that the cocktail composed of four novel (PYO2, DEV, E215 and E217) and two previously characterized (PAK_P1 and PAK_P4) phages was able to lyse P. aeruginosa both in planktonic liquid cultures and in biofilm. In addition, we showed that the phage cocktail could cure acute respiratory infection in mouse and treat bacteremia in the wax moth Galleria mellonella larvae. Furthermore, administration of the cocktail to larvae prior to bacterial infection provided prophylaxis. In this regard, efficiency of the phage cocktail was found to be unaffected by the MDR or mucoid phenotype of the pseudomonal strain. The cocktail was found to be superior to individual phages in destroying biofilms and providing a faster treatment in mice. We also found the Galleria larvae model to be cost-effective for testing clinical strains susceptibility to phages, suggesting that it could be implemented in the frame of developing personalized phage therapies.

PMID: 29555626 [PubMed - as supplied by publisher]

Cystic fibrosis patient registries: A valuable source for clinical research.

J Cyst Fibros. 2018 Mar 16;:

Authors: Dasenbrook EC, Sawicki GS

Abstract
Cystic Fibrosis (CF) patient registries are valuable data sources for researchers studying the natural history, treatment paradigms, and long-term health outcomes of individuals with CF. In this review, we discuss the role of CF patient registries in facilitating comparative effectiveness research, particularly evaluating therapies and variation in health care delivery. We also discuss the limitations of registry-based research, particularly indication bias, as well as statistical methods that can be used to address these issues.

PMID: 29555479 [PubMed - as supplied by publisher]

Fertility and infertility: Definition and epidemiology.

Clin Biochem. 2018 Mar 16;:

Authors: Mélodie VB, Christine W

Abstract
Infertility is a disease characterized by the failure to establish a clinical pregnancy after 12 months of regular and unprotected sexual intercourse. It is estimated to affect between 8 and 12% of reproductive-aged couples worldwide. Males are found to be solely responsible for 20-30% of infertility cases but contribute to 50% of cases overall. Secondary infertility is the most common form of female infertility around the globe, often due to reproductive tract infections. The three major factors influencing the spontaneous probability of conception are the time of unwanted non-conception, the age of the female partner and the disease-related infertility. The chance of becoming spontaneously pregnant declines with the duration before conception. The fertility decline in female already starts around 25-30 years of age and the median age at last birth is 40-41 years in most studied populations experiencing natural fertility. The disease-related infertility may affect both genders or be specific to one gender. The factors affecting both genders' fertility are hypogonadotrophic hypogonadism, hyperprolactinemia, disorders of ciliary function, cystic fibrosis, infections, systemic diseases and lifestyle related factors/diseases. Premature ovarian insufficiency, polycystic ovary syndrome, endometriosis, uterine fibroids and endometrial polyps may play a role in female infertility. Male infertility may be due to testicular and post-testicular deficiencies. Semen decline that has been observed over the years, endocrine disrupting chemicals and consanguinity are other factors that may be involved.

PMID: 29555319 [PubMed - as supplied by publisher]

Non-Tuberculous Mycobacteria multispecies biofilms in cystic fibrosis: development of an in vitro Mycobacterium abscessus and Pseudomonas aeruginosa dual species biofilm model.

Int J Med Microbiol. 2018 Mar 06;:

Authors: Rodríguez-Sevilla G, García-Coca M, Romera-García D, Aguilera-Correa JJ, Mahíllo-Fernández I, Esteban J, Pérez-Jorge C

Abstract
Lung disease in cystic fibrosis (CF) is characterized by the progressive colonization of the respiratory tract by different bacteria, which develop polymicrobial biofilms. In the past decades, there has been an increase in the number of CF patients infected with Non-Tuberculous Mycobacteria (NTM). Although Mycobacterium abscessus is the main NTM isolated globally, little is known about M. abscessus multispecies biofilm formation. In the present study we developed an in vitro model to study the phenotypic characteristics of biofilms formed by M. abscessus and Pseudomonas aeruginosa, a major pathogen in CF. For that purpose, dual species biofilms were grown on polycarbonate membranes with a fixed concentration of P. aeruginosa and different inoculums of M. abscessus. The biofilms were sampled at 24, 48, and 72 h and bacteria were quantified in specific media. The results revealed that the increasing initial concentration of M. abscessus in dual species biofilms had an effect on its population only at 24 and 48 h, whereas P. aeruginosa was not affected by the different concentrations used of M. abscessus. Time elapsed increased biofilm formation of both species, specially between 24 and 48 h. According to the results, the conditions to produce a mature dual species biofilm in which the relative species distribution remained stable were 72 h growth of the mixed microbial culture at a 1:1 ratio. A significant decrease in mycobacterial population in dual compared to single species biofilms was found, suggesting that P. aeruginosa has a negative influence on M. abscessus. Finally, in a proof of concept experiment, young and mature dual species biofilms were exposed to clarithromycin.

PMID: 29555180 [PubMed - as supplied by publisher]

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Polymorphism genotyping based on loop-mediated isothermal amplification and smartphone detection.

