Apnea central del sueño como única manifestación de agenesia del cuerpo calloso / Central sleep apnea as the only manifestation of agenesis of the corpus callosum

La apnea central del sueño (ACS) es un trastorno que se caracteriza por la presencia durante el sueño de apneas que se acompañan de disminución o abolición del esfuerzo respiratorio. Su frecuencia no es bien conocida, pero se estima menor al 5%, presentándose en un grupo heterogéneo de entidades como serían la ACS primaria, con respiración periódica Cheyne-Stokes, condiciones médicas no Cheyne-Stokes, respiración periódica en las alturas, medicaciones o sustancias y emergente al tratamiento. Se describe el caso de un varón de 53 años con diagnóstico de ACS y hallazgo de agenesia del cuerpo calloso como único hallazgo patológico predisponente

Central sleep apnea (CSA) is a disorder characterized by the presence of apneas during sleep that are accompanied by a decrease or abolition of respiratory effort. Its frequency is not well known, but it is estimated to be less than 5%, occurring in a heterogeneous group of entities such as primary CSA, with periodic Cheyne-Stokes respiration, non-Cheyne-Stokes medical conditions, periodic respiration at heights, medications or substances and emergent to treatment. The case of a 53-year-old man with a diagnosis of CSA and finding agenesis of the corpus callosum as the only predisposing pathological finding is described

A respiratory/Hirschsprung phenotype in a three-generation family associated with a novel pathogenic PHOX2B splice donor mutation.

BACKGROUND: Mutations in the PHOX2B gene cause congenital central hypoventilation syndrome (CCHS), a rare autonomic nervous system dysfunction disorder characterized by a decreased ventilatory response to hypercapnia. Affected subjects develop alveolar hypoventilation requiring ventilatory support particularly during the non-REM phase of sleep. In more severe cases, hypoventilation may extend into wakefulness. CCHS is associated with disorders characterized by the defective migration/differentiation of neural crest derivatives, including aganglionic megacolon or milder gastrointestinal phenotypes, such as constipation. Most cases of CCHS are de novo, caused by heterozygosity for polyalanine repeat expansion mutations (PARMs) in exon 3. About 10% of cases are due to heterozygous non-PARM missense, nonsense or frameshift mutations. METHODS: We describe a three-generation Maltese-Caucasian family with a variable respiratory/Hirschsprung phenotype, characterized by chronic constipation, three siblings with Hirschsprung disease necessitating surgery, chronic hypoxia, and alveolar hypoventilation requiring non-invasive ventilation. RESULTS: The sequencing of PHOX2B revealed a novel heterozygous c.241+2delT splice variant in exon 1 that segregates with the CCHS/Hirschsprung phenotype in the family. The mutation generates a non-functional splice site with a deleterious effect on protein structure and is pathogenic according to ACMG P VS1, PM2, and PP1 criteria. CONCLUSION: This report is significant as no PHOX2B splice-site mutations have been reported. Additionally, it highlights the variability in clinical expression and disease severity of non-PARM mutations.

Causative and common PHOX2B variants define a broad phenotypic spectrum.

Paired Like homeobox 2B (PHOX2B) is a gene crucial for the differentiation of the neural lineages of the autonomic nervous system (ANS), whose coding mutations cause congenital central hypoventilation syndrome (CCHS). The vast majority of PHOX2B mutations in CCHS is represented by expansions of a polyalanine region in exon 3, collectively defined PARMs (PolyAlanine Repeat Mutations), the minority being frameshift, missense and nonsense mutations, defined as NPARMs (Non-PARMs). While PARMs are nearly exclusively associated with isolated CCHS, most of NPARMs is detected in syndromic CCHS, presenting with neuroblastoma and/or Hirschsprung disease. More recently, evidence of a complex role of PHOX2B in the pathogenesis of a wider spectrum of ANS disorders has emerged. Indeed, common and hypomorphic PHOX2B variants, including synonymous, polyalanine-contractions, gene deletions may influence the occurrence of either apparent life-threatening event (ALTE), Sudden Infant Death Syndrome (SIDS), neuroblastoma, or isolated HSCR, likely through small effects on PHOX2B expression levels. After an introduction to the role of PHOX2B in the ANS development, causative mutations, common variants, and gene expression deregulation of the PHOX2B gene are discussed, though the involvement of synonymous variants and contractions requires further confirmations with respect to ANS disorders and molecular mechanisms underlying the PHOX2B phenotypic heterogeneity.

