Literature search from ms 29/4/2010

Trang, H., A. Girard, et al. (2005). "Short-term blood pressure and heart rate variability in congenital central hypoventilation syndrome (Ondine's curse)." CLINICAL SCIENCE 108(3): 225-30.

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.

Trang, H., B. Laudier, et al. (2004). "PHOX2B gene mutation in a patient with late-onset central hypoventilation." PEDIATRIC PULMONOLOGY 38(4): 349-51.

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.

Tranmer, B. I., W. S. Tucker, et al. (1987). "Sleep apnea following percutaneous cervical cordotomy." CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES 14(3): 262-7.

Sleep apnea (Ondine's Curse) is an uncommon but potentially fatal complication of percutaneous cervical cordotomy. The authors have had the opportunity to review the case histories of 6 patients who have died of sleep apnea following this procedure. In a series of 112 patients, 144 cervical percutaneous cordotomies were performed from 1977 to 1985--80 unilateral cordotomies and 32 staged bilateral cordotomies. Six (5%) patients died as the result of sleep apnea. Five patients (16%) died following bilateral cordotomy and one (1%) patient with pulmonary disease died following unilateral cordotomy. The clinical data of these 6 patients are presented and unique spinal cord pathology is described in this report. The pathophysiology of the sleep apnea syndrome is also discussed.

Tremblay, S., S. Dahinten, et al. (2003). "Factors related to adolescents' self-perceived health." HEALTH REPORTS 14 Suppl: 7-16.

OBJECTIVES: This analysis examines self-perceived health among Canadian adolescents aged 12 to 17, and factors associated with ratings of very good/excellent health. DATA SOURCE: The data are from cycle 1.1 of the 2000/01 Canadian Community Health Survey (CCHS), conducted by Statistics Canada. The sample consisted of 12,715 adolescents aged 12 to 17. ANALYTICAL TECHNIQUES: Cross-tabulations were used to estimate the prevalence of various characteristics and health behaviours for the 12-to-14 and 15-to-17 age groups. Multiple logistic regression was used to model associations between very good/excellent self-reported health and selected characteristics. MAIN RESULTS: In 2000/01, nearly 30% of 12- to 17-year-olds rated their health as poor, fair or good. At ages 15 to 17, girls were less likely than boys to report very good/excellent health and were more likely to have a chronic condition and to have experienced depression in the past year. When other factors were taken into account, the odds of reporting very good/excellent health were significantly lower for teens who were daily smokers, episodic heavy drinkers, physically inactive during leisure time, infrequent consumers of fruit and vegetables, or obese, compared with teens who did not have these characteristics.

Trobliger, R., C. M. Zaroff, et al. (2010). "A nonverbal learning disability in a case of central hypoventilation syndrome without a PHOX2B gene mutation." Child Neuropsychology 16(2): 202-8.

This study examines the neuropsychological profile of a boy with congenital central hypoventilation syndrome (CCHS) without a paired-like homeobox gene (PHOX2B) mutation. CCHS is a rare disorder of autonomic nervous system development characterized by an impaired ventilatory response to hypercarbia and hypoxemia. Mild intellectual deficits are common but a specific cognitive profile is not established in CCHS. We describe a nonverbal learning disorder as a CCHS endophenotype and recommend that detailed neuropsychological testing be performed on all individuals with CCHS. Defining the psycho-educational needs in CCHS may avert compounding the emotional and medical stresses of this already debilitating disorder.

Trochet (2005). "Erratum: PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome (The American Journal of Human Genetics (2005) 76 (421-426))." AMERICAN JOURNAL OF HUMAN GENETICS 76(4): 715.

Trochet, D., F. Bourdeaut, et al. (2004). "Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma." AMERICAN JOURNAL OF HUMAN GENETICS 74(4): 761-4.

