One year effect of tezacaftor and ivacaftor on functional exercise capacity and muscle strength in people with cystic fibrosis.

Background: The 1-min sit-to-stand test (1STST) is a practical tool to evaluate physical capacity. The aim of this study was to assess the impact of tezacaftor and ivacaftor on functional exercise capacity, muscle strength and symptoms in people with cystic fibrosis (PwCF). Methods: The assessments were performed during the first year of tezacaftor and ivacaftor using the 1STST, 6-min walk test (6MWT), MicroFET2 dynamometer®, CF Questionnaire-Revised (CFQ-R), Leicester Cough Questionnaire (LCQ). Forced expiratory volume in 1 s (FEV1), body mass index (BMI), pancreatic sufficiency status, genotype and microbiologic data were also collected. Results: Fifty-four PwCF participated to the study and took at least one dose of tezacaftor-ivacaftor. Mean age was 26y±10 (±SD), median BMI 20.9 kg/m2 (interquartile range) (19.4; 23.5) and mean FEV1 82 percent of predicted values (%PV) ± 21. Significant correlations were found at baseline between the 1STST and the 6MWT (r = 0.617, p < 0.0001), the quadriceps strength (r = 0.6556, p < 0.0001) and the FEV1 (r = 0.29, p = 0.03). After one year of treatment, the 1STST increased significantly in terms of number of repetitions (n) (median 50 versus 58.5, p < 0.0001), %PV (101.1 versus 115.2%PV, p = 0.0003) and n times weight in kg (2885 versus 3389nxkg, p < 0.0001). The 6MWT distance and quadriceps strength were not modified after treatment but during the 6MWT, oxygen desaturation decreased significantly. FEV1, BMI, CFQ-R, LCQ improved as previously demonstrated. Conclusion: After one year of tezacaftor and ivacaftor, the 1STST improves, suggesting that the 1STST seems more responsive than the 6MWT and the MicroFET2 dynamometer® to assess the effects of CFTR modulators.

Epstein-Barr Virus-associated Pulmonary Tumor: A Pediatric Case and Discussion of the Literature.

Epstein-Barr virus-associated smooth pulmonary tumor is a rare condition that mostly affects immunosuppressed patients. This case describes a young boy with a history of kidney transplantation who presented recurrent pneumonia. Multiple endobronchial soft tissue tumors affecting both right and left bronchial tree were found and partially removed by bronchoscopy. Immunohistologic analysis demonstrated Epstein-Barr virus-associated smooth pulmonary tumor. Immunosuppressive therapy was changed from tacrolimus to sirolimus. A few months later, new right upper lobe and inferior left lobe tumors were found. Recurrent left lower lobe pneumonia prompted lobectomy. In the present case, complete resection and change of immunosuppressive treatment were effective.

Screening for oropharyngeal dysphagia in adult patients with neuromuscular diseases using the Sydney Swallow Questionnaire.

INTRODUCTION/AIMS: Oropharyngeal dysphagia is common in patients with neuromuscular diseases (NMDs). Its early recognition is vital for proper management. We tested a large cohort of adult NMD patients for oropharyngeal dysphagia using the Sydney Swallow Questionnaire (SSQ). We also looked for possible differences in characteristics of oropharyngeal dysphagia in various NMD groups and diseases. Finally, we compared results of this screening with those from their corresponding medical records for eventual "clinical history" of dysphagia. METHODS: We asked patients to fill in the SSQ during follow-up outpatient visits at our neuromuscular reference center. A total score above the cutoff score of 118.5 out of 1700 was indicative of oropharyngeal dysphagia. RESULTS: Of the 304 adult patients assessed for eligibility, 201 NMD patients (96 women and 105 men, aged 49.0 ± 16.2 years) were included and tested in this study. Oropharyngeal dysphagia was detected in 45% of all the NMD patients when using the SSQ, whereas only 12% had a positive medical record for dysphagia. The median SSQ scores for patients with myotonic syndromes (including myotonic dystrophy type 1), with amyotrophic lateral sclerosis, and with facioscapulohumeral dystrophy were above the cutoff score. The SSQ scores obtained revealed distinct oropharyngeal dysphagia characteristics in the different NMD groups and diseases. DISCUSSION: The SSQ tests positively for oropharyngeal dysphagia in a higher proportion of NMD patients compared with their medical records. The distinct oropharyngeal dysphagia characteristics we revealed in different NMD groups and diseases may help to elaborate adapted clinical approaches in the management of oropharyngeal dysphagia.

