Cristina Skrypnyk- MD, PhD  University of Oradea,  Romania Faculty of Medicine and Pharmacy, Genetics Department
<ul><li>a contiguous gene syndrome caused by the loss of function of genes situated within the  </li></ul><ul><li>15q11-q1...
Genotype-phenotype correlation in PWS <ul><li>Diagnosis  of PWS: </li></ul><ul><li>C linical observations </li></ul><ul><l...
 
Genotype-phenotype correlation in PWS <ul><li>G enes have been mapped within the PWS/AS region   </li></ul><ul><li>SNRPN  ...
 
Genotype-phenotype correlation in PWS <ul><li>G enes have been mapped within the PWS region   </li></ul><ul><li>GABRB3,   ...
<ul><li>G enes have been mapped within the PWS/AS region   </li></ul><ul><li>NECDIN (NDN)  gene  which encodes a  DNA -bin...
<ul><li>G enes have been mapped within the PWS region   </li></ul><ul><li>MAGEL2   and  MKRN3  a re   genes  in proximity ...
<ul><li>G enes have been mapped within the PWS region   </li></ul><ul><li>P  (OCA2)  gene , which codes for tyrosinase-pos...
 
<ul><li>Distinct differences have been reported between individuals with Prader-Willi syndrome resulting from  deletion  c...
Genotype-phenotype correlation in PWS <ul><li>individuals with 15q  deletion   showed a  lower birth weight at term,  high...
Genotype-phenotype correlation in PWS <ul><li>individuals with  UPD  are less likely to have the typical facial appearance...
Genotype-phenotype correlation in PWS <ul><li>P sychosis </li></ul><ul><li>the affective psychosis  and autism spectrum di...
 
Genotype-phenotype correlation in PWS <ul><li>E xcessive sleepiness and sleep disordered breathing (SDB)  </li></ul><ul><l...
Genotype-phenotype correlation in PWS <ul><li>GH therapy results </li></ul><ul><li>3-year retrospective study on 46 PWS pa...
Genotype-phenotype correlation in PWS <ul><li>Scoliosis </li></ul><ul><li>a retrospective longitudinal, clinical, and radi...
Genotype-phenotype correlation in PWS <ul><li>C entral adrenal insufficiency   </li></ul><ul><li>The high percentage  (60%...
Genotype-phenotype correlation in PWS <ul><li>Understanding the influence of gene expression on  the particular phenotype ...
T H A N K  Y O U  !!!
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Genotype Phenotype Correlation In Prader Willi Syndrome

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Genotype Phenotype Correlation In Prader Willi Syndrome