A novel PHOX2B gene mutation in an extremely low birth weight infant with congenital central hypoventilation syndrome and variant Hirschsprung's disease.

Congenital central hypoventilation syndrome is a disorder of respiratory control caused by mutations in the paired-like homeobox 2B gene. Mutations in the paired-like homeobox 2B gene are also responsible for Hirschsprung's disease. Variant Hirschsprung's disease is a rarer disorder that does not meet the diagnostic criteria of Hirschsprung's disease, although severe functional bowel obstruction persists. We present a case of an extremely low birth weight infant with congenital central hypoventilation syndrome and variant Hirschsprung's disease. A male infant who was diagnosed to have fetal growth restriction and polyhydramnios was delivered by emergency cesarean section at 30 weeks and 3 days of gestational age due to non-reassuring fetal status. The birth weight was 979 g, and intensive care was started immediately following delivery. The patient exhibited refractory apnea and was diagnosed with congenital central hypoventilation syndrome by genetic testing of the paired-like homeobox 2B gene. The patient also exhibited refractory functional bowel obstruction and was diagnosed to have variant Hirschsprung's disease through pathological examination of his intestinal specimens. The patient grew slowly but surely with intensive care including mechanical ventilation and parenteral nutrition. However, the patient repeatedly suffered from sepsis and died of fungemia at 197 days of age. This is the first congenital central hypoventilation syndrome case that was accompanied with variant Hirschsprung's disease, and the paired-like homeobox 2B mutation detected in this case (NM_003924.3: c.441G > C; p.(Gln147His)) is novel. This case suggests that the paired-like homeobox 2B mutation causes not only congenital central hypoventilation syndrome and Hirschsprung's disease, but also variant Hirschsprung's disease in humans. It also highlights the extreme difficulty in treating premature infants with severe and prolonged functional bowel obstruction.

Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice.

The respiratory rhythm is generated by the preBötzinger complex in the medulla oblongata, and is modulated by neurons in the retrotrapezoid nucleus (RTN), which are essential for accelerating respiration in response to high CO2 Here we identify a LBX1 frameshift (LBX1FS ) mutation in patients with congenital central hypoventilation. The mutation alters the C-terminal but not the DNA-binding domain of LBX1 Mice with the analogous mutation recapitulate the breathing deficits found in humans. Furthermore, the mutation only interferes with a small subset of Lbx1 functions, and in particular with development of RTN neurons that coexpress Lbx1 and Phox2b. Genome-wide analyses in a cell culture model show that Lbx1FS and wild-type Lbx1 proteins are mostly bound to similar sites, but that Lbx1FS is unable to cooperate with Phox2b. Thus, our analyses on Lbx1FS (dys)function reveals an unusual pathomechanism; that is, a mutation that selectively interferes with the ability of Lbx1 to cooperate with Phox2b, and thus impairs the development of a small subpopulation of neurons essential for respiratory control.

Atypical presentations associated with non-polyalanine repeat PHOX2B mutations.

Congenital central hypoventilation syndrome (CCHS) is a disorder of ventilatory control and autonomic dysregulation that can be caused by mutations in the paired-like homeobox 2B (PHOX2B) gene. The majority of CCHS cases are caused by polyalanine repeat mutations (PARMs) in PHOX2B; however, in rare cases, non-polyalanine repeat mutations (NPARMs) have been identified. Here, we report two patients with NPARMs in PHOX2B. Patient 1 has a mild CCHS phenotype seen only on polysomnogram, which was performed for desaturations and stridor following a bronchiolitis episode, and characterized by night-time hypoventilation and a history of ganglioneuroblastoma. She carried a novel de novo missense variant, p.R102S (c.304C > A), in exon 2. Patient 2 has an atypical CCHS phenotype including micrognathia, gastroesophageal reflux, stridor, hypopnea, and intermittent desaturations. Sleep study demonstrated that Patient 2 had daytime and night-time hypercarbia with obstructive sleep apnea, requiring tracheostomy. On PHOX2B sequencing, she carried a recently identified nonsense variant, p.Y78* (c.234C > G), in exon 1. In summary, we present two patients with CCHS and identified NPARMs in PHOX2B who have distinct differences in phenotype severity, further elucidating the range of clinical outcomes in CCHS and illustrating the necessity of considering PHOX2B mutations when encountering atypical CCHS presentations.

