Sensitivity of ivacaftor to drug-drug interactions with rifampin, a cytochrome P450 3A4 inducer.

Pediatr Pulmonol. 2018 Feb 28;:

Authors: Guimbellot JS, Acosta EP, Rowe SM

Abstract
The CFTR potentiator ivacaftor is responsible for significant clinical improvements among a subset of patients with cystic fibrosis. Because it is a substrate of the cytochrome P450 system, specifically CYP3A4/5, ivacaftor is subject to significant drug-drug interactions, including due to commonly used antimicrobials such as rifampin. While the interaction of rifampin and ivacaftor has been examined in vitro, severe adverse events resulting from this interaction have not been reported in the literature. In this report, we describe the termination of steady, long-term improvement in a patient taking ivacaftor, resulting from the use of rifampin and precipitating a significant pulmonary exacerbation.

PMID: 29488691 [PubMed - as supplied by publisher]

Amikacin containing self-emulsifying delivery systems via pulmonary administration for treatment of bacterial infections of cystic fibrosis patients.

Nanomedicine (Lond). 2018 Feb 28;:

Authors: Hetényi G, Griesser J, Fontana S, Gutierrez AM, Ellemunter H, Niedermayr K, Szabó P, Bernkop-Schnürch A

Abstract
AIM: The aim of the study was to develop self-emulsifying delivery systems (SEDDS) exhibiting improved permeation rate for pulmonary delivery of amikacin for treatment of cystic fibrosis (CF) patients.
MATERIALS & METHODS: Solubility of amikacin in lipids was improved by hydrophobic ion pairing with sodium myristyl sulfate. The complex was loaded into SEDDS. Drug-release studies were performed and the permeation properties of SEDDS through human CF mucus were examined.
RESULTS: A total of 10% complex could be loaded into SEDDS. SEDDS exhibited sustained release. Up to twofold more amounts of amikacin permeated through the CF mucus compared with reference.
CONCLUSION: The developed SEDDS with amikacin may be a promising tool for the treatment of certain bacterial infections of CF patients.

PMID: 29488425 [PubMed - as supplied by publisher]

Hyperthyrotropinemia in newly diagnosed cystic fibrosis patients with pancreatic insufficiency reversed by enzyme therapy.

Eur J Pediatr. 2018 Feb 27;:

Authors: Giannakopoulos A, Katelaris A, Noni M, Karakonstantakis T, Kanaka-Gantenbein C, Doudounakis S

Abstract
Patients with cystic fibrosis (CF) commonly present with an elevated TSH concentration, suggesting subclinical hypothyroidism. Its relation to concomitant pancreatic insufficiency and its natural course upon initiation of enzyme replacement have not been adequately studied. Herein, we investigated the thyroid function in newly diagnosed infants with CF and monitored the course of thyroid function response to pancreatic enzyme substitution treatment. Fourteen, newly diagnosed infants with CF and pancreatic insufficiency, were followed every 6-8 weeks for 6 months ensuing onset of pancreatic enzyme substitution therapy. All infants had normal TSH values on neonatal screening. Ten out of 14 (71%) had hyperthyrotropinemia and normal freeT4 values at presentation. No patient received thyroxine. Upon follow-up, after 6 months, TSH values normalized in 90% of infants with CF and hyperthyrotropinemia. Serum selenium levels were negatively correlated with TSH levels.
CONCLUSION: Mild TSH elevation is a frequent finding in newly diagnosed cystic fibrosis patients with pancreatic insufficiency during infancy. TSH elevation resolves in most cases after initiation of enzyme substitution and improvement of nutritional status without any substitutive therapy with thyroxine. What is Known: • Newly diagnosed infants with cystic fibrosis often present with a state of hyperthyrotropinemia suggesting subclinical hypothyroidism. What is New: • Pancreatic enzyme substitution and improvement of nutrition restores normal TSH levels without the need of thyroxine therapy.

PMID: 29487998 [PubMed - as supplied by publisher]

Meconium Ileus.

