Biomedical subjects

Ha Trang

Publications and source records attributed to Ha Trang.

15 recordsLinked to original sources

PubMed2006

[Ondine syndrome or central congenital hypoventilation syndrome].

Congenital central hypoventilation syndrome (CCHS) is a rare disease due to a severely impaired central autonomic control of breathing and dysfunction of the autonomous nervous system. The incidence is estimated to be at 1 of 200,000 livebirths. A heterozygous mutation of PHOX-2B gene is found in 90% of the patients. Association with a Hirschsprung's disease is observed in 16% of the cases. Despite a high mortality rate and a lifelong dependence to mechanical ventilation, the long-term outcome of CCHS should be ultimately improved by multidisciplinary and coordinated follow-up of the patients.

Genes, Dominant↗

PubMed2005

Pediatric disorders with autonomic dysfunction: what role for PHOX2B?

Hirschsprung disease, neuroblastomas, and congenital central hypoventilation syndrome can occur in combination, and familial cases have been reported in all three conditions. This suggests variable expression of a single genetic abnormality as the common cause to these neural crest disorders. Because the PHOX2B gene is pivotal in the development of most relays of the autonomic nervous system, including all autonomic neural crest derivatives, it was considered a candidate gene for the above conditions. Recent studies have shown that 1) PHOX2B is the main disease-causing gene for congenital central hypoventilation syndrome, an autosomal dominant disorder with incomplete penetrance; 2) PHOX2B is the first gene for which germline mutations have been demonstrated to predispose to neuroblastoma; and 3) Hirschsprung disease was associated with an intronic single-nucleotide polymorphism of the PHOX2B gene in a case-control study. For clarifying the variable clinical expression of the autonomic nervous system dysfunction observed in neural crest disorders, international databases of clinical symptoms and molecular test results should be established. Furthermore, the development of genetic mouse models should help to improve our understanding of the molecular mechanisms underlying neural crest disorders.

Animals↗

PubMed2005

PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome.

The Phox2b gene is necessary for autonomic nervous-system development. Phox2b-/- mice die in utero with absent autonomic nervous system circuits, since autonomic nervous system neurons either fail to form or degenerate. We first identified the Phox2b human ortholog, PHOX2B, as the gene underlying congenital central hypoventilation syndrome (CCHS, or Ondine curse), with an autosomal dominant mode of inheritance and de novo mutation at the first generation. We have subsequently shown that heterozygous mutations of PHOX2B may account for several combined or isolated disorders of autonomic nervous-system development--namely, tumors of the sympathetic nervous system (TSNS), such as neuroblastoma and late-onset central hypoventilation syndrome. Here, we report the clinical and molecular assessments of a cohort of 188 probands with CCHS, either isolated or associated with Hirschsprung disease and/or TSNS. The mutation-detection rate was 92.6% (174/188) in our series, and the most prevalent mutation was an in-frame duplication leading to an expansion of +5 to +13 alanines in the 20-alanine stretch at the carboxy terminal of the protein. Such findings suggest PHOX2B mutation screening as a simple and reliable tool for the diagnosis of CCHS, independent of the clinically variable phenotype. In addition, somatic mosaicism was detected in 4.5% of parents. Most interestingly, analysis of genotype-phenotype interactions strongly supports the contention that patients with CCHS who develop malignant TSNS will harbor either a missense or a frameshift heterozygous mutation of the PHOX2B gene. These data further highlight the link between congenital malformations and tumor predisposition when a master gene in development is mutated.

Animals↗

PubMed2005

Relevance of a portable spirometer for detection of small airways obstruction.