[Clinical and neuropsychological characteristics in congenital central hypoventilation syndrome]. / Aspectos clinicos y neuropsicologicos del sindrome de hipoventilacion central congenita.

INTRODUCTION: Congenital central hypoventilation syndrome (CCHS) syndrome is a rare disease caused by mutations in the PHOX2B gene. Patients show a reduced response to hypercapnia and hypoxia accompanied by diffuse disturbances of the autonomic nervous system and occasionaly also disturbances in neuroimaging. A specific neuropsychological profile has not been described in children and adolescents with CCHS. CASE REPORTS: We describe three cases (aged between 4 and 19 years) with different profiles of affectation in cognitive and functionality. These profiles are compared with the features described in the literature about neuropsychology in CCHS. CONCLUSIONS: The profile of functional impairment in the CCHS is variable: in case 1, a severe global developmental delay with autistic features and marked functional involvement is described. In case 2, bilateral atrophy of the hippocampus is associated with involvement in social cognition and in executive functions with moderate functional repercussion. Case 3 shows difficulties in some cognitive executive functions (planning and non-verbal fluency), but without functional repercussion. Neuropsychological assessment can help in the clinical management of these patients by determining and guiding the need for rehabilitation treatments.

TITLE: Aspectos clinicos y neuropsicologicos del sindrome de hipoventilacion central congenita.Introduccion. El sindrome de hipoventilacion central congenita (SHCC) es una enfermedad rara producida por mutaciones en el gen PHOX2B. Los pacientes muestran una reducida respuesta a la hipercapnia e hipoxia acompañada de alteraciones difusas del sistema nervioso autonomo y ocasionalmente alteraciones en neuroimagen. No se ha descrito un perfil neuropsicologico especifico en los niños y adolescentes con SHCC. Casos clinicos. Se presentan tres casos (de edades comprendidas entre 4 y 19 años) con diferente perfil de afectacion cognitiva y funcional. Se comparan los perfiles de los tres casos con los hallazgos descritos en la bibliografia sobre neuropsicologia en el SHCC. Conclusiones. El perfil de afectacion funcional en el SHCC es variable: en el caso 1 se describe un grave retraso global en el desarrollo con rasgos autistas y acusadas implicaciones funcionales. En el caso 2, la atrofia bilateral del hipocampo se asocia a deficit en cognicion social y alteraciones en funciones ejecutivas con moderada repercusion funcional. El caso 3 muestra dificultades en algunas funciones ejecutivas cognitivas (planificacion y fluidez no verbal), pero sin repercusion funcional. La evaluacion neuropsicologica puede ayudar en el manejo clinico de estos pacientes determinando y orientando la necesidad de tratamientos rehabilitadores.

Inhalational Anesthetics Induce Neuronal Protein Aggregation and Affect ER Trafficking.

Anesthetic agents have been implicated in the causation of neurological and cognitive deficits after surgery, the exacerbation of chronic neurodegenerative disease, and were recently reported to promote the onset of the neurologic respiratory disease Congenital Central Hypoventilation Syndrome (CCHS), related to misfolding of the transcription factor Phox2B. To study how anesthetic agents could affect neuronal function through alterations to protein folding, we created neuronal cell models emulating the graded disease severity of CCHS. We found that the gas anesthetic isoflurane and the opiate morphine potentiated aggregation and mislocalization of Phox2B variants, similar to that seen in CCHS, and observed transcript and protein level changes consistent with activation of the endoplasmic reticulum (ER) unfolded protein response. Attenuation of ER stress pathways did not result in a correction of Phox2B misfolding, indicating a primary effect of isoflurane on protein structure. We also observed that isoflurane hindered the folding and activity of proteins that rely heavily on ER function, like the CFTR channel. Our results show how anesthetic drugs can alter protein folding and induce ER stress, indicating a mechanism by which these agents may affect neuronal function after surgery.

