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(LES) pressure and percent relaxation,mean peak esophageal body contrac-tions, and percent of swallows withabnormal peristalsis were quantified.

Results: Patients with GERD (n = 13) ordysphagia (n = 11) had 37% and 34% ofswallows followed by abnormalesophageal peristalsis, respectively, com-pared to 8% in patients without symp-toms (P < 0.01). Patients withfundoplication (n = 4) had 45% of swal-lows followed by abnormal esophagealperistalsis versus 17% in those withoutfundoplication (P < 0.05).Fundoplication patients showed higherLES resting pressures (35 mmHg vs 23.5mmHg, P < 0.01) compared withpatients without previous anti-refluxsurgery. There was no associationbetween esophageal motor disturbancesand MECP2 mutations.

Vol. 7, No. 3, 2007 The Journal of Applied Research

Esophageal Motility Dysfunction inChildren With Rett Syndrome,Gastroesophageal Reflux, andDysphagia

KEY WORDS: Rett syndrome,manometry, gastroesophageal refluxdisease (GERD), dysphagia

ABSTRACTBackground: Rett syndrome is a neu-rodevelopmental disorder associatedwith gastroesophageal reflux disease(GERD) and dysphagia.

Objective: Correlate esophageal motilitydisturbances with symptoms of GERDand dysphagia and with MECP2 genemutations in children with Rett syn-drome.

Study Design: Thirty-two consecutiveRett patients with a mean (range) age of6.2 (2.3-14) years with prior history offeeding problems underwent esophagealmanometry. Lower esophageal sphincter

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Conclusions: Decreased esophagealperistalsis is a common finding in Rettpatients with symptoms of GERD anddysphagia with or without fundoplica-tion. Prospective studies are needed todetermine if esophageal manometryshould be used to screen Rett patientsfor esophageal motility dysfunctionbefore anti-reflux procedures.

INTRODUCTIONRett syndrome is a neurodevelopmentaldisorder affecting postnatal braingrowth that characteristically occurs infemales with a prevalence of 1:10,000 to1:22,000.1 In approximately 70%-80% ofpatients, clinical features of Rett syn-drome are associated with mutations inthe methyl CpG binding protein 2(MECP2) gene located in the chromo-some Xq28 region.2-4 Failure of braingrowth results in developmental regres-sion and is accompanied by seizures, res-piratory irregularities, and severe mentalretardation. Patients also have signifi-cant autonomic involvement resulting ingastrointestinal (GI) abnormalities andperipheral vasomotor instability.5,6 Thecommon GI manifestations seen in Rettsyndrome include gastroesophagealreflux disease (GERD), dysphagia, feed-ing impairment that often results in fail-ure to thrive, and constipation. We havepreviously shown that patients withmutations closer to the MECP2 amino-

terminus (proximal) had a greater num-ber of gastrointestinal problems andoften required early gastrostomy forsevere malnutrition.7

The primary GI neuromuscular ormotility mechanism underlying GERDand dysphagia in Rett patients has notyet been defined. It is unclear if thepathophysiology of GERD in patientswith Rett syndrome can simply beexplained through transient relaxationsof the lower esophageal sphincter(TLESRs).8-11 Gastroesophageal refluxdisease and dysphagia may also be influ-enced by disordered esophageal bodyperistalsis resulting in impaired clear-ance of acid from the esophagus or dis-ruption of bolus transit, respectively.Although dysmotility of the esophagusmay occur as a secondary phenomenonrelated to esophageal injury from chron-ic exposure to refluxed gastric contents,an underlying inherent motility disorderof the esophageal body may contributeto symptoms of GERD and dysphagia inchildren with neurologic impairment.12-14

Antireflux surgery has been a main-stay of treatment for severe GERD inchildren since the 1960s.15,16 A review ofthe Pediatric Health Information Surveydatabase has shown an upward trend inthe rate of fundoplication.17 Amongthese patients, 14% underwent fundopli-cation without a prior gastroenterologyconsultation.17,18 Common side effects

Table 1. Percentage abnormal esophageal peristalsis during esophageal manometry afterswallows in patients with Rett syndrome. Asymptomatic patients served as controls. Subjectswith symptoms of GERD or dysphagia were compared to controls. Patients with GERD only (nodysphagia), dysphagia only (no GERD), and patients with both GERD and dysphagia werealso compared to controls.

Symptoms Abnormal Peristalsis (%) P ValueControls (n = 15) 8GERD (n = 13) 37 0.004Dysphagia (n = 11) 34 0.007GERD only (n = 5) 31 0.02Dysphagia only (n = 3) 18 0.16Both GERD and dysphagia (n = 8) 41 0.003

in terms of mutations at the MECP2gene and esophageal symptoms andmanometric findings.