Neuroblastoma (NB) is a frequent pediatric tumor for which recurrent somatic rearrangements are known. Germline mutations of predisposing gene(s) are suspected on the basis of rare familial cases and the association of NB with other genetically determined congenital malformations of neural crest-derived cells--namely, Hirschsprung disease (HSCR) and/or congenital central hypoventilation syndrome (CCHS). We recently identified the paired-like homeobox 2B (PHOX2B) gene as the major disease-causing gene in isolated and syndromic CCHS, which prompted us to regard it as a candidate gene in NB. Here, we report on germline mutations of PHOX2B in both a familial case of NB and a patient with the HSCR-NB association. PHOX2B, therefore, stands as the first gene for which germline mutations predispose to NB.
Trochet, D., L. de Pontual, et al. (2008). "Homozygous mutation of the PHOX2B gene in congenital central hypoventilation syndrome (Ondine's Curse)." HUMAN MUTATION 29(5): 770.

Homozygosity for a dominant allele is relatively rare and preferentially observed in communities with high inbreeding. According to the definition of true dominance, similar phenotypes should be observed in patients heterozygous and homozygous for a dominant mutation. However, the homozygous phenotype usually tends to be more severe than the heterozygous one. In these cases, the wild-type and mutant alleles are semi-dominant. Here we report a patient with a Congenital Central Hypoventilation Syndrome (CCHS) phenotype and homozygosity for a PHOX2B gene mutation leading to an alanine expansion shorter than the threshold hitherto observed in CCHS patients with a heterozygous mutation. This observation adds the concept of mutational threshold per se to the discussion about dominant and recessive alleles.

Trochet, D., L. de Pontual, et al. (2008). "PHOX2B germline and somatic mutations in late-onset central hypoventilation syndrome." AMERICAN JOURNAL OF RESPIRATORY & CRITICAL CARE MEDICINE 177(8): 906-11.

RATIONALE: Late-onset central hypoventilation syndrome (LO-CHS) is a rare disorder that may manifest as early as infancy or as late as during adulthood. The potential overlap of LO-CHS with congenital CHS is under debate, even though both disorders can result from heterozygous PHOX2B gene mutations. OBJECTIVES: To characterize the PHOX2B status in a series of 25 patients with LO-CHS referred from 3 months of age to adulthood. Whenever a PHOX2B mutation was identified, we ascertained its germline or somatic origin in both patients with LO-CHS and in 15 parents of probands with congenital CHS found to harbor a PHOX2B mutation. METHODS: The PHOX2B gene was analyzed by direct DNA sequencing and origin of the mutation evaluated by fluorescent PCR. MEASUREMENTS AND MAIN RESULTS: We have identified a heterozygous PHOX2B gene mutation in 17 of 25 patients with LO-CHS. The far most frequent mutation results in a germline +5 alanine expansion in the series of 20 alanines (15 cases) that show incomplete penetrance and variable expressivity, possibly resulting from combined environmental and genetic factors. PHOX2B frameshift and missense mutations have also been identified in patients with LO-CHS. Importantly, one parent found to harbor a somatic mosaic for a +8 alanine expansion developed alveolar hypoventilation in his 40s. CONCLUSIONS: These data indicate that PHOX2B gene mutations should be systematically examined in any adult with unexplained central hypoventilation and raise the question of follow-up for apparently healthy parents found to harbor a somatic mosaic for the PHOX2B mutation identified in their child.

Trochet, D., S. J. Hong, et al. (2005). "Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction." HUMAN MOLECULAR GENETICS 14(23): 3697-708.