While portable spirometers are increasingly used, little attention has been paid to test their validity for measurement of flows in small airways. The aim of this study was to compare the Spirotel portable spirometer to a laboratory spirometer (Jeager PFT), with regard to accuracy in measuring forced expiratory flows, and more specifically those influenced by small airways (FEF(25-75)). Fifty-nine children (mean age, 12 years; range, 7-17), were studied at baseline and after a bronchodilator inhalation. Spirometers were tested separately in a randomly designed order. A total of 117 sessions of flow-volume curves was performed with each spirometer. We obtained at least two acceptable and reproducible curves in 88% and 76% of the sessions, with the laboratory and the portable spirometers, respectively. Unacceptable curves were easily detected by visual inspection of flow-time and flow-volume waveforms. Agreement was excellent between spirometers for the measurement of all expiratory flows, both at baseline and postbronchodilator. More specifically, agreement between spirometers was as high for measurements of FEF(25-75) (intraclass correlation coefficients 0.97) as for proximal flows. High correlations were found between baseline expiratory flows measured by each spirometer (and expressed as percent of predicted values), both in large and small airways (P < 0.001). The portable spirometer was highly sensitive for detecting small airways obstruction, as compared to the laboratory spirometer. Finally, the magnitudes of bronchodilator-related flow changes were also highly correlated, both in large and small airways (P < 0.001 and P = 0.004, respectively). We conclude that the Spirotel portable spirometer is reliable for measurement of forced expiratory flows, in large and small airways, provided that all curve waveforms can be stored and available for visual inspection.

Administration, Inhalation↗

PubMed2005

Short-term blood pressure and heart rate variability in congenital central hypoventilation syndrome (Ondine's curse).

The effect of CCHS (congenital central hypoventilation syndrome, or Ondine's curse) on short-term BP (blood pressure) and HR (heart rate) variability was evaluated in 16-year-old subjects presenting a form of CCHS requiring night ventilatory assistance. The 12 patients were compared with 12 age- and gender-matched healthy volunteers. Recordings were obtained during daytime while the subjects were breathing spontaneously. Continuous BP was measured with a Finapres device in the supine, head-up tilt and standing positions. The manoeuvre of actively standing was also analysed. HR levels were elevated in CCHS subjects at supine rest (+23%) with a reduced HR overall variability (-88%). The low- and high-frequency components of HR variability were affected. BP levels were preserved at rest, but the manoeuvres demonstrated a limited capacity to elevate BP. There was no overshoot in BP during the manoeuvre of actively standing, and steady standing BP levels in patients were not higher than supine BP levels as usually observed in healthy controls. The spontaneous baroreflex sensitivity estimated using the sequence technique or the cross-spectral analysis fell in the patients to approx. one-third of the sensitivity estimated in the healthy controls whatever the position. This cardiovascular profile suggests a predominant vagal dysfunction with signs of vagal withdrawal and baroreflex failure, and relative preservation of the cardiac and vascular sympathetic function. It is likely that the impaired ontogeny of the visceral reflexes, considered now to cause CCHS syndrome, includes the baroreceptive pathway and mainly its vagal component.

Adolescent↗

PubMed2005

The French Congenital Central Hypoventilation Syndrome Registry: general data, phenotype, and genotype.

OBJECTIVE: To analyze the main clinical features, genetic mutations, and outcomes of patients of the French Congenital Central Hypoventilation Syndrome (CCHS) Registry. DESIGN: A country-wide cohort established throughout a long-term multicenter effort. PATIENTS: Seventy French patients with CCHS (29 male patients and 41 female patients). METHODS: The following items were analyzed: the most important moments of the disease course; the main clinical characteristics; associated pathologic conditions; management; clinical outcome; and genetic mutations. RESULTS: An average of four new cases of CCHS per year was observed in the last 5 years. Thus, the incidence may be estimated to be 1 per 200,000 live births in France. The median age at diagnosis was 3.5 months (range, 0.5 to 15 months) before 1995 and < 2 weeks in the last 5 years (p = 0.01). CCHS occurred in isolation in 58 of 70 patients. In the remainder, it was associated with Hirschsprung disease (HSCR) [nine patients], Hirschsprung and neural crest tumor (two patients), and growth hormone deficiency (one patient). Among the 50 patients who lived beyond 1 year of age, all but one received nighttime ventilation, with 10 of them (20%) receiving it noninvasively. Three patients (6%) required daytime ventilatory support in addition to nighttime ventilation. The overall mortality rate was 38% (95% confidence interval [CI], 27 to 49%). The median age at death was 3 months (range, 0.4 months to 21 years). The 2-year mortality rate was greater in male patients than in female patients (p = 0.02; relative risk [RR], 2.71; 95% CI, 1.14 to 6.47) but was not affected by HSCR (p = 0.93; RR, 0.95; 95% CI, 0.28 to 3.2). The 43 patients who are currently alive (11 men; sex ratio, 0.4) have a mean age of 9 years (range, 2 months to 27 years). Among the 34 patients tested thus far, heterozygous mutations of the paired-like homeobox gene 2B (PHOX2B) gene were found in 31 patients (91%). CONCLUSION: Our four major findings are the extreme rarity of CCHS, the improved recognition over time, the lack of effect of HSCR on the mortality rate, and the high frequency of PHOX2B mutations.