Congenital central hypoventilation syndrome: An overview of etiopathogenesis, associated pathologies, clinical presentation, and management.

Congenital central hypoventilation syndrome (CCHS), known colloquially as Ondine's curse, is a rare disorder characterized by impaired autonomic control of breathing during sleep from the loss of vagal input and diminished sensitivity of CO2 receptors in the medulla. CCHS correlates to the malformation of the neural crest located in the brainstem; this consequently affects the loss of sensitivity of CO2 chemoreceptors, bringing about hypoventilation during sleep. The primary cause of CCHS is the mutation of the paired-like homeobox PHO2XB gene, found in 90% of the patients. This mutation not only affects breathing but also drives neurological abnormalities such as autonomic and neurocognitive dysfunction. Though typically congenital, there have been late-onset (i.e., acquired) cases reported. It is vital for physicians and clinicians to be able to diagnose CCHS due to its similar presentation to other syndromes and disorders, which may cause it to be misdiagnosed and may account for its deleterious effects. CCHS can lead to a constellation of symptoms, and consideration of diseases that present concomitantly with CCHS affords us a better understanding of the etiology of this illness. Although a rare syndrome, we aim to review the current literature to emphasize the pathogenesis, etiology, clinical presentation, symptoms, diagnosis, and current treatment methods of CCHS for clinicians to better identify and understand this condition.

Nonsense pathogenic variants in exon 1 of PHOX2B lead to translational reinitiation in congenital central hypoventilation syndrome.

Pathogenic variants in PHOX2B lead to congenital central hypoventilation syndrome (CCHS), a rare disorder of the nervous system characterized by autonomic dysregulation and hypoventilation typically presenting in the neonatal period, although a milder late-onset (LO) presentation has been reported. More than 90% of cases are caused by polyalanine repeat mutations (PARMs) in the C-terminus of the protein; however non-polyalanine repeat mutations (NPARMs) have been reported. Most NPARMs are located in exon 3 of PHOX2B and result in a more severe clinical presentation including Hirschsprung disease (HSCR) and/or peripheral neuroblastic tumors (PNTs). A previously reported nonsense pathogenic variant in exon 1 of a patient with LO-CCHS and no HSCR or PNTs leads to translational reinitiation at a downstream AUG codon producing an N-terminally truncated protein. Here we report additional individuals with nonsense pathogenic variants in exon 1 of PHOX2B. In vitro analyses were used to determine if these and other reported nonsense variants in PHOX2B exon 1 produced N-terminally truncated proteins. We found that all tested nonsense variants in PHOX2B exon 1 produced a truncated protein of the same size. This truncated protein localized to the nucleus and transactivated a target promoter. These data suggest that nonsense pathogenic variants in the first exon of PHOX2B likely escape nonsense mediated decay (NMD) and produce N-terminally truncated proteins functionally distinct from those produced by the more common PARMs.

Association between central sleep apnea and left ventricular structure: the Multi-Ethnic Study of Atherosclerosis.

We assessed whether the presence of central sleep apnea is associated with adverse left ventricular structural changes. We analysed 1412 participants from the Multi-Ethnic Study of Atherosclerosis who underwent both overnight polysomnography and cardiac magnetic resonance imaging. Subjects had been recruited 10 years earlier when free of cardiovascular disease. Our main exposure is the presence of central sleep apnea as defined by central apnea-hypopnea index = 5 or the presence of Cheyne-Stokes breathing. Outcome variables were left ventricular mass/height, left ventricular ejection fraction, and left ventricular mass/volume ratio. Multivariate linear regression models adjusted for age, gender, race, waist circumference, tobacco use, hypertension, and the obstructive apnea-hypopnea index were fit for the outcomes. Of the 1412 participants, 27 (2%) individuals had central sleep apnea. After adjusting for covariates, the presence of central sleep apnea was significantly associated with elevated left ventricular mass/volume ratio (ß = 0.11 ± 0.04 g mL-1 , P = 0.0071), an adverse cardiac finding signifying concentric remodelling.