Clin Colon Rectal Surg. 2018 Mar;31(2):121-126

Authors: Waldhausen JHT, Richards M

Abstract
Cystic fibrosis is one of the most common inheritable traits in Caucasians. Meconium ileus and its potential complications are the most likely reasons that these patients will need surgical care. Surgical intervention is usually needed in the neonatal period but may also be required later in life. This article discusses the various ways cystic fibrosis can affect the gastrointestinal tract. Both the operative and nonoperative management of complicated and uncomplicated meconium ileus are discussed in the neonatal period as well as long-term issues, such as distal intestinal obstructive syndrome, fibrosing colonopathy, and rectal prolapse, all of which may be seen in older children and adults.

PMID: 29487495 [PubMed]

[Clinical and evolutionary characteristics of a child with aquagenic keratoderma: A retrospective study of 12 patients].

Ann Dermatol Venereol. 2018 Feb 24;:

Authors: Denos C, Dreyfus I, Chiaverini C, Labreze C, Abasq C, Phan A, Mallet S, Monteil L, Mazereeuw-Hautier J, Groupe de Recherche Clinique en Dermatologie Pédiatrique

Abstract
INTRODUCTION: Aquagenic keratoderma (AK) is a rare condition characterized by wrinkled and edematous appearance of the skin of the hands occurring within minutes of immersion in water. Other than in a setting of cystic fibrosis, AK has rarely been reported in children, with only 13 clinical cases on record. Many clinicians are unfamiliar with AK and have fears relating to the association with cystic fibrosis The aim of this study is to describe the characteristics and to discuss management of the disease.
METHODS: Retrospective, multicentre study, including children aged under 16 years presenting AK.
RESULTS: 12 children were included. KA started at a mean age of 9.25 years (range: 20 months to 15 years). Clinical appearance and mode of onset were classical, with the palms being more severely affected than the soles. Pruritus or pain were reported in six cases. The median impact on daily life was 1.5/10. Some of the children underwent investigations: two had a negative sweat test, three had molecular analysis of the gene CFTR: one was negative and two had a heterozygote mutation. The course of the disease was variable: eight stabilizations, two exacerbations, one cure and one improvement.
DISCUSSION: This is the first series on childhood KA. Clinical characteristics were similar to those seen in adults. Impact was moderate and the disease course was variable. Systematic medical check-up for cystic fibrosis does not appear warranted in children since to date, cystic fibrosis has not been diagnosed in any patients presenting AK alone.
CONCLUSION: AK is rare in children and should not cause erroneous concern, and improvement can occur.

PMID: 29487017 [PubMed - as supplied by publisher]

Cystic fibrosis epithelial cells are primed for apoptosis as a result of increased Fas (CD95).

J Cyst Fibros. 2018 Feb 24;:

Authors: Chen Q, Pandi SPS, Kerrigan L, McElvaney NG, Greene CM, Elborn JS, Taggart CC, Weldon S

Abstract
BACKGROUND: Previous work suggests that apoptosis is dysfunctional in cystic fibrosis (CF) airways with conflicting results. We evaluated the relationship between dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) and apoptosis in CF airway epithelial cells.
METHODS: Apoptosis and associated caspase activity were analysed in non-CF and CF tracheal and bronchial epithelial cell lines.
RESULTS: Basal levels of apoptosis and activity of caspase-3 and caspase-8 were significantly increased in CF epithelial cells compared to controls, suggesting involvement of extrinsic apoptosis signalling, which is mediated by the activation of death receptors, such as Fas (CD95). Increased levels of Fas were observed in CF epithelial cells and bronchial brushings from CF patients compared to non-CF controls. Neutralisation of Fas significantly inhibited caspase-3 activity in CF epithelial cells compared to untreated cells. In addition, activation of Fas significantly increased caspase-3 activity and apoptosis in CF epithelial cells compared to control cells.
CONCLUSIONS: Overall, these results suggest that CF airway epithelial cells are more sensitive to apoptosis via increased levels of Fas and subsequent activation of the Fas death receptor pathway, which may be associated with dysfunctional CFTR.

PMID: 29486923 [PubMed - as supplied by publisher]

Information needs of parents of infants diagnosed with cystic fibrosis: Results of a pilot study.

