Microbial clues lead to a diagnosis of cystic fibrosis in late adulthood

2020 ◽  
Vol 13 (4) ◽  
pp. e233470
Author(s):  
Colm Kerr ◽  
David Morrissy ◽  
Mary Horgan ◽  
Barry J Plant
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Testing ◽  
Genetic Disorder ◽  
Good Effect ◽  
Transmembrane Conductance Regulator ◽  
Old Irish ◽  
Common Life ◽  
Sweat Testing ◽  
History Of ◽  
Tract Infections

Cystic fibrosis (CF) is the most common life-limiting autosomal recessive genetic disorder among Caucasian populations. The majority of CF cases are diagnosed in childhood; however, increasing numbers of adults are being diagnosed with the condition. We present the case of a 65-year-old Irish woman presenting with a chronic cough and a history of recurrent respiratory tract infections. Staphylococcus aureus, Scedosporium apiospermum and Stenotrophomonas maltophilia were grown from bronchoalveolar lavage raising suspicion for CF. Sweat testing was negative; however, genetic testing revealed the presence of ∆F508 and R117H CF mutations, the latter mutation conferring a milder form of CF. The patient commenced treatment with the cystic fibrosis transmembrane conductance regulator (CFTR) potentiator medication ivacaftor to good effect. Novel CFTR potentiators and modulators have significant potential to benefit morbidity and mortality in this group. In this case, the microbiological results were key in pursuing genetic testing and diagnosing CF.

scholarly journals Cystic Fibrosis in two Ghanaian Children

2021 ◽  
Vol 2 ◽  
pp. 167-170 ◽  
Author(s):  
Sandra Kwarteng Owusu ◽  
Gabrielle Obeng-Koranteng ◽  
Sandra Laryea Odai ◽  
Marie Charlyne Fatima Kilba ◽  
Parbie Abbeyquaye ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Testing ◽  
Severe Acute Malnutrition ◽  
Case Reports ◽  
African Descent ◽  
Genetic Disorder ◽  
Pancreatic Insufficiency ◽  
Acute Malnutrition ◽  
Diagnostic Tools ◽  
Sweat Testing

Cystic fibrosis (CF) is a severe life-limiting genetic disorder resulting from mutations in the cystic fibrosis transmembrane regulator gene and is reported to be more prevalent among Caucasians than people of African descent. The past three decades have seen a gradual increase in the reporting of CF in non-European populations with CF in all regions including Africa. We report on the first two known Ghanaian children diagnosed with CF presenting early in infancy. The first patient presented with severe acute malnutrition and persistent diarrhea resulting from severe exocrine pancreatic insufficiency. In the second patient, there were recurrent wheeze and recurrent pneumonia, severe dehydration with metabolic alkalosis. Diagnosis of CF in Ghana is challenging due to the absence of diagnostic tools such as sweat testing equipment. In the first patient, sweat testing and genetic testing were done in South Africa. In the second patient, sweat testing was not done but diagnosis was confirmed by genetic testing. Both patients presented with classical CF symptoms including Pseudomonas aeruginosa airway infection before age 6 months. Both children are currently alive and healthy on appropriate treatment. These case reports highlight the growing evidence of CF occurring in people of African descent and the diagnostic challenges faced in Africa.

scholarly journals Human Genetics Society of Australasia Position Statement: Population-Based Carrier Screening for Cystic Fibrosis

2014 ◽  
Vol 17 (6) ◽  
pp. 578-583 ◽  
Author(s):  
Martin B. Delatycki ◽  
Jo Burke ◽  
Louise Christie ◽  
Felicity Collins ◽  
Michael Gabbett ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Human Genetics ◽  
Genetic Disorder ◽  
Position Statement ◽  
Population Based ◽  
Heterozygous Mutation ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Common Life ◽  
Cystic Fibrosis Transmembrane

Since the discovery in 1989 that mutations in cystic fibrosis transmembrane conductance regulator (CFTR) underlie cystic fibrosis (CF), the most common life shortening genetic disorder in Caucasians, it has been possible to identify heterozygous mutation carriers at risk of having affected children. The Human Genetics Society of Australasia has produced a position statement with recommendations in relation to population-based screening for CF. These include: (1) that screening should be offered to all relatives of people with or carriers of CF (cascade testing) as well as to all couples planning to have children or who are pregnant; (2) the minimum CFTR mutation panel to be tested consists of 17 mutations which are those mutations that are associated with typical CF and occur with a frequency of 0.1% or higher among individuals diagnosed with CF in Australasia; (3) that genetic counselling is offered to all couples where both members are known to have one or two CFTR mutations and that such couples are given the opportunity to meet with a physician with expertise in the management of CF as well as a family/individual affected by the condition.

scholarly journals Recurrent Cough and Expectoration for 10 Years: A Case Report

2019 ◽  
Vol 6 ◽  
pp. 2333794X1983372
Author(s):  
Ting Huang ◽  
Caihong Li ◽  
Daishun Liu
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Mutation ◽  
Definitive Diagnosis ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Children's Hospital ◽  
Children’S Hospital ◽  
Sweat Testing ◽  
Tract Infections ◽  
Cystic Fibrosis Transmembrane