Esophageal Trachea, a Unique Foregut Malformation Requiring Multistage Surgical Reconstruction: Case Report.

Abnormal connections between the esophagus and low respiratory tract can result from embryological defects in foregut development. Beyond well-known malformations, including tracheo-esophageal fistula and laryngo-tracheo-esophageal cleft, rarer anomalies have also been reported, including communicating bronchopulmonary foregut malformations and tracheal atresia. Herein, we describe a case of what we have called "esophageal trachea," which, to our knowledge, has yet to be reported. A full-term neonate was born in our institution presenting with a foregut malformation involving both the middle esophagus and the distal trachea, which were found to be longitudinally merged into a common segment, 3 cm in length, located just above the carina and consisted of esophageal tissue without cartilaginous rings. At birth, the esophagus and trachea were surgically separated via right thoracotomy, the common segment kept on the tracheal side only, creating a residual long-gap esophageal atresia. The resulting severe tracheomalacia was treated via simultaneous posterior splinting of such diseased segment using an autologous pericardium patch, as well as by anterior aortopexy. Terminal esophagostomy and gastrostomy were created at that stage due to the long distance between esophageal segments. Between ages 18 and 24 months, the patient underwent native esophageal reconstruction using a multistage traction-and-growth surgical strategy that combined Kimura extra-thoracic esophageal elongations at the upper esophagus and Foker external traction at the distal esophagus. Ten months after esophageal reconstruction, prolonged, refractory, and severe tracheomalacia was further treated via anterior external stenting using a semitubular ringed Gore-Tex® prosthesis, through simultaneous median sternotomy and tracheoscopy. Currently, 2 years after the last surgery, respiratory stabilization, and full oral feeding were stably achieved. Multidisciplinary management was crucial for assuring lifesaving procedures, correctly assessing anatomy, and planning for multiple sequential surgical approaches that aimed to restore long-term respiratory and digestive functions.

Screening for sleep-disordered breathing with Pediatric Sleep Questionnaire in children with underlying conditions.

The Pediatric Sleep Questionnaire described by Chervin et al. (Sleep Medicine, 2000, 1, 21-32) was originally validated for children with obstructive sleep apnoea syndrome but without other disorders. The aim of our study was to check the applicability of this questionnaire in children with underlying chronic medical conditions. Children aged 2-18 years who underwent a diagnostic sleep study at Great Ormond Street Hospital were recruited over a 10-month period. The Pediatric Sleep Questionnaire completed by their parents and cardiorespiratory polygraphy were scored. Sensitivities and specificities of the Pediatric Sleep Questionnaire were calculated using a Pediatric Sleep Questionnaire score of 0.33 as being indicative of sleep-disordered breathing. A total of 561 patients were reviewed. Neuromuscular disorders (n = 108), craniofacial anomalies (n = 58) and the obstructive sleep apnea syndrome control group (n = 155) were best represented. The sensitivity for patients with isolated obstructive sleep apnoea syndrome was 76.5% when using an apnoea-hypopnoea index ≥ 5, but this was much lower when looking at specific sub-groups such as neuromuscular patients (25%) or patients with Trisomy 21 (36.7%). Sensitivities remained unchanged for patients with obstructive sleep apnoea syndrome (77.3%) when an apnoea-hypopnoea index of ≥ 1 was used, but improved for neuromuscular disorders sub-groups (36.7%) and Trisomy 21 (84%). In conclusion, the Pediatric Sleep Questionnaire is not a good screening tool for obstructive sleep apnoea syndrome in children with complex underlying disorders when a cut-off apnoea-hypopnoea index of ≥ 5 is used, and it cannot replace cardiorespiratory polygraphy recording.

Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients.