Heterozygous mutations of the PHOX2B gene account for a broad variety of disorders of the autonomic nervous system, either isolated or combined, including congenital central hypoventilation syndrome (CCHS), tumours of the sympathetic nervous system and Hirschsprung disease. In CCHS, the prevalent mutation is an expansion of a 20-alanine stretch ranging from +5 to +13 alanines, whereas frameshift and missense mutations are found occasionally. To determine the molecular basis of impaired PHOX2B function, we assayed the transactivation and DNA binding properties of wild-type and mutant PHOX2B proteins. Furthermore, we investigated aggregate formation by proteins with polyalanine tract expansions ranging from +5 to +13 alanines using immunofluorescence of transfected cells and gel filtration of in vitro translated proteins. We found that transactivation of the dopamine beta-hydroxylase promoter by PHOX2B proteins with frameshift and missense mutations was abolished or severely curtailed, as was in vitro DNA binding although the proteins localized to the nucleus. The transactivation potential of proteins with polyalanine tract expansions declined with increasing length of the polyalanine stretch, and DNA binding was affected for an expansion of +9 alanines and above. Cytoplasmic aggregation in transfected cells was only observed for the longest expansions, whereas even the short expansion mutants were prone to form multimers in vitro. Such a tendency to protein misfolding could explain loss of transactivation for alanine expansion mutations. However, additional mechanisms such as toxic gain-of-function may play a role in the pathogenic process.

Trochet, D., Y. Mathieu, et al. (2009). "In Vitro studies of non poly alanine PHOX2B mutations argue against a loss-of-function mechanism for congenital central hypoventilation." HUMAN MUTATION 30(2): E421-31.

A wide range of autonomic dysfunctions, i.e. Central Hypoventilation Syndromes, Hirschsprung disease and Tumours of the Sympathetic Nervous System have been ascribed to heterozygous PHOX2B mutations in man. The PHOX2B mutations reported include polyalanine expansions in a 20 alanines tract, missense, frameshift mutations and nonsense mutation. Some genotype/phenotype correlations have been drawn, but the molecular mechanism(s) underlying them remain(s) unclear. So far, loss-of-function, gain-of-function and dominant negative effects have been proposed as disease-causing mechanisms for polyalanine expansions. Indeed, mutant with an expanded polyalanine tract result in decreased transactivation of known target genes and protein misfolding leading to oligomerisation in vitro for all expansions and to cytoplasmic protein aggregation for longer expansions. We extended the molecular studies to other non-polyalanine expansion mutations and show that most PHOX2B protein mutants oligomerize even in the absence of the normal 20 alanines tract. Conversely, a premature stop codon mutation in a CHS patient leads to the production of an N-terminally truncated protein by re-initiation of translation that does not form oligomers. Therefore, PHOX2B misfolding is not the only mechanism leading to dysfunction of the ventilatory autonomic system. (c) 2008 Wiley-Liss, Inc.

Trochet, D., L. M. O'Brien, et al. (2005). "PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome.[Erratum appears in Am J Hum Genet. 2005 Apr;76(4):715 Note: Niemann, Stephan [added]]." AMERICAN JOURNAL OF HUMAN GENETICS 76(3): 421-6.

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.

Trois, M. S. G. and C. L. Marcus (2003). "Sleep-disordered breathing in children: Keys to assessment." Journal of Respiratory Diseases - For Pediatricians 5(2): 53-60.

Sleep-disordered breathing, such as obstructive sleep apnea syndrome (OSAS), is common in children and can be associated with significant morbidity. It is important to ask about snoring during routine office visits, since parents often do not volunteer this information. Children with OSAS may have normal physical findings or nonspecific findings related to adenoidal hypertrophy, such as mouth-breathing, nasal obstruction, adenoidal facies, and hyponasal speech. In addition to snoring and apnea, associated signs include daytime neurobehavioral abnormalities and sleepiness. A sleep study is the best way to confirm the diagnosis. Treatment of OSAS usually consists of tonsillectomy and adenoidectomy. Continuous positive airway pressure is an option for some patients. Children with congenital central hypoventilation syndrome usually present with apnea or cyanosis at birth and require ventilatory support during sleep.

Truelsen, T., R. Bonita, et al. (1998). "Stroke incidence and case fatality in two populations: the Auckland Stroke Study and the Copenhagen City Heart Study." NEUROEPIDEMIOLOGY 17(3): 132-8.