Sleep-disordered breathing and its management in children with achondroplasia.

Sleep-disordered breathing is a common feature in children with achondroplasia. The aim of our study was to review the poly(somno)graphic (P(S)G) findings and consequent treatments in children with achondroplasia followed in the national reference center for skeletal dysplasia. A retrospective review of the clinical charts and P(S)G of 43 consecutive children (mean age 3.9 ± 3.5 years) with achondroplasia seen over a period of 2 years was performed. Twenty four (59%) children had obstructive sleep apnea (OSA). Thirteen children had an obstructive apnea-hypopnea index (OAHI) < 5/hr, four had an OAHI between 5 and 10/hr, and seven had an OAHI ≥ 10/hr. Ten of the 15 children who had previous upper airway surgery still had an abnormal P(S)G. All the patients with an AHI ≥ 10/hr were under 7 years of age and none had a prior tonsillectomy. The children who underwent adeno-tonsillectomy, coupled in most cases with turbinectomy, were significantly older (mean age 7.5 ± 3.5 vs. 3.5 ± 1.7 years old, P = 0.015) and had significantly better P(S)G results than those who underwent only adeno-turbinectomy. No correlation was observed between the mean AHI value at the baseline P(S)G and the type of academic course (standard, supported or specialized). In conclusion, OSA is common in children with achondroplasia. The observation of a reduced prevalence of OSA after (adeno-)tonsillectomy is in favor of this type of surgery when possible.

Central Sleep Apnea at High Altitude.

The discovery of central sleep apnea (CSA) at high altitude is usually attributed to Angelo Mosso who published in 1898. It can occur in susceptible individuals at altitude above 2000 m, but at very high altitude, say above 5000 m, it will occur in most subjects. Severity is correlated with ventilatory responsiveness, particularly to hypoxia. Theoretically, it should spontaneously improve with time and acclimatization. Although the time course of resolution is not well described, it appears to persist for more than a month at 5000 m.It occurs due to the interaction of hypocapnia with stages 1 and 2 NREM sleep, in the presence of increased loop-gain. The hypocapnia is secondary to hypoxic ventilatory drive. With acclimatization, one might expect that the increase in PaO2 and cerebral blood flow (CBF) would mitigate the CSA. However, over time, both the hypoxic and hypercapnic ventilatory responses increase, causing an increase in loop gain which is a counteracting force.The severity of the CSA can be reduced by descent, supplemental oxygen therapy, oral or intravenous acetazolamide. Recent studies suggest that acute further increases in cerebral blood flow will substantially, but temporarily, reduce central sleep apnea, without altering acid based balance. Very recently, bi-level noninvasive ventilation has also been shown to help (mechanism unknown). Sleep quality can be improved independent of the presence of CSA by the use of benzodiazepine sedation.

Respiratory and autonomic dysfunction in congenital central hypoventilation syndrome.

The developmental lineage of the PHOX2B-expressing neurons in the retrotrapezoid nucleus (RTN) has been extensively studied. These cells are thought to function as central respiratory chemoreceptors, i.e., the mechanism by which brain Pco2 regulates breathing. The molecular and cellular basis of central respiratory chemoreception is based on the detection of CO2 via intrinsic proton receptors (TASK-2, GPR4) as well as synaptic input from peripheral chemoreceptors and other brain regions. Murine models of congenital central hypoventilation syndrome designed with PHOX2B mutations have suggested RTN neuron agenesis. In this review, we examine, through human and experimental animal models, how a restricted number of neurons that express the transcription factor PHOX2B play a crucial role in the control of breathing and autonomic regulation.

Oncologic Phenotype of Peripheral Neuroblastic Tumors Associated With PHOX2B Non-Polyalanine Repeat Expansion Mutations.