Biosens Bioelectron. 2018 Mar 08;109:177-183

Authors: Yamanaka ES, Tortajada-Genaro LA, Pastor N, Maquieira Á

Abstract
The genotyping of a single-nucleotide polymorphism (SNP) is addressed through methods based on loop-mediated isothermal amplification (LAMP) combined with user-friendly optical read-outs to cover the current demand for point-of-care DNA biomarker detection. The modification of primer design and reaction composition improved the assay selectivity yielding allele-specific results and reducing false-positive frequency. Furthermore, the reduced cost, ease of use and effectiveness of colorimetric detection (solution and hybridisation chip formats) were availed for the image capture by a smartphone, reching high sensitivity. In order to evaluate their discriminating capacities, LAMP-based methods were applied to human samples to genotype a SNP biomarker (rs1954787) located in the GRIK4 gene and related to the treatment response to anti-depressants drugs. Sensitive (limit of detection: 100 genomic DNA copies), reproducible (< 15% error), fast (around 70 min) and low-cost assays were accomplished. Patient subgroups were correctly discriminated, agreeing with reference sequencing techniques. The achieved analytical performances using the developed amplification-detection principles confirmed the approach potential for point-of-care optical DNA testing.

PMID: 29558731 [PubMed - as supplied by publisher]

When the Safe Alternative Is Not That Safe: Tramadol Prescribing in Children.

Front Pharmacol. 2018;9:148

Authors: Rodieux F, Vutskits L, Posfay-Barbe KM, Habre W, Piguet V, Desmeules JA, Samer CF

Abstract
Children represent a vulnerable population in which management of nociceptive pain is complex. Drug responses in children differ from adults due to age-related differences. Moreover, therapeutic choices are limited by the lack of indication for a number of analgesic drugs due to the challenge of conducting clinical trials in children. Furthermore the assessment of efficacy as well as tolerance may be complicated by children's inability to communicate properly. According to the World Health Organization, weak opioids such as tramadol and codeine, may be used in addition to paracetamol and ibuprofen for moderate nociceptive pain in both children and adults. However, codeine prescription has been restricted for the last 5 years in children because of the risk of fatal overdoses linked to the variable activity of cytochrome P450 (CYP) 2D6 which bioactivates codeine. Even though tramadol has been considered a safe alternative to codeine, it is well established that tramadol pharmacodynamic opioid effects, efficacy and safety, are also largely influenced by CYP2D6 activity. For this reason, the US Food and Drug Administration recently released a boxed warning regarding the use of tramadol in children. To provide safe and effective tramadol prescription in children, a personalized approach, with dose adaptation according to CYP2D6 activity, would certainly be the safest method. We therefore recommend this approach in children requiring chronic or recurrent nociceptive pain treatment with tramadol. In case of acute inpatients nociceptive pain management, prescribing tramadol at the minimal effective dose, in a child appropriate dosage form and after clear instructions are given to the parents, remains reasonable based on current data. In all other situations, morphine should be preferred for moderate to severe nociceptive pain conditions.

PMID: 29556194 [PubMed]

Pharmacokinetic Study of 7 Compounds Following Oral Administration of Fructus Aurantii to Depressive Rats.

Front Pharmacol. 2018;9:131

Authors: Zhang X, Han L, Liu J, Xu Q, Guo Y, Zheng W, Wang J, Huang X, Ren P

Abstract
In the present study, the pharmacokinetics of multi-components (naringenin, nobiletin, meranzin hydrate, narirutin, naringin, hesperidin, and neohesperidin) were investigated in acute depressive rats following oral administration of Fructus Aurantii (Zhi-Qiao, ZQ) extract (20 g/kg). A rapid and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established to quantitatively or qualitatively analyze the 7 absorbed ingredients in the plasma, hippocampus and cortex of acute depressive rats. Biological samples were separated on a 300SB-C18 column, and the 7 compounds were detected with sequential positive and negative ionization modes. Our results confirmed that ZQ has antidepressant effects by decreasing the immobility time. In addition, this validated method showed good linearity (r ≥ 0.9987), and the lower limits of quantification were 2.73-16.38 ng/mL for the 7 analytes. This method successfully determined the pharmacokinetics of the 7 compounds and separated two pairs of isomers in plasma of acute depressive rats following oral administration of ZQ extracts. The 7 active ingredients were also identified as marked compounds in target tissues and should be further examined in pharmacokinetic studies with acute depressive rats. So, pharmacokinetic compounds were precisely linked with the antidepressant effect of ZQ in our study. This relationship is well-understood and contributes to the application of Traditional Chinese Medicine (TCM).

PMID: 29556193 [PubMed]

Array Comparative Genomic Hybridization as the First-line Investigation for Neonates with Congenital Heart Disease: Experience in a Single Tertiary Center.