Comparison of stroke incidence and case fatality in different parts of the world provides information that may lead to a better understanding of the disease. In this report we have investigated these two aspects in two large populations, one in Auckland, New Zealand, and the other in Copenhagen, Denmark (the Copenhagen City Heart Study, CCHS). Incidence rates of stroke are higher for men than women in both studies. The stroke incidence rate ratios between Auckland men and CCHS men are significantly different in most age groups, whereas in women the incidence rates differ only in one age group. The age- and sex-adjusted incidence rates are higher in the CCHS for both men and women as compared to the Auckland Stroke Study. The age-adjusted incidence rate ratio is higher for men than women in both studies: 1.29 in the Auckland Stroke Study and 1.54 in the CCHS. The 28-day case fatality is also higher in the CCHS than in Auckland and is higher for women than men in both studies. The incidence rate of stroke and the 28-day case fatality is higher in the CCHS as compared to the Auckland Stroke Study in both men and women. A very high proportion of smokers in CCHS may explain some of the differences in incidence rates in the two populations.

Tsarovina, K., A. Pattyn, et al. (2004). "Essential role of Gata transcription factors in sympathetic neuron development." DEVELOPMENT 131(19): 4775-4786.

Sympathetic neurons are specified during their development from neural crest precursors by a network of crossregulatory transcription factors, which includes Mash1, Phox2b, Hand2 and Phox2a. Here, we have studied the function of Gata2 and Gata3 zinc-finger transcription factors in autonomic neuron development. In the chick, Gata2 but not Gata3 is expressed in developing sympathetic precursor cells. Gata2 expression starts after Mash1, Phox2b, Hand2 and Phox2a expression, but before the onset of the noradrenergic marker genes Th and Dbh, and is maintained throughout development. Gata2 expression is affected in the chick embryo by Bmp gain- and loss-of-function experiments, and by overexpression of Phox2b, Phox2a, Hand2 and Mash1. Together with the lack of Gata2/3 expression in Phox2b knockout mice, these results characterize Gata2 as member of the Bmp-induced cluster of transcription factors. Loss-of-function experiments resulted in a strong reduction in the size of the sympathetic chain and in decreased Th expression. Ectopic expression of Gata2 in chick neural crest precursors elicited the generation of neurons with a non-autonomic, Th-negative phenotype. This implies a function for Gata factors in autonomic neuron differentiation, which, however, depends on co-regulators present in the sympathetic lineage. The present data establish Gata2 and Gata3 in the chick and mouse, respectively, as essential members of the transcription factor network controlling sympathetic neuron development.

Tsarovina, K., J. Schellenberger, et al. (2008). "Progenitor cell maintenance and neurogenesis in sympathetic ganglia involves Notch signaling." Molecular and Cellular Neuroscience 37(1): 20-31.

Differentiation of noradrenergic neurons from neural crest-derived precursors results in the formation of primary sympathetic ganglia. As sympathetic neurons continue to divide after the acquisition of adrenergic and neuronal properties it was unclear, whether the increase in neuron number during neurogenesis is due to neuron proliferation rather than differentiation of progenitor cells. Here, we demonstrate Sox10-positive neural crest progenitor cells and continuous sympathetic neuron generation from Phox2b-positive autonomic progenitors during early chick sympathetic ganglion development. In vivo activation of Notch signaling resulted in a decreased neuronal population, whereas expression of the Notch signaling inhibitor Su(H)^DBM increased the proportion of Scg10-positive neurons. Similar results were obtained for sensory dorsal root ganglia (DRG). The effects of Notch gain- and loss-of-function experiments support the notion that progenitor maintenance and neuron differentiation from progenitor cells are essential for neurogenesis also during early sympathetic ganglion development. copyright 2007 Elsevier Inc. All rights reserved.

Tu, E., R. D. Bagnall, et al. (2010). "Post-mortem pathologic and genetic studies in "dead in bed syndrome" cases in type 1 diabetes mellitus." HUMAN PATHOLOGY 41(3): 392-400.