J Child Health Care. 2018 Jan 01;:1367493518760734

Authors: Edwards DJ, Wicking K, Smyth W, Shields L, Douglas T

Abstract
This study investigated the information needs, priorities and information-seeking behaviours of parents of infants recently diagnosed with cystic fibrosis (CF) following newborn screening, by piloting the 'Care of Cystic Fibrosis Families Survey'. The questionnaires were posted to eligible parents ( n = 66) attending CF clinics in hospitals in two Australian states; reply-paid envelopes were provided for return of the questionnaires. Twenty-six were returned (response rate 39.4%). The most common questions to which parents required answers during their initial education period related to what CF is, how it is treated and how to care for their child. Parents preferred face-to-face consultations to deliver information, and yet all reported using the Internet to search for more information at some point during the education period. Many parents provided negative feedback about being given their child's CF diagnosis via telephone. The timing, content and method of information delivery can all affect the initial education experience. We can deliver education to better suit the information needs and priorities for education of parents of infants recently diagnosed with CF. The Care of Cystic Fibrosis Families Survey was successfully piloted and recommendations for amendments have been made for use in a larger study across Australia.

PMID: 29486591 [PubMed - as supplied by publisher]

The Genetics of Usher Syndrome in the Israeli and Palestinian Populations.

Invest Ophthalmol Vis Sci. 2018 Feb 01;59(2):1095-1104

Authors: Khalaileh A, Abu-Diab A, Ben-Yosef T, Raas-Rothschild A, Lerer I, Alswaiti Y, Chowers I, Banin E, Sharon D, Khateb S

Abstract
Purpose: Usher syndrome (USH) is the most common cause for deaf-blindness. It is genetically and clinically heterogeneous and prevalent in populations with high consanguinity rate. We aim to characterize the set of genes and mutations that cause USH in the Israeli and Palestinian populations.
Methods: Seventy-four families with USH were recruited (23 with USH type 1 [USH1], 33 with USH2, seven with USH3, four with atypical USH, and seven families with an undetermined USH type). All affected subjects underwent a full ocular evaluation. A comprehensive genetic analysis, including Sanger sequencing for the detection of founder mutations, homozygosity mapping, and whole exome sequencing in large families was performed.
Results: In 79% of the families (59 out of 74), an autosomal recessive inheritance pattern could be determined. Mutation detection analysis led to the identification of biallelic causative mutations in 51 (69%) of the families, including 21 families with mutations in USH2A, 17 in MYO7A, and seven in CLRN1. Our analysis revealed 28 mutations, 11 of which are novel (including c.802G>A, c.8558+1G>T, c.10211del, and c.14023A>T in USH2A; c.285+2T>G, c.2187+1G>T, c.3892G>A, c.5069_5070insC, c.5101C>T, and c.6196C>T in MYO7A; and c.15494del in GPR98).
Conclusions: We report here novel homozygous mutations in various genes causing USH, extending the spectrum of causative mutations. We also prove combined sequencing techniques as useful tools to identify novel disease-causing mutations. To the best of our knowledge, this is the largest report of a genetic analysis of Israeli and Palestinian families (n = 74) with different USH subtypes.

PMID: 29490346 [PubMed - in process]

Managing Bardet-Biedl Syndrome-Now and in the Future.

Front Pediatr. 2018;6:23

Authors: Forsythe E, Kenny J, Bacchelli C, Beales PL

Abstract
Bardet-Biedl syndrome is a rare autosomal recessive multisystem disorder caused by defects in genes encoding for proteins that localize to the primary cilium/basal body complex. Twenty-one disease-causing genes have been identified to date. It is one of the most well-studied conditions in the family of diseases caused by defective cilia collectively known as ciliopathies. In this review, we provide an update on diagnostic developments, clinical features, and progress in the management of Bardet-Biedl syndrome. Advances in diagnostic technologies including exome and whole genome sequencing are expanding the spectrum of patients who are diagnosed with Bardet-Biedl syndrome and increasing the number of cases with diagnostic uncertainty. As a result of the diagnostic developments, a small number of patients with only one or two clinical features of Bardet-Biedl syndrome are being diagnosed. Our understanding of the syndrome-associated renal disease has evolved and is reviewed here. Novel interventions are developing at a rapid pace and are explored in this review including genetic therapeutics such as gene therapy, exon skipping therapy, nonsense suppression therapy, and gene editing. Other non-genetic therapies such as gene repurposing, targeted therapies, and non-pharmacological interventions are also discussed.