Korean Circ J. 2018 Mar;48(3):209-216

Authors: Choi BG, Hwang SK, Kwon JE, Kim YH

Abstract
BACKGROUND AND OBJECTIVES: The purpose of the present study was to investigate the advantages and disadvantages of verifying genetic abnormalities using array comparative genomic hybridization (a-CGH) immediately after diagnosis of congenital heart disease (CHD).
METHODS: Among neonates under the age of 28 days who underwent echocardiography from January 1, 2014 to April 30, 2016, neonates whose chromosomal and genomic abnormalities were tested using a-CGH in cases of an abnormal finding on echocardiography were enrolled.
RESULTS: Of the 166 patients diagnosed with CHD, 81 underwent a-CGH and 11 patients (11/81, 13.5%) had abnormal findings on a-CGH. 22q11.2 deletion syndrome was the most common (4/11, 36.4%). On the first a-CGH, 4 patients were negative (4/81, 5%). Three of them were finally diagnosed with Williams syndrome using fluorescent in situ hybridization (FISH), 1 patient was diagnosed with Noonan syndrome through exome sequencing. All of them exhibited diffuse pulmonary artery branch hypoplasia, as well as increased velocity of blood flow, on repeated echocardiography. Five patients started rehabilitation therapy at mean 6 months old age in outpatient clinics and epilepsy was diagnosed in 2 patients. Parents of 2 patients (22q11.2 deletion syndrome and Patau syndrome) refused treatment due to the anticipated prognosis.
CONCLUSIONS: Screening tests for genetic abnormalities using a-CGH in neonates with CHD has the advantage of early diagnosis of genetic abnormality during the neonatal period in which there is no obvious symptom of genetic abnormality. However, there are disadvantages that some genetic abnormalities cannot be identified on a-CGH.

PMID: 29557107 [PubMed]

Congenital glaucoma and CYP1B1: an old story revisited.

Hum Genet. 2018 Mar 19;:

Authors: Alsaif HS, Khan AO, Patel N, Alkuraya H, Hashem M, Abdulwahab F, Ibrahim N, Aldahmesh MA, Alkuraya FS

Abstract
Primary congenital glaucoma is a trabecular meshwork dysgenesis with resultant increased intraocular pressure and ocular damage. CYP1B1 mutations remain the most common identifiable genetic cause. However, important questions about the penetrance of CYP1B1-related congenital glaucoma remain unanswered. Furthermore, mutations in other genes have been described although their exact contribution and potential genetic interaction, if any, with CYP1B1 mutations are not fully explored. In this study, we employed modern genomic approaches to re-examine CYP1B1-related congenital glaucoma. A cohort of 193 patients (136 families) diagnosed with congenital glaucoma. We identified biallelic CYP1B1 mutations in 80.8% (87.5 and 66.1% in familial and sporadic cases, respectively, p < 0.0086). The large family size of the study population allowed us to systematically examine penetrance of all identified alleles. With the exception of c.1103G>A (p.R368H), previously reported pathogenic mutations were highly penetrant (91.2%). We conclude from the very low penetrance and genetic epidemiological analyses that c.1103G>A (p.R368H) is unlikely to be a disease-causing recessive mutation in congenital glaucoma as previously reported. All cases that lacked biallelic CYP1B1 mutations underwent whole exome sequencing. No mutations in LTBP2, MYOC or TEK were encountered. On the other hand, mutations were identified in genes linked to other ophthalmic phenotypes, some inclusive of glaucoma, highlighting conditions that might phenotypically overlap with primary congenital glaucoma (SLC4A4, SLC4A11, CPAMD8, and KERA). We also encountered candidate causal variants in genes not previously linked to human diseases: BCO2, TULP2, and DGKQ. Our results both expand and refine the genetic spectrum of congenital glaucoma with important clinical implications.

PMID: 29556725 [PubMed - as supplied by publisher]

De novo apparent loss-of-function mutations in PRR12 in three patients with intellectual disability and iris abnormalities.

Hum Genet. 2018 Mar 19;:

Authors: Leduc MS, Mcguire M, Madan-Khetarpal S, Ortiz D, Hayflick S, Keller K, Eng CM, Yang Y, Bi W

Abstract
PRR12 encodes a proline-rich protein nuclear factor suspected to be involved in neural development. Its nuclear expression in fetal brains and in the vision system supports its role in brain and eye development more specifically. However, its function and potential role in human disease has not been determined. Recently, a de novo t(10;19) (q22.3;q13.33) translocation disrupting the PRR12 gene was detected in a girl with intellectual disability and neuropsychiatric alterations. Here we report on three unrelated patients with heterozygous de novo apparent loss-of-function mutations in PRR12 detected by clinical whole exome sequencing: c.1918G>T (p.Glu640*), c.4502_4505delTGCC (p.Leu1501Argfs*146) and c.903_909dup (p.Pro304Thrfs*46). All three patients had global developmental delay, intellectual disability, eye and vision abnormalities, dysmorphic features, and neuropsychiatric problems. Eye abnormalities were consistent among the three patients and consisted of stellate iris pattern and iris coloboma. Additional variable clinical features included hypotonia, skeletal abnormalities, sleeping problems, and behavioral issues such as autism and anxiety. In summary, we propose that haploinsufficiency of PRR12 is associated with this novel multisystem neurodevelopmental disorder.

PMID: 29556724 [PubMed - as supplied by publisher]