Dead in bed syndrome is a poorly understood cause of sudden death in young people with type 1 diabetes. The underlying cause remains unknown. One possible explanation may involve prolongation of the QT interval followed by a terminal malignant arrhythmia. Risk factors associated with QT interval prolongation include hypoglycemia and cardiac autonomic neuropathy. We sought to identify myocardial cellular changes and genetic influences that may contribute to the pathogenesis of dead in bed syndrome. Post-mortem reports between 1994 and 2006 from the 2 largest Departments of Forensic Medicine in Australia were reviewed for dead in bed syndrome cases. Post-mortem heart sections were immunohistochemically stained for collagen types I and III and connective tissue growth factor (CTGF). Genomic DNA was prepared from post-mortem samples, and genetic analysis was performed in the SCN5A, G6PC, PHOX2B, and CTGF genes. Twenty-two dead in bed syndrome cases were identified and staining of heart sections for collagen I and III, and CTGF showed no differences between dead in bed syndrome cases and controls. Genetic screening of SCN5A revealed 3 silent polymorphisms A29A, E1061E, and D1819D and 1 protein-changing variant H558R. No genetic variants were found in G6PC, PHOX2B, and CTGF, and dead in bed syndrome cases were not associated with the G-945C CTGF promoter polymorphism. In conclusion, this study is the first to investigate potential pathogenic mechanisms underlying the dead in bed syndrome in type 1 diabetes with the results substantially adding to knowledge of this condition. Understanding the causes and triggers of dead in bed syndrome will be critical in facilitating the identification of patients with type 1 diabetes at highest risk of developing sudden death. Copyright 2010 Elsevier Inc. All rights reserved.

Umphrey, G. J., O. Kendall, et al. (2001). "Assessing the surveillance capability of Canada's national health surveys." CHRONIC DISEASES IN CANADA 22(2): 50-6.

We assessed Canada's national health surveys as surveillance instruments, with emphasis on comparing the temporal structure of data sets with those generated by the US Behavioral Risk Factor Surveillance System (BRFSS). Only the Canadian Tobacco Use Monitoring Survey (CTUMS) has the BRFSS capability to generate continuous, uniform time series with monthly intervals. These time series can offer substantial extra value for retrospective analysis such as program evaluation in addition to surveillance. Expanding CTUMS is a simple option for providing an ongoing, uniform monthly survey instrument for non-tobacco variables. The Canadian Community Health Survey (CCHS) will generate monthly data, and could potentially generate useful continuous time series even though surveys at the health region and provincial levels will alternate annually. Reconfiguring the CCHS, or even implementing a provincial surveillance survey based on the BRFSS model are other viable options, but each option has associated tradeoffs or obstacles.

Unsicker, K., K. Huber, et al. (2005). "The chromaffin cell and its development." NEUROCHEMICAL RESEARCH 30(6-7): 921-925.

This article summarizes some of the recent progress in understanding the development of chromaffin cells. These cells are derivatives of the neural crest and are intimately associated with the sympathetic nervous system. Although a common sympathoadrenal (SA) progenitor cell for chromaffin cells and sympathetic neurons has been postulated, there is evidence to suggest that chromaffin progenitors are already distinct, at least in part, from neuronal SA progenitors prior to invading the adrenal gland. The concept of an essential role of glucocorticoid signalling for chromaffin cell development has been shaken by the observation that chromaffin cells in mice lacking the glucocorticoid receptor develop largely normal. Distinct developmental requirements of chromaffin cells and sympathetic neurons must also be assumed based on the analyses of mice carrying targeted mutations of the genes for two transcription factors, MASH1 and Phox2B. Both genes are expressed by SA progenitors, but are distinctly required for the development of chromaffin cells and sympathetic neurons. There is an ongoing search for molecules selectively operating at the sites, where chromaffin cells develop. Such molecules may be candidates for triggering the distinct developmental pathway of chromaffin cells, as opposed to sympathetic neurons. copyright 2005 Springer Science+Business Media, Inc.