Congenital Central Hypoventilation Syndrome; a 先天性中枢性低通气综合征一.pptVIP

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Congenital Central Hypoventilation Syndrome; a 先天性中枢性低通气综合征一.ppt

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Bristol Genetics Laboratory 2010 Bristol Genetics Laboratory 2010 Congenital Central Hypoventilation Syndrome; a polyalanine repeat disorder- the UK cohort Sarah Burton-Jones Bristol Genetics Laboratory Bristol Genetics Laboratory 2010 Congenital Central Hypoventilation Syndrome(Formerly called ‘Ondine’s Curse’) Autonomic nervous system disorder Incidence ? 1 in 20000-50000 live births Diagnosis in infancy / early childhood (NB. can be later onset) Characteristic respiratory phenotype Failure of autonomic control of ventilation Same respiratory rate awake and asleep ? hypoventilation No automatic response to hypoxia/hypercarbia ‘Asphyxia’ when awake, without exertion Congenital Central Hypoventilation Syndrome More severe phenotype: Hirschprung’s Disease colon aganglionosis Neural crest tumours e.g. neuroblastoma, ganglioneuroma Can also present with: cardiac irregularities, dysphagia, eye abnormalities, temperature regulation problems, altered perception of anxiety and pain, and other symptoms PHOX2B now known as ‘the disease-defining gene for CCHS’ Bristol Genetics Laboratory 2010 Bristol Genetics Laboratory 2010 Paired-Like Homeobox 4p12, 3 exons, 314 amino acids Highly conserved homeodomain transcription factor 2 polyalanine repeat tracts (9 and 20 Ala) Imperfect repeats; can expand by unequal allelic recombination The PHOX2B Gene 5’ 3’ 1 2 3 NH2 COOH PHOX2B structure PHOX2B transcript Adapted : Amiel et al. (2003) Nature Genetics 33(4), 459-461 Ala repeats Bristol Genetics Laboratory 2010 Distribution of PHOX2B Mutations Figure from Weese-Mayer DE et al (2009) Pediatric Pulmonology 44:521-535 A de novo interstitial 4p12 deletion encompassing the PHOX2B gene has also been reported Benailly HK et al Clin Genet 2003; 64: 204-209. Pathogenic PHOX2B Variants Feature Polyalanine expansion (+4 to +13 Ala) Frameshift / missense mutation (NPARM) Location in PHOX2B 20 alanine tract in exon 3 Exon 3 or end of exon 2 (most) Proportion of all pathogenic varian