Female↗

PubMed2004

Genetics and early disturbances of breathing control.

Early disturbances in breathing control, including apneas of prematurity and apparently life-threatening events, account for some cases of sudden infant death syndrome and for a rare disorder called congenital central hypoventilation syndrome (CCHS). Data suggesting a genetic basis for CCHS have been obtained. Recently, we found heterozygous de novo mutations of the PHOX2B gene in 18 of 29 individuals with CCHS. Most mutations consisted of five to nine alanine expansions within a 20-residue polyalanine tract, probably resulting from nonhomologous recombination. Other mutations, generally inherited from one of the parents, in the coding regions of genes involved in the endothelin and RET signaling pathways and in the brain-derived-neurotrophic factor (BDNF) gene have been found in a few CCHS patients. Interestingly, all these genes are involved in the development of neural crest cells. Targeted disruption of these genes in mice has provided information on the pathophysiological mechanisms underlying CCHS. Despite the identification of these genes involved in breathing control, none of the genetically engineered mice developed to date replicate the full human CCHS respiratory phenotype. Recent insights into the genetic basis for CCHS may shed light on the genetics of other early disturbances in breathing control, such as apnea of prematurity and sudden infant death syndrome.

Animals↗

PubMed2004

Sleep desaturation: comparison of two oximeters.

Oxygen saturation is measured by pulse oximetry during sleep studies. Body movements and peripheral vasoconstriction related to respiratory events may interfere with measurements by conventional oximeters. Our objective was to compare the detection rate of sleep desaturations by two oximeters, one of which used new motion-resistant technology. We studied 34 children (median age, 13 years; range, 3-18) with suspected sleep-disordered breathing. During polysomnography, oxygen saturation was measured by two oximeters set on fast mode: the motion-resistant Radical oximeter (2-sec averaging), and the conventional Nellcor N-200 oximeter (2-3-sec averaging). Respiratory events were identified based on airflow signal. The numbers of respiratory event-related desaturations > or =3% or > or =5% detected by each oximeter were determined. Valid desaturations were defined using the Nellcor plethysmographic waveform and the Radical signal-quality data. Hypoxemic respiratory events were those with associated valid desaturation. In total, 1,278 respiratory events were identified and pooled. Basal oxygen saturation measured just before event onset was not different between oximeters (Radical: 98%; range, 84-100; Nellcor: 97%; range, 86-100; P = ns). However, the Radical detected a greater number of valid desaturations than did the Nellcor for any level of desaturation (respectively, N = 651 and 476 desaturations > or =3%, P < 0.001; and N = 232 and 146 desaturations > or =5%, P = 0.01). Consequently, for each patient, the number of hypoxemic respiratory events per hour of sleep was greater using the Radical than using the Nellcor (P = 0.002, and P = 0.021, for desaturation > or =3% and > or =5%, respectively). In conclusion, standardized oximeter settings are required to achieve more accurate assessments of hypoxemia in children with sleep-disordered breathing.

Child↗

PubMed2004

PHOX2B gene mutation in a patient with late-onset central hypoventilation.