PATIENTS AND METHODSPatientsThirty-two consecutive patients withRett syndrome who were seen betweenSeptember 2004 and March 2006 wereincluded in this study. These patients hada history of feeding problems and werereferred for neurologic assessmenteither to the Johns Hopkins UniversityChildrens Center or the Kennedy-Kreiger Institute. Feeding problemswere defined as inability to consumeadequate calories orally, prolonged feed-ing time, or food refusal/selectivity.Gastroesophageal reflux disease wasdefined based on prior clinical assess-ment and diagnostic evaluation ofpatients referring physician. Children

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related to the surgery include: dyspha-gia, gagging and retching, nausea, andabdominal distension. Postoperativecomplications or procedure failure canbe as high as 25% in neurologicallyimpaired children and may reflect aninherent esophageal or gastric motilitydisorder.19-26

Studies defining the manometriccharacteristics of the esophagus in neu-rologically impaired children before andafter fundoplication are limited.27 Sincechildren with Rett syndrome demon-strate a high incidence of GERD anddysphagia in the setting of severe neuro-logical impairment, it was the objectiveof this study to better define esophagealneuromuscular function in these chil-dren. We also assessed esophageal motil-ity in Rett patients with previousfundoplication. Finally, we examined theassociation between patients genotype

Table 2. Classification of patients by mutation type and GI symptoms. Number of patients withproximal, distal, and no mutation of the MECP2 gene and the clinical GI symptoms for eachmutation are listed. Specific mutation types are noted for each category.

Number of Patients Reflux Failure to Thrive Dysphagia ConstipationProximalT158M 8 4 7 3 6R133C 4 0 1 1 0R168X 1 1 1 1 1Deletion exon 3 & 4 1 0 1 0 11164 del/A140V 1 1 0 0 1DistalR270X 4 1 2 3 3R306H 2 1 2 0 1R306C 2 2 1 1 1R294X 2 1 1 0 1R255X 1 0 0 0 1P322L 1 0 0 0 0Del 1152-1192 1 1 0 0 0996_997 ins A 1 1 1 1 0807 del 1 1 1 1 11163 del 26 1 1 1 0 11161 del 6 1 0 0 0 0No mutation 2 0 2 0 0

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were considered to have GERD forsymptoms of effortless regurgitation orvomiting and improvement of symptomsafter acid suppression, a history of anabnormal pH probe, or endoscopic evi-dence of esophagitis. A diagnosis of dys-phagia was based on evaluation by apediatric gastroenterologist in consulta-tion with a speech pathologist. Childrenwere considered to have dysphagia ifthey exhibited symptoms of gagging orchoking with oral intake, complaints ofpain with eating, or an abnormal videofluoroscopic swallow study performedwith a speech pathologist. A diagnosis offailure to thrive was made by a pediatricgastroenterologist in consultation with apediatric dietitian using Waterlows cri-teria.28 A history of prior gastrostomy orNissen fundoplication and gastrostomywas also noted for all patients. All sub-jects underwent MECP2 mutationanalysis and esophageal manometrytesting. The study was approved by TheJohns Hopkins University InstitutionalReview Board.

Esophageal ManometryEsophageal manometry was performedwithout sedation after a 4-hour fastingperiod. A flexible 4-channel Koningbergsolid-state catheter (MedicalMeasurement Systems USA, Inc.[MMS], Dover, New Hampshire, USA)was utilized. Pressure results from theesophageal body and LES were ana-lyzed using MMS computer software.Patients were studied for approximately20-30 minutes. Pressure readings wereobtained at the LES and the esophagealbody at distances 3-5 cm and 5-10 cmproximal to the LES based on the sizeof the patient. Pressure results afterapproximately 5-10 wet swallows (mini-mum 3 mL of water or juice) wererecorded in mmHg.

The following manometry resultswere quantified: LES resting pressure,mean percent LES relaxation after allswallows, mean LES residual pressureafter all swallows, mean peak amplitudefor esophageal contractions after allswallows, and percent of swallows fol-

Figure 1. The lower panel shows failure of LES relaxation in a child with Rett syndrome and symp-toms of GERD and dysphagia. The mean LES resting pressure for this patient was approximately26 mmHg (arrow). The top and middle panels show esophageal peristalsis immediately after awet swallow. Time is represented in minutes.

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lowed by abnormal esophageal peristal-sis. Lower esophageal sphincter restingpressures from 6-25 mmHg were consid-ered normal; LES relaxation less than90% and LES residual pressures greaterthan or equal to 8 mmHg were consid-ered abnormal. Esophageal peristalsiswas considered abnormal if less than80% of waves propagated in an ante-grade direction, or if the peak amplitudeof contraction was greater than 100mmHg or less than 30 mmHg.

Genomic DNA Isolation, PCR,Genotyping, and Mutation Analysis ofMECP2Genomic DNA was isolated fromperipheral blood samples or lym-phoblast cell lines using methodsdescribe