PMID: 29487844 [PubMed]

Exome sequencing reveals a novel PLP1 mutation in a Moroccan family with connatal Pelizaeus-Merzbacher disease: a case report.

BMC Pediatr. 2018 Feb 27;18(1):90

Authors: Lyahyai J, Oulad Amar Bencheikh B, Elalaoui SC, Mansouri M, Boualla L, DIonne-Laporte A, Spiegelman D, Dion PA, Cossette P, Rouleau GA, Sefiani A

Abstract
BACKGROUND: Epilepsy regroups a common and diverse set of chronic neurological disorders that are characterized by spontaneous, unprovoked, and recurrent epileptic seizures. Epilepsies have a highly heterogeneous background with a strong genetic contribution and various mode of inheritance. X-linked epilepsy usually manifests as part of a syndrome or epileptic encephalopathy. The variability of clinical manifestations of X-linked epilepsy may be attributed to several factors including the causal genetic mutation, making diagnosis, genetic counseling and treatment decisions difficult. We report the description of a Moroccan family referred to our genetic department with X-linked epileptic seizures as the only initial diagnosis.
CASE PRESENTATION: Knowing the new contribution of Next-Generation Sequencing (NGS) for clinical investigation, and given the heterogeneity of this group of disorders we performed a Whole-Exome Sequencing (WES) analysis and co-segregation study in several members of this large family. We detected a novel pathogenic PLP1 missense mutation c.251C > A (p.Ala84Asp) allowing us to make a diagnosis of Pelizaeus-Merzbacher Disease for this family.
CONCLUSION: This report extends the spectrum of PLP1 mutations and highlights the diagnostic utility of NGS to investigate this group of heterogeneous disorders.

PMID: 29486744 [PubMed - in process]

The contribution of CACNA1A, ATP1A2 and SCN1A mutations in hemiplegic migraine: A clinical and genetic study in Finnish migraine families.

Cephalalgia. 2018 Jan 01;:333102418761041

Authors: Hiekkala ME, Vuola P, Artto V, Häppölä P, Häppölä E, Vepsäläinen S, Cuenca-León E, Lal D, Gormley P, Hämäläinen E, Ilmavirta M, Nissilä M, Säkö E, Sumelahti ML, Harno H, Havanka H, Keski-Säntti P, Färkkilä M, Palotie A, Wessman M, Kaunisto MA, Kallela M

Abstract
Objective To study the position of hemiplegic migraine in the clinical spectrum of migraine with aura and to reveal the importance of CACNA1A, ATP1A2 and SCN1A in the development of hemiplegic migraine in Finnish migraine families. Methods The International Classification of Headache Disorders 3rd edition criteria were used to determine clinical characteristics and occurrence of hemiplegic migraine, based on detailed questionnaires, in a Finnish migraine family collection consisting of 9087 subjects. Involvement of CACNA1A, ATP1A2 and SCN1A was studied using whole exome sequencing data from 293 patients with hemiplegic migraine. Results Overall, hemiplegic migraine patients reported clinically more severe headache and aura episodes than non-hemiplegic migraine with aura patients. We identified two mutations, c.1816G>A (p.Ala606Thr) and c.1148G>A (p.Arg383His), in ATP1A2 and one mutation, c.1994C>T (p.Thr665Met) in CACNA1A. Conclusions The results highlight hemiplegic migraine as a clinically and genetically heterogeneous disease. Hemiplegic migraine patients do not form a clearly separate group with distinct symptoms, but rather have an extreme phenotype in the migraine with aura continuum. We have shown that mutations in CACNA1A, ATP1A2 and SCN1A are not the major cause of the disease in Finnish hemiplegic migraine patients, suggesting that there are additional genetic factors contributing to the phenotype.

