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Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome.

ABSTRACT: 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 (

SUBMITTER: Nobuta H

PROVIDER: S-EPMC4503865 | biostudies-other | 2015 Aug

REPOSITORIES: biostudies-other

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Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome.

Nobuta Hiroko H Cilio Maria Roberta MR Danhaive Olivier O Tsai Hui-Hsin HH Tupal Srinivasan S Chang Sandra M SM Murnen Alice A Kreitzer Faith F Bravo Verenice V Czeisler Catherine C Gokozan Hamza Numan HN Gygli Patrick P Bush Sean S Weese-Mayer Debra E DE Conklin Bruce B Yee Siu-Pok SP Huang Eric J EJ Gray Paul A PA Rowitch David D Otero José Javier JJ

Acta neuropathologica 20150515 2

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 impor ...[more]

PMID: 25975378

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Neurocognition in Congenital Central Hypoventilation Syndrome (CCHS)

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Congenital central hypoventilation syndrome mimicking mitochondrial disease.

Project description:Later-onset congenital central hypoventilation syndrome (LO-CCHS) does not present only breathing problems but can be present as episodic multiple organs involvement. Our unique case demonstrated LO-CCHS should be considered in the differential diagnosis of mitochondrial diseases and having nontypical polysomnography result.

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Identification of new therapeutic candidates for Congenital Central Hypoventilation Syndrome

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Neurocognitive functioning in individuals with congenital central hypoventilation syndrome.

Project description:BackgroundCongenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by respiratory system abnormalities, including alveolar hypoventilation and autonomic nervous system dysregulation. CCHS is associated with compromised brain development and neurocognitive functioning. Studies that evaluate cognitive skills in CCHS are limited, and no study has considered cognitive abilities in conjunction with psychosocial and adaptive functioning. Moreover, the roles of pertinent medical variables such as genetic characteristics are also important to consider in the context of neurocognitive functioning.MethodsSeven participants with CCHS ranging in age from 1 to 20 years underwent neuropsychological evaluations in a clinic setting.ResultsNeurocognitive testing indicated borderline impaired neurocognitive skills, on average, as well as relative weaknesses in working memory. Important strengths, including good coping skills and relatively strong social skills, may serve as protective factors in this population.ConclusionCCHS was associated with poor neurocognitive outcomes, especially with some polyalanine repeat expansion mutations (PARMS) genotype. These findings have important implications for individuals with CCHS as well as medical providers for this population.

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Expanding the phenotype of congenital central hypoventilation syndrome impacts management decisions.

Project description:Congenital central hypoventilation syndrome (CCHS) is a neurocristopathy caused by pathogenic heterozygous variants in the gene paired-like homeobox 2b (PHOX2B). It is characterized by severe infantile alveolar hypoventilation. Individuals may also have diffuse autonomic nervous system dysfunction, Hirschsprung disease and neural crest tumors. We report three individuals with CCHS due to an 8-base pair duplication in PHOX2B; c.691_698dupGGCCCGGG (p.Gly234Alafs*78) with a predominant enteral and neural crest phenotype and a relatively mild respiratory phenotype. The attenuated respiratory phenotype reported here and elsewhere suggests an emergent genotype:phenotype correlation which challenges the current paradigm of invoking mechanical ventilation for all infants diagnosed with CCHS. Best treatment requires careful clinical judgment and ideally the assistance of a care team with expertise in CCHS.

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Research Advances on Therapeutic Approaches to Congenital Central Hypoventilation Syndrome (CCHS).

Project description:Congenital central hypoventilation syndrome (CCHS) is a genetic disorder of neurodevelopment, with an autosomal dominant transmission, caused by heterozygous mutations in the PHOX2B gene. CCHS is a rare disorder characterized by hypoventilation due to the failure of autonomic control of breathing. Until now no curative treatment has been found. PHOX2B is a transcription factor that plays a crucial role in the development (and maintenance) of the autonomic nervous system, and in particular the neuronal structures involved in respiratory reflexes. The underlying pathogenetic mechanism is still unclear, although studies in vivo and in CCHS patients indicate that some neuronal structures may be damaged. Moreover, in vitro experimental data suggest that transcriptional dysregulation and protein misfolding may be key pathogenic mechanisms. This review summarizes latest researches that improved the comprehension of the molecular pathogenetic mechanisms responsible for CCHS and discusses the search for therapeutic intervention in light of the current knowledge about PHOX2B function.

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

Project description: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.

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A Novel c.676_677insG <i>PHOX2B</i> Mutation in Congenital Central Hypoventilation Syndrome.

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