Congenital central hypoventilation syndrome, which is related to abnormal autonomic control of breathing and typically manifests at birth, was recently associated with PHOX2B gene mutations. In contrast, central hypoventilation with later onset constitutes a poorly defined group of unknown etiology. Here, we report on the identification of a de novo heterozygous PHOX2B mutation in a patient with central hypoventilation manifesting in childhood. This finding suggests that some of these cases may be genetically determined and allelic to congenital central hypoventilation syndrome.

Base Sequence↗

PubMed2003

Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse).

Congenital central hypoventilation syndrome (CCHS, Ondine's curse) is a rare disorder of the chemical control of breathing. It is frequently associated with a broad spectrum of dysautonomic symptoms, suggesting the involvement of genes widely expressed in the autonomic nervous system. In particular, the HASH-1-PHOX2A-PHOX2B developmental cascade was proposed as a candidate pathway because it controls the development of neurons with a definitive or transient noradrenergic phenotype, upstream from the RET receptor tyrosine kinase and tyrosine hydroxylase. We recently showed that PHOX2B is the major CCHS locus, whose mutation accounts for 60% of cases. We also studied the proneural HASH-1 gene and identified a heterozygous nucleotide substitution in three CCHS patients. To analyze the functional consequences of HASH-1 mutations, we developed an in vitro model of noradrenergic differentiation in neuronal progenitors derived from the mouse vagal neural crest, reproducing in vitro the HASH-PHOX-RET pathway. All HASH-1 mutant alleles impaired noradrenergic neuronal development, when overexpressed from adenoviral constructs. Thus, HASH-1 mutations may contribute to the CCHS phenotype in rare cases, consistent with the view that the abnormal chemical control of breathing observed in CCHS patients is due to the impairment of noradrenergic neurons during early steps of brainstem development.

Alleles↗

PubMed2003

Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS or Ondine's curse; OMIM 209880) is a life-threatening disorder involving an impaired ventilatory response to hypercarbia and hypoxemia. This core phenotype is associated with lower-penetrance anomalies of the autonomic nervous system (ANS) including Hirschsprung disease and tumors of neural-crest derivatives such as ganglioneuromas and neuroblastomas. In mice, the development of ANS reflex circuits is dependent on the paired-like homeobox gene Phox2b. Thus, we regarded its human ortholog, PHOX2B, as a candidate gene in CCHS. We found heterozygous de novo mutations in PHOX2B in 18 of 29 individuals with CCHS. Most mutations consisted of 5-9 alanine expansions within a 20-residue polyalanine tract probably resulting from non-homologous recombination. We show that PHOX2B is expressed in both the central and the peripheral ANS during human embryonic development. Our data support an essential role of PHOX2B in the normal patterning of the autonomous ventilation system and, more generally, of the ANS in humans.

Alanine↗

PubMed2003

Exclusion of RNX as a major gene in congenital central hypoventilation syndrome (CCHS, Ondine's curse).

Congenital central hypoventilation syndrome (CCHS) is a rare condition for which segregation analyses have suggested genetic factors. The respiratory phenotype of Rnx knock-out mice together with the Rnx expression at the brainstem level prompted us to consider the RNX gene as a candidate for CCHS in human. The screening of the RNX gene in a series of 25 patients with CCHS did not reveal any significant nucleotide variation. We therefore conclude that RNX is not a major gene for CCHS in human.

DNA↗

PubMed2003

24-hour BP in children with congenital central hypoventilation syndrome.