PMID: 29486580 [PubMed - as supplied by publisher]

Funding Opportunity PA-18-687 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages grant applications from institutions or organizations that propose multidisciplinary, investigator-initiated basic translational and clinical research in developmental pharmacodynamics This FOA encourages grant applications that propose studies to increase and establish data on developmental pharmacodynamic in the pediatric age groups and allows the determination of pharmacokinetic-pharmacodynamic relationship of drugs used in this population.

Funding Opportunity PA-18-688 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages grant applications from institutions or organizations that propose multidisciplinary, investigator-initiated basic translational and clinical research in developmental pharmacodynamics This FOA seek grant applications that propose studies to increase and establish data on developmental pharmacodynamics in the pediatric age groups and allows the determination of pharmacokinetic-pharmacodynamic relationship of drugs used in this population.

Funding Opportunity PAR-18-689 from the NIH Guide for Grants and Contracts. This FOA encourages research relevant to the development of therapeutic interventions for potentially fatal or disabling conditions that have been identified through newborn screening, as well as "high priority" genetic conditions where screening may be possible in the near future. Demonstrating the benefits of treatment is often a primary criterion for including a condition on a newborn screening panel; therefore, this FOA, a "high priority" condition is one where screening is not currently recommended but would significantly benefit from early identification and treatment.

Funding Opportunity PAR-18-690 from the NIH Guide for Grants and Contracts. This FOA encourages research relevant to the development of therapeutic interventions for potentially fatal or disabling conditions that have been identified through newborn screening, as well as "high priority" genetic conditions where screening may be possible in the near future. Demonstrating the benefits of treatment is often a primary criterion for including a condition on a newborn screening panel; therefore, this FOA, a "high priority" condition is one where screening is not currently recommended but would significantly benefit from early identification and treatment.

Funding Opportunity PAR-18-691 from the NIH Guide for Grants and Contracts. This FOA encourages research relevant to the development of therapeutic interventions for potentially fatal or disabling conditions that have been identified through newborn screening, as well as "high priority" genetic conditions where screening may be possible in the near future. Demonstrating the benefits of treatment is often a primary criterion for including a condition on a newborn screening panel; therefore, this FOA, a "high priority" condition is one where screening is not currently recommended but would significantly benefit from early identification and treatment.

Notice NOT-NR-18-007 from the NIH Guide for Grants and Contracts

Notice NOT-NR-18-011 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-18-686 from the NIH Guide for Grants and Contracts. The purpose of the NINDS Postdoctoral Mentored Career Development Award is to support the ability of outstanding, mentored postdoctoral researchers to develop a potentially impactful research project with a comprehensive career development plan that will enable them to launch an independent research program. Candidates are encouraged to apply for support from this NINDS K01 any time between the second through fourth year of cumulative mentored postdoctoral research experience, and may be supported by this NINDS K01 within the first 6 years of cumulative postdoctoral research experience. Because the completion of a strong, well-planned, thorough career development plan, in addition to development of an impactful research project, is a critical aspect of this K01, applications are strongly encouraged early in the postdoctoral eligibility window. By the end of the proposed K01 award period, the candidate should be poised to begin an independent research career with a well-developed, impactful research project and the expertise required to become a leader in the field.

Funding Opportunity PAR-18-685 from the NIH Guide for Grants and Contracts. The purpose of the NINDS Postdoctoral Mentored Career Development Award is to support the ability of outstanding, mentored postdoctoral researchers to develop a potentially impactful research project with a comprehensive career development plan that will enable them to launch an independent research program. Candidates are encouraged to apply for support from this NINDS K01 any time between the second through fourth year of cumulative mentored postdoctoral research experience, and may be supported by this NINDS K01 within the first 6 years of cumulative postdoctoral research experience. Because the completion of a strong, well-planned, thorough career development plan, in addition to development of an impactful research project, is a critical aspect of this K01, applications are strongly encouraged early in the postdoctoral eligibility window. By the end of the proposed K01 award period, the candidate should be poised to begin an independent research career with a well-developed, impactful research project and the expertise required to become a leader in the field.