BACKGROUND: Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype. METHODS: Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient. RESULTS: In total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions. The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favourable prognosis, compared to the other two frequent mutations. Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001). With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations. CONCLUSIONS: Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clusters within the ATP1A3 gene. Our description of the clinical profile of patients with the most frequent mutations and the clinical picture of those with less common mutations confirms the results from previous studies, and further expands the spectrum of genotype-phenotype correlations. Our results may be useful to confirm diagnosis and may influence decisions to ensure appropriate early medical intervention in patients with AHC. They provide a stronger basis for the constitution of more homogeneous groups to be included in clinical trials.

Functional studies and proteomics in platelets and fibroblasts reveal a lysosomal defect with increased cathepsin-dependent apoptosis in ATP1A3 defective alternating hemiplegia of childhood.

Alternating hemiplegia of childhood (AHC) is a rare syndrome with repeated hemiplegic episodes, paroxysmal events and global neurological impairment. Recently, heterozygous de novo ATP1A3 missense mutations have been identified in AHC patients, but the underlying pathogenesis mechanism remains unknown. Mutation analysis of ATP1A3 in 9 unrelated AHC cases revealed mostly D801N or E815K variants. As platelets represent a good cellular model to study defects in neuropathologies, morphological and functional experiments were performed in these subjects. Platelets from the AHC patients presented with structural and functional abnormalities of granules positive for the lysosomal marker CD63. Similar structural granule abnormalities were detected in patients' fibroblasts. Proteomic analysis of platelets and fibroblasts showed a total of 93 differentially expressed proteins in AHC mainly involved in metabolism. Interestingly, 7 of these proteins were detected in both cell types, including the lysosomal protein cathepsin. AHC fibroblasts revealed significantly increased levels of activated cathepsin B, which induces a stronger activation of apoptosis. Our study is the first to link ATP1A3 defects in AHC to a platelet and fibroblast lysosomal defect with evidence of increased apoptosis. Further studies are needed to define how this lysosomal defect is related to decreased ATPase activity. Biological Significance Only recently, the genetic cause of AHC was identified as heterozygous ATP1A3 mutations, but the underlying pathophysiological mechanism still remains unknown. By performing functional, morphological and proteomic studies in AHC patients we found a structural and functional granule defect in AHC platelets and fibroblasts that was specifically found in granules positive for the lysosomal marker CD63. In particular, proteomics identified several differentially expressed proteins in fibroblasts and platelets from AHC cases that are predicted to have an important role in cell function and maintenance, a pathway typically attributed to lysosomes. The lysosomal protein cathepsin was found to be differentially expressed in both platelets and fibroblasts of AHC patients, inducing a stronger activation of mainly the intrinsic apoptosis. Despite the precise mechanism for the increased lysosomal cathepsin B-dependent apoptosis detected in AHC in relation to impaired ATP1A3 deserves further studies, we could here show some evidence for a defective regulation of apoptosis in AHC, a disease that still has no biochemical or neuroradiological parameters for diagnosis.

Homozygosity for aquaporin 7 G264V in three unrelated children with hyperglyceroluria and a mild platelet secretion defect.

PURPOSE: Aquaporin 7 (AQP7) belongs to the aquaglyceroporin family, which transports glycerol and water. AQP7-deficient mice develop obesity, insulin resistance, and hyperglyceroluria. However, AQP7's pathophysiologic role in humans is not yet known. METHODS: Three children with psychomotor retardation and hyperglyceroluria were screened for AQP7 mutations. The children were from unrelated families. Urine and plasma glycerol levels were measured using a three-step enzymatic approach. Platelet morphology and function were studied using electron microscopy, aggregations, and adenosine triphosphate (ATP) secretion tests. RESULTS: The index patients were homozygous for AQP7 G264V, which has previously been shown to inhibit transport of glycerol in Xenopus oocytes. We also detected a subclinical platelet secretion defect with reduced ATP secretion, and the absence of a secondary aggregation wave after epinephrine stimulation. Electron microscopy revealed round platelets with centrally located granules. Immunostaining showed AQP7 colocalization, with dense granules that seemed to be released after strong platelet activation. Healthy relatives of these patients, who were homozygous (not heterozygous) for G264V, also had hyperglyceroluria and platelet granule abnormalities. CONCLUSION: The discovery of an association between urine glycerol loss and a platelet secretion defect is a novel one, and our findings imply the involvement of AQPs in platelet secretion. Additional studies are needed to define whether AQP7 G264V is also a risk factor for mental disability.