BACKGROUND: Germline non-polyalanine repeat expansion mutations in PHOX2B (PHOX2B NPARM) predispose to peripheral neuroblastic tumors (PNT), frequently in association with other neurocristopathies: Hirschsprung disease (HSCR) or congenital central hypoventilation syndrome (CCHS). Although PHOX2B polyalanine repeat expansions predispose to a low incidence of benign PNTs, the oncologic phenotype associated with PHOX2B NPARM is still not known in detail. METHODS: We analyzed prognostic factors, treatment toxicity, and outcome of patients with PNT and PHOX2B NPARM. RESULTS: Thirteen patients were identified, six of whom also had CCHS and/or HSCR, one also had late-onset hypoventilation with hypothalamic dysfunction (LO-CHS/HD), and six had no other neurocristopathy. Four tumours were "poorly differentiated," and nine were differentiated, including five ganglioneuromas, three ganglioneuroblastomas, and one differentiating neuroblastoma, hence illustrating that PHOX2B NPARM are predominantly associated with differentiating tumors. Nevertheless, three patients had stage 4 and one patient had stage 3 disease. Segmental chromosomal alterations, correlating with poor prognosis, were found in all the six tumors analyzed by array-comparative genomic hybridization. One patient died of tumor progression, one is on palliative care, one died of hypoventilation, and 10 patients are still alive, with median follow-up of 5 years. CONCLUSIONS: Based on histological phenotype, our series suggests that heterozygous PHOX2B NPARM do not fully preclude ganglion cell differentiation in tumors. However, this tumor predisposition syndrome may also be associated with poorly differentiated tumors with unfavorable genomic profiles and clinically aggressive behaviors. The intrafamilial variability and the unpredictable tumor prognosis should be considered in genetic counseling.

Synaptogenesis and Myelination in the Nucleus/Tractus Solitarius: Potential Role in Apnea of Prematurity, Congenital Central Hypoventilation, and Sudden Infant Death Syndrome.

Fetuses as early as 15 weeks' gestation exhibit rhythmical respiratory movements shown by real-time ultrasonography. The nucleus/tractus solitarius is the principal brainstem respiratory center; other medullary nuclei also participate. The purpose was to determine temporal maturation of synaptogenesis. Delayed synaptic maturation may explain neurogenic apnea or hypoventilation of prematurity and some cases of sudden infant death syndrome. Sections of medulla oblongata were studied from 30 human fetal and neonatal brains 9 to 41 weeks' gestation. Synaptophysin demonstrated the immunocytochemical sequence of synaptogenesis. Other neuronal markers and myelin stain also were applied. The nucleus/tractus solitarius was similarly studied in fetuses with chromosomopathies, metabolic encephalopathies, and brain malformations. Synapse formation in the nucleus solitarius begins at about 12 weeks' gestation and matures by 15 weeks; myelination initiated at 33 weeks. Synaptogenesis was delayed in 3 fetuses with different conditions, but was not specific for only nucleus solitarius. Delayed synaptogenesis or myelination in the nucleus solitarius may play a role in neonatal hypoventilation, especially in preterm infants and in some sudden infant death syndrome cases.

Is MRI Necessary in the Evaluation of Pediatric Central Sleep Apnea?

OBJECTIVES: (1) To determine the prevalence of central nervous system (CNS) pathology identified on head magnetic resonance imaging (MRI) scans in children with central sleep apnea (CSA); (2) to assess the yield of MRI in evaluation of CSA; and (3) to identify factors that predict CNS pathology in children with CSA. STUDY DESIGN: Case series with chart review. SETTING: Tertiary children's hospital. SUBJECTS AND METHODS: A chart review was conducted over 12 years. Patients 6 months to 18 years of age who underwent head MRI for evaluation of CSA were included. CSA was diagnosed on polysomnogram as central apnea index >1. RESULTS: Forty children were included in the CSA group. Twenty-two patients were male, and the mean age was 60 ± 41.5 months. The mean central apnea index was 3.8 ± 1.9, while the mean obstructive apnea hypopnea index was 3.4 (interquartile range, 0.7-3.8). Eighteen percent (7 of 40) of children with CSA had evidence of CNS pathology on MRI, with the most common finding (n = 3) being arachnoid cyst. Children with CSA who had gastroesophageal reflux disease or abnormal neurologic examinations were more likely to have CNS pathology. Other factors, such as prematurity, did not improve the yield of MRI in children with CSA. CONCLUSIONS: While routine evaluation of children with elevated central apnea index by MRI is not indicated, providers should consider neuroimaging in children with CSA and abnormal neurologic examination findings or gastroesophageal reflux disease. Further research is necessary to identify other tests with improved diagnostic yield for evaluation of pediatric CSA.

Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome.

Human congenital central hypoventilation syndrome (CCHS), resulting from mutations in transcription factor PHOX2B, manifests with impaired responses to hypoxemia and hypercapnia especially during sleep. To identify brainstem structures developmentally affected in CCHS, we analyzed two postmortem neonatal-lethal cases with confirmed polyalanine repeat expansion (PARM) or Non-PARM (PHOX2B∆8) mutation of PHOX2B. Both human cases showed neuronal losses within the locus coeruleus (LC), which is important for central noradrenergic signaling. Using a conditionally active transgenic mouse model of the PHOX2B∆8 mutation, we found that early embryonic expression (

The upper airway in sleep-disordered breathing: UA in SDB.

Sleep disordered breathing (SDB) is a common condition and could be a risk factor for cardiovascular morbidity and mortality. However, the pathogenesis of SDB remains to be elucidated. In general, SDB is divided into two forms, obstructive and central sleep apnea (OSA and CSA, respectively). OSA results from the sleep-related collapse of the upper airway (UA) in association with multiple factors like race, gender, obesity and UA dimensions. CSA primarily results from a fall in PaCO2 to a level below the apnea threshold during sleep through the reflex inhibition of central respiratory drive. It has been reported that UA alterations (i.e., collapse or dilation) can be observed in CSA. This review highlights the roles of the UA in the pathogenesis and pathophysiology of SDB.

Brainstem involvement as a cause of central sleep apnea: pattern of microstructural cerebral damage in patients with cerebral microangiopathy.

BACKGROUND: The exact underlying pathomechanism of central sleep apnea with Cheyne-Stokes respiration (CSA-CSR) is still unclear. Recent studies have demonstrated an association between cerebral white matter changes and CSA. A dysfunction of central respiratory control centers in the brainstem was suggested by some authors. Novel MR-imaging analysis tools now allow far more subtle assessment of microstructural cerebral changes. The aim of this study was to investigate whether and what severity of subtle structural cerebral changes could lead to CSA-CSR, and whether there is a specific pattern of neurodegenerative changes that cause CSR. Therefore, we examined patients with Fabry disease (FD), an inherited, lysosomal storage disease. White matter lesions are early and frequent findings in FD. Thus, FD can serve as a "model disease" of cerebral microangiopathy to study in more detail the impact of cerebral lesions on central sleep apnea. PATIENTS AND METHODS: Genetically proven FD patients (n = 23) and age-matched healthy controls (n = 44) underwent a cardio-respiratory polysomnography and brain MRI at 3.0 Tesla. We applied different MR-imaging techniques, ranging from semiquantitative measurement of white matter lesion (WML) volumes and automated calculation of brain tissue volumes to VBM of gray matter and voxel-based diffusion tensor imaging (DTI) analysis. RESULTS: In 5 of 23 Fabry patients (22%) CSA-CSR was detected. Voxel-based DTI analysis revealed widespread structural changes in FD patients when compared to the healthy controls. When calculated as a separate group, DTI changes of CSA-CSR patients were most prominent in the brainstem. Voxel-based regression analysis revealed a significant association between CSR severity and microstructural DTI changes within the brainstem. CONCLUSION: Subtle microstructural changes in the brainstem might be a neuroanatomical correlate of CSA-CSR in patients at risk of WML. DTI is more sensitive and specific than conventional structural MRI and other advanced MR analyses tools in demonstrating these abnormalities.