Multichannel impedance monitoring for distinguishing nonerosive reflux esophagitis with minor changes on endoscopy in children.

OBJECTIVES: There are reports describing the relationship between baseline impedance level and esophageal mucosal integrity at endoscopy, such as erosive and nonerosive reflux esophagitis. However, many children with symptoms of gastroesophageal reflux disease have normal findings or minor changes on esophagogastroduodenoscopy. We aimed to examine whether modest changes at esophagogastroduodenoscopy can be evaluated and correlated with esophageal multichannel intraluminal impedance monitoring. METHODS: Patients (ages 0-17 years) with upper gastrointestinal symptoms who underwent combined esophagogastroduodenoscopy and multichannel intraluminal impedance monitoring at the Women's and Children's Hospital, Adelaide, Australia, between 2014 and 2016 were retrospectively studied and the following data were collected and used for analysis: demographics, multichannel intraluminal impedance data, included baseline impedance. Endoscopic findings were classified by modified Los Angeles grading, Los Angeles N as normal, Los Angeles M as with minimal change such as the erythema, pale mucosa, or friability of the mucosa following biopsy. Patients on proton pump inhibitor were excluded. RESULTS: Seventy patients (43 boys; 61%) were enrolled with a mean age of 7.9 years (range 10 months to 17 years). Fifty-one patients (72.9%) were allocated to Los Angeles N, while Los Angeles M was evident in 19 patients (27.1%). Statistically significant differences were observed in the following parameters: frequency of acid and nonacid reflux and baseline impedance in channels 5 and 6. The median values of the data were 18.3 episodes, 16.0 episodes, 2461.0 Ω, 2446.0 Ω in Los Angeles N, 36.0 episodes, 31.0 episodes, 2033.0 Ω, 2009.0 Ω in Los Angeles M, respectively. CONCLUSION: Lower baseline impedance is helpful in predicting minimal endoscopic changes in the lower esophagus. A higher frequency of acid and nonacid reflux episodes was also predictive of minimal endoscopic change in the lower esophagus.

High-resolution esophageal manometry in pediatrics: Effect of esophageal length on diagnostic measures.

BACKGROUND: High-resolution esophageal manometry (HREM), derived esophageal pressure topography metrics (EPT), integrated relaxation pressure (IRP), and distal latency (DL) are influenced by age and size. Combined pressure and intraluminal impedance also allow derivation of metrics that define distension pressure and bolus flow timing. We prospectively investigated the effects of esophageal length on these metrics to determine whether adjustment strategies are required for children. METHODS: Fifty-five children (12.3 ± 4.5 years) referred for HREM, and 30 healthy adult volunteers (46.9 ± 3.8 years) were included. Studies were performed using the MMS system and a standardized protocol including 10 × 5 mL thin liquid bolus swallows (SBM kit, Trisco Foods) and analyzed via Swallow Gateway (www.swallowgateway.com). Esophageal distension pressures and swallow latencies were determined in addition to EGJ resting pressure and standard EPT metrics. Effects of esophageal length were examined using partial correlation, correcting for age. Adult-derived upper limits were adjusted for length using the slopes of the identified linear equations. KEY RESULTS: Mean esophageal length in children was 16.8 ± 2.8 cm and correlated significantly with age (r = 0.787, P = .000). Shorter length correlated with higher EGJ resting pressure and 4-s integrated relaxation pressures (IRP), distension pressures, and shorter contraction latencies. Ten patients had an IRP above the adult upper limit. Adjustment for esophageal length reduced the number of patients with elevated IRP to three. CONCLUSIONS & INFERENCES: We prospectively confirmed that certain EPT metrics, as well as potential useful adjunct pressure-impedance measures such as distension pressure, are substantially influenced by esophageal length and require adjusted diagnostic thresholds specifically for children.

Pressure-Flow Analysis for the Assessment of Pediatric Oropharyngeal Dysphagia.

OBJECTIVES: To determine which objective pressure-impedance measures of pharyngeal swallowing function correlated with clinically assessed severity of oropharyngeal dysphagia (OPD) symptoms. STUDY DESIGN: Forty-five children with OPD and 34 control children without OPD were recruited and up to 5 liquid bolus swallows were recorded with a solid-state high-resolution manometry with impedance catheter. Individual measures of pharyngeal and upper esophageal sphincter (UES) function and a swallow risk index composite score were derived for each swallow, and averaged data for patients with OPD were compared with those of control children without OPD. Clinical severity of OPD symptoms and oral feeding competency was based on the validated Dysphagia Disorders Survey and Functional Oral Intake Scale. RESULTS: Those objective measures that were markers of UES relaxation, UES opening, and pharyngeal flow resistance differentiated patients with and without OPD symptoms. Patients demonstrating abnormally high pharyngeal intrabolus pressures and high UES resistance, markers of outflow obstruction, were most likely to have signs and symptoms of overt Dysphagia Disorders Survey (OR 9.24, P = .05, and 9.7, P = .016, respectively). CONCLUSION: Pharyngeal motor patterns can be recorded in children by the use of HRIM and pharyngeal function can be defined objectively with the use of pressure-impedance measures. Objective measurements suggest that pharyngeal dysfunction is common in children with clinical signs of OPD. A key finding of this study was evidence of markers of restricted UES opening.

ARX homeodomain mutations abolish DNA binding and lead to a loss of transcriptional repression.

Mutations in the Aristaless-related homeobox (ARX) gene are one of the most frequent causes of X-linked intellectual disability (ID). Several missense mutations, clustered in the paired-type homeodomain of ARX, have been identified. These mutations lead to a range of phenotypes from X-linked lissencephaly with abnormal genitalia to seizure disorders without brain malformations including X-linked infantile spasms with ID (ISSX-ID) and X-linked myoclonic epilepsy with spasticity and ID (XMESID). The effect of these mutations on the DNA-binding and transcriptional activity has been evaluated. Luciferase reporter assays showed altered repression activity of ARX by all mutations, causing brain malformations and ISSX-ID phenotypes, but not by the P353L mutation implicated in a milder phenotype of XMESID. Similarly, transient overexpression of wild-type ARX repressed endogenous expression of known ARX targets, LMO1 and SHOX2, when measured by real-time quantitative polymerase chain reaction. Overall, the molecular consequence of missense mutations correlated well with the severity of the clinical phenotype. In all mutations tested, except P353L, the DNA binding was abolished. Electrophoretic mobility shift assay results were validated using chromatin immunoprecipitation following overexpression of normal and selected missense mutations. Unlike wild-type ARX and clinically less severe mutations, the mutations leading to severe clinical phenotypes were not able to specifically bind to DNA upstream of known, endogenous ARX-regulated genes, LMO1 and SHOX2. In conclusion, the missense mutations in the ARX homeodomain represent loss-of-function mutations, which lead to a reduced or complete loss of DNA binding and as a consequence, a loss of transcriptional repression.