Rationale. Most cases of cystic fibrosis occur in Europe, with only a few occurring in Asia. Pulmonary cystic fibrosis is not a rare disease, but in children it is a potentially life-threatening condition. Children suffering from pulmonary cystic fibrosis rarely survive to adulthood, and responses to treatment are generally poor. The most common cause of cystic fibrosis is a genetic mutation on chromosome 7. Patient concerns. A 15-year-old boy with healthy parents suffered from a recurrent cough and expectoration for nearly 10 years. Six years previously, a definitive diagnosis of pulmonary cystic fibrosis and hepatic cirrhosis was made at the Beijing Children’s Hospital. The first occurrence of hematemesis occurred 1 year ago. The main symptoms, which caused this period of hospitalization, were cough, expectoration, and hematemesis. Diagnoses. The underlying cause was finally determined to be the cystic fibrosis transmembrane conductance regulator gene (p.G970D). After genetic and sweat testing performed at the Beijing Children’s Hospital in 2012, a definitive diagnosis of cystic fibrosis was made. Interventions. The patient was administered hemostatic treatment, antibiotics, and cough relief and sputum reduction therapy. Outcomes. The patient’s condition rapidly improved and continued to remain stable, though future relapse is possible following respiratory tract infections. Lessons. This case indicates that in the case of any child that presents a recurrent cryptogenic cough and expectoration, whether accompanied by hematemesis or not, pulmonary cystic fibrosis should be considered. In order to determine underlying causes and prepare for cystic fibrosis transmembrane conductance regulator modulator therapy, genetic and sweat testing are recommended to be conducted if available.

scholarly journals Surveillance of Colorectal Cancer (CRC) in Cystic Fibrosis (CF) Patients

2021 ◽  
Vol 3 (2) ◽  
pp. 84-95
Author(s):  
Fabio Ingravalle ◽  
Giovanni Casella ◽  
Adriana Ingravalle ◽  
Claudio Monti ◽  
Federica De Salvatore ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cystic Fibrosis ◽  
General Population ◽  
Genetic Disorder ◽  
The United States ◽  
Screening Colonoscopy ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Increased Risk ◽  
Speciality Training

Cystic Fibrosis (CF) is the commonest inherited genetic disorder in Caucasians due to a mutation in the gene CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), and it should be considered as an Inherited Colorectal Cancer (CRC) Syndrome. In the United States, physicians of CF Foundation established the “Developing Innovative Gastroenterology Speciality Training Program” to increase the research on CF in gastrointestinal and hepatobiliary diseases. The risk to develop a CRC is 5–10 times higher in CF patients than in the general population and even greater in CF patients receiving immunosuppressive therapy due to organ transplantation (30-fold increased risk relative to the general population). Colonoscopy should be considered the best screening for CRC in CF patients. The screening colonoscopy should be started at the age of 40 in CF patients and, if negative, a new colonoscopy should be performed every 5 years and every 3 years if adenomas are detected. For transplanted CF patients, the screening colonoscopy could be started at the age of 35, in transplanted patients at the age of 30 and, if before, at the age of 30. CF transplanted patients, between the age of 35 and 55, must repeat colonoscopy every 3 years. Our review draws attention towards the clinically relevant development of CRC in CF patients, and it may pave the way for further screenings and studies.

scholarly journals Late Onset Atypical Pantothenate-Kinase-Associated Neurodegeneration

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Natalie Diaz
Keyword(s):  
Cognitive Impairment ◽  
Genetic Testing ◽  
Late Onset ◽  
Genetic Disorder ◽  
Iron Accumulation ◽  
Pantothenate Kinase ◽  
Radiographic Findings ◽  
Current Time ◽  
Initial Symptoms ◽  
History Of

Introduction. Pantothenate-kinase-associated neurodegeneration (PKAN) is a rare genetic disease and a form of neurodegeneration with brain iron accumulation (NBIA). It most commonly begins in the first two decades of life but should be considered in the differential diagnosis of patients at any age with an atypical progressive extrapyramidal disorder and cognitive impairment. Few late-adult cases have been reported.Case Report. A 50-year-old woman presented with a history of progressive dysarthria and dysphagia secondary to orolingual dystonia. Initial work-up was normal. There was no family history. Her initial symptoms were followed by the onset of blepharospasm, cervical dystonia, Parkinsonism, and cognitive impairment. Follow-up MRI four years after presentation revealed the diagnostic “eye-of-the-tiger” sign. Genetic testing confirmed a homozygous missense mutation consistent with the diagnosis of PKAN.Conclusion. Although PKAN is a rare genetic disorder most commonly seen in childhood, it should be considered in adult patients with a history of progressive focal dystonia or atypical Parkinsonism. As the radiographic findings are quite characteristic, genetic testing should be performed if the MRI shows evidence of iron accumulation. Optimal treatment strategies are not known, and at the current time therapies should be directed at the specific manifestations of the disease.