OBJECTIVE: To study circadian BP patterns in patients with congenital central hypoventilation syndrome (CCHS). DESIGN: Case-control study. SETTING: Teaching hospital in Paris, France. PATIENTS: Eleven patients with CCHS (median age, 13 years; range, 6 to 18 years) and 11 sex- and height-matched control subjects. INTERVENTION: None. METHODS: Each subject underwent 24-h ambulatory BP monitoring. Oxygen saturation and end-tidal PCO(2) were monitored noninvasively. Polysomnography was performed to determine sleep times. All patients with CCHS received mechanical ventilation during sleep. Mean values for systolic BP (SBP) and diastolic BP (DBP) during wakefulness and sleep were analyzed. Nocturnal BP "dipping" was defined as the difference in mean SBP (and/or DBP) between wakefulness and sleep, divided by individual waking mean values. BP "dippers" were defined as subjects showing at least 10% nocturnal dipping. RESULTS: Patients with CCHS had BPs in the low normal range of normative data. As compared to control subjects, patients with CCHS had lower BP during wakefulness (p = 0.003 and p = 0.016 for SBP and DBP, respectively), and higher BP during sleep (p = 0.016 and p = 0.002). Nocturnal BP dipping was abnormally reduced in patients with CCHS (p = 0.000). Ten of the 11 patients with CCHS were BP nondippers, compared to none of the control subjects. CONCLUSION: The abnormal circadian BP pattern observed in children and adolescents with CCHS may be related to autonomic nervous dysfunction. Lifelong cardiovascular follow-up is recommended for patients with CCHS.

Adolescent↗

PubMed2002

Use of nasal cannula for detecting sleep apneas and hypopneas in infants and children.

We evaluated tolerance of nasal cannula (NC) by 14 infants (median age, 2.6 months) and 16 children (median age, 5.5 years) with suspected obstructive sleep apnea syndrome and compared the efficacy of the NC with that of a nasobuccal thermistor in detecting obstructive apneas (OA) and obstructive hypopneas (OH) on polysomnography traces. The relationship between cannula flow and esophageal pressure was assessed in six patients. Time spent with an uninterpretable flow signal was longer when using a cannula than when using a thermistor in infants (p < 0.05) and children (p < 0.01), and it was longer in the younger patients (p < 0.05). Among the 650 OA-OH detected by either method, only 38% were detected by both, and 58% were detected by the cannula and missed by the thermistor, so that the apnea-hypopnea index was higher with cannula than with thermistor in each age group (p < 0.01). More hypopneas than apneas were detected by the cannula and missed by the thermistor (p < 0.001). Out-of-phase thoracic and abdominal motions and/or changes in the end-tidal CO(2) signal shape were associated with 86% of OH identified by cannula. In the six patients whose esophageal pressure was measured, all respiratory events identified using a cannula were associated with increased "airway resistance." Thus, the NC is more likely than the thermistor to detect OA and OH in infants and children, and this superiority is particularly marked for hypopneas.

Adolescent↗

PubMed2002

Abnormal esophageal motility in children with congenital central hypoventilation syndrome.

BACKGROUND & AIMS: Congenital central hypoventilation syndrome, an unexplained disorder of the central control of breathing that may reflect widespread dysfunction of brainstem structures, is regarded as a form of neuro cristopathy. Because swallowing-induced peristalsis is centrally controlled and depends on neural crest-derived esophageal innervation, we looked for esophageal dysmotility in patients with congenital central hypoventilation syndrome. METHODS: Seven patients without dysphagia or any other upper gastrointestinal tract symptoms were studied prospectively (5 girls and 2 boys; median age, 14 years; range, 11-18 years). They were compared with 7 age- and sex-matched controls. Esophageal manometry was performed using a low-compliance infusion system and the station pull-through technique. At least 10 wet swallows were analyzed in each subject. RESULTS: Pressure wave propagation was abnormal in all 7 patients (median percentage of swallows propagated, 18%, and range, 0-66; controls, 90% and 80-100; P < 0.001). Lower esophageal sphincter relaxation was abnormal in 5 patients (patients, 73% and 53-100; controls, 95% and 90-100; P = 0.01). In 2 patients, lower esophageal sphincter pressure was above the 95th percentile of control values. CONCLUSIONS: These abnormalities are strong evidence of lower esophageal dysfunction in congenital central hypoventilation syndrome. We speculate that the underlying mechanism may be dysfunction of the central structures that control swallowing.

Adolescent↗