scholarly journals VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1

2013 ◽  
Vol 24 (19) ◽  
pp. 3016-3024 ◽  
Author(s):  
Hong Yu Ren ◽  
Diane E. Grove ◽  
Oxana De La Rosa ◽  
Scott A. Houck ◽  
Pattarawut Sopha ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Transport ◽  
Genetic Disorder ◽  
Missense Mutations ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Regulator Protein ◽  
Folding Defect ◽  
Membrane Spanning ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR.

scholarly journals Motion-Genetic Testing is Useful in the Diagnosis of Nonhereditary Pancreatic Conditions: Arguments Against the Motion

2003 ◽  
Vol 17 (1) ◽  
pp. 53-55 ◽  
Author(s):  
Jonathan A Cohn
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Testing ◽  
Gene Interactions ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cystic Fibrosis Lung Disease ◽  
Increased Risk ◽  
Idiopathic Chronic Pancreatitis ◽  
Cystic Fibrosis Transmembrane ◽  
Compound Heterozygotes

Mutations of two genes, the cystic fibrosis transmembrane conductance regulator gene (CFTR) and the pancreatic secretory trypsin inhibitor gene (PSTI), are associated with an increase in the risk of idiopathic chronic pancreatitis. Persons who have mutations of bothCFTRalleles (one severely and one mildly affected) are especially susceptible to this disease. Because these compound heterozygotes have sufficient residualCFTRfunction, they do not develop cystic fibrosis lung disease. OnePSTImutation, N34S, independently increases the risk of pancreatitis. Thus, the risk of pancreatitis is greatest among individuals who areCFTRcompound heterozygotes and who also have thePSTImutation. Nonetheless, most people withCFTRandPSTImutations do not develop pancreatitis. This fact indicates that environmental influences and gene-gene interactions also affect pancreatitis risk. AlthoughCFTRandPSTIgenetic testing can identify persons at an increased risk of pancreatitis, there are several reasons why the routine screening of individuals with nonhereditary pancreatitis is not recommended at this time: most disease-associated mutations are not detected by readily available techniques, genetic counselling guidelines do not exist, most patients with mutations do not develop pancreatitis and the results of testing do not affect the clinical management of pancreatitis.

scholarly journals CFTR misfolds during native-centric simulations due to entropic penalties of native state formation

2018 ◽  
Author(s):  
J. Shi ◽  
T. Cleveland ◽  
A. C. Powe ◽  
G. McGaughey ◽  
V. S. Pande
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Disorder ◽  
Dynamics Simulation ◽  
Transmembrane Conductance Regulator ◽  
Free Energy Surface ◽  
Transmembrane Conductance ◽  
Regulator Protein ◽  
Kinetic Traps ◽  
Induced Defects

AbstractCystic fibrosis (CF) is a common genetic disorder that affects approximately 70,000 people worldwide. It is caused by mutation-induced defects in synthesis, folding, processing, or function of the Cystic Fibrosis Transmembrane conductance Regulator protein (CFTR), a chloride-selective ion channel required for the proper functioning of secretory epithelia in tissues such as the lung, pancreas, and skin. The most common cause of CF is the single-residue deletion of F508 (F508del), a mutation present in one or both alleles in 90% of patients that induces severe folding defects and results in greatly reduced expression of the protein. Despite its medical importance, high-resolution mechanistic information about CFTR folding is lacking. In this study, we used molecular dynamics simulation with a native-centric force field to examine the folding and assembly of both full-length CFTR and the isolated first nucleotide-binding domain (NBD1). We observed that the protein was capable of substantial misfolding on both the intradomain and interdomain scale due to entropically favorable kinetic traps that exist on CFTR’s folding free energy surface. These results suggest that even wild type CFTR, in the absence of any disease-related mutations, has suboptimal folding efficiency. We speculate that such entropically-driven misfolding also occurs in disease-prone mutants such as F508del and contributes to the protein’s poor in vivo activity.

scholarly journals Homozygous Deletion of the CFTR Gene Caused by Interstitial Maternal Isodisomy in a Peruvian Child with Cystic Fibrosis

2019 ◽  
Vol 08 (03) ◽  
pp. 147-152
Author(s):  
Flor Vásquez Sotomayor ◽  
Hugo Hernán Abarca-Barriga
Keyword(s):  
Cystic Fibrosis ◽  
Pancreatic Insufficiency ◽  
Chromosomal Rearrangements ◽  
Correct Diagnosis ◽  
Homozygous Deletion ◽  
Cftr Gene ◽  
Molecular Testing ◽  
Transmembrane Conductance Regulator ◽  
First Case ◽  
History Of

AbstractWe report the first case in Peru of cystic fibrosis caused by a homozygous deletion of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A 10-month-old child who presented with meconium ileus and pancreatic insufficiency was tested for cystic fibrosis. Both parents of the child are of Peruvian background, are nonconsanguineous, and have no personal or family history of the disease. Chromosome microarray analysis revealed a homozygous deletion of the CFTR gene on chromosome 7 (7q31.2) within a maternally derived 12.8-Mb region of loss of heterozygosity with deletion of a region that includes the CFTR gene. Parental testing confirmed this finding. This case highlights the great importance of molecular testing and the study of chromosomal rearrangements in reaching a correct diagnosis and providing proper genetic counseling to the affected families.

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