  1. 1. Cristina Skrypnyk- MD, PhD University of Oradea, Romania Faculty of Medicine and Pharmacy, Genetics Department
  2. 2. <ul><li>a contiguous gene syndrome caused by the loss of function of genes situated within the </li></ul><ul><li>15q11-q13 region </li></ul><ul><li>the molecular events underlying the disorder </li></ul><ul><li>- interstitial deletions (70%) </li></ul><ul><li>- uniparental disomy (UPD) (25%) </li></ul><ul><li>- imprinting center defects (<5%) </li></ul><ul><li>- chromosomal translocations (<1%) </li></ul><ul><li>- a balanced chr. rear.breaking within 15q11.2-q13 (<1%) </li></ul>
  3. 3. Genotype-phenotype correlation in PWS <ul><li>Diagnosis of PWS: </li></ul><ul><li>C linical observations </li></ul><ul><li>DNA methylation studies </li></ul><ul><li>(absence of a paternal methylation pattern within 15q11) </li></ul><ul><li>(FISH) fluorescence in situ hybridization analysis </li></ul><ul><li>(deletion or nondeletion) </li></ul><ul><li>The main limitation s : </li></ul><ul><li>- can not determine the size of the molecular deletions </li></ul><ul><li>- can not detect microdeletions in the PWS imprinting center </li></ul><ul><li>R eal-time PCR assay using genomic DNA determine the size of the chromosomal deletions in patients with PWS </li></ul>
  4. 5. Genotype-phenotype correlation in PWS <ul><li>G enes have been mapped within the PWS/AS region </li></ul><ul><li>SNRPN (small nuclear ribonucleoprotein N), the best-described gene that is likely to cause some features of PWS </li></ul><ul><li>Based on studies in the mouse and human, gene expression is from the paternally inherited chromosome 15 only and is primarily in brain and heart </li></ul>
  5. 7. Genotype-phenotype correlation in PWS <ul><li>G enes have been mapped within the PWS region </li></ul><ul><li>GABRB3, GABRA5, and GABRG3 </li></ul><ul><li>all GABA-receptor subunit genes </li></ul>
  6. 8. <ul><li>G enes have been mapped within the PWS/AS region </li></ul><ul><li>NECDIN (NDN) gene which encodes a DNA -binding protein (necdin) mediates intracellular processes essential for neurite outgrowth, is an antiapoptotic or survival factor in the early development of the nervous system </li></ul><ul><li>loss of necdin impinges on axonal outgrowth </li></ul><ul><li>Necdin gene- reduced sympathetic function provides a plausible explanation for deficiencies of salivary gland function </li></ul><ul><li>Lee et all 2005, Andrieu et al 2006 </li></ul><ul><li>Tnnesse AA et all Dev Dyn. 2008 Jul;237(7):1935-43. </li></ul>
  7. 9. <ul><li>G enes have been mapped within the PWS region </li></ul><ul><li>MAGEL2 and MKRN3 a re genes in proximity to the NDN locus ; transcribed only by the paternal allele and expressed predominantly in the brain. </li></ul><ul><li>shown the role in circadian rhythm and have demonstrated several findings that are associated with PWS : neonatal growth retardation, excessive weight gain due to hyperphagia, and increased adiposity with altered metabolism in adulthood </li></ul><ul><li>O Neil al 2005, Bischof et al 2007, Koylov et al 2007 </li></ul>
  8. 10. <ul><li>G enes have been mapped within the PWS region </li></ul><ul><li>P (OCA2) gene , which codes for tyrosinase-positive albinism; its deletion is associated with the hypopigmentation seen in one-third of individuals with PWS </li></ul><ul><li>NIPA1, NIPA2, CYFIP1 , and GCP5 genes are considered responsible by the obsesive behaviour and a low IQ in patients with big deletions (3 Mb) </li></ul><ul><li>Bittel et al. 2006 </li></ul>
  9. 12. <ul><li>Distinct differences have been reported between individuals with Prader-Willi syndrome resulting from deletion compared with uniparental maternal disomy 15 in physical, cognitive, and behavioral parameters </li></ul>Genotype-phenotype correlation in PWS
  10. 13. Genotype-phenotype correlation in PWS <ul><li>individuals with 15q deletion showed a lower birth weight at term, higher frequency of need for special feeding techniques, sleep disturbance, hypopigmentation, speech articulation defects , hypogonadism and a low IQ </li></ul><ul><li>Lin et al 2007, Torrado et al 2007 </li></ul><ul><li>patients with deletions with breakpoint 1 (breaking more proximally) were reported to have more behavior problems than those with deletions with breakpoint 2 </li></ul><ul><li>t he ir behavior problems included poorer reading and math skills , poorer adaptive behavior skills and specific obsessive-compulsive behaviors and physical depression </li></ul><ul><li>Hartley et al 2005 </li></ul>
  11. 14. Genotype-phenotype correlation in PWS <ul><li>individuals with UPD are less likely to have the typical facial appearance, hy popigmentation, or skill with jigsaw puzzles; they also have a somewhat higher IQ and milder behavior problems </li></ul><ul><li>Dykens et al 2002, Hartley et al 2005 </li></ul><ul><li>Some data confirm an increased maternal age in UPD group </li></ul><ul><li>Lin et al 2007 </li></ul>
  12. 15. Genotype-phenotype correlation in PWS <ul><li>P sychosis </li></ul><ul><li>the affective psychosis and autism spectrum disorders associated with PWS has been found to be mainly confined to UPD(15)mat (62%) rather than to those with a deletion (16%) </li></ul><ul><li>psychosis may be related to the presence of two copies rather than a single copy of a gene or genes located in the distal half of the region which is paternally imprinted, but maternally active </li></ul><ul><li>thus all of the people with psychosis had two active copies of any imprinted genes in the region while all non-psychotic people (including controls) had only one </li></ul><ul><li>Milner et al 2005, Verhoeven et al.2006, Sony et al 2007 </li></ul><ul><li>Dimitropolous et al 2007 </li></ul><ul><li>Webb T et all. Am J Med Genet A. 2008 Apr 1;146(7):843-53. </li></ul>
  13. 17. Genotype-phenotype correlation in PWS <ul><li>E xcessive sleepiness and sleep disordered breathing (SDB) </li></ul><ul><li>polysomnograms (PSGs) and multiple sleep latency tests (MSLTs) performed in a cohort of PWS patients in relationship with BMI scores, daytime sleepiness, growth hormone (GH) treatments. </li></ul><ul><li>Despite the positive correlation between the body-mass index and apnea-hypopnea index, the type and severity of sleep disordered breathing were not predictable based on underlying genetic defect. </li></ul><ul><li>Williams et all. J Clin Sleep Med. 2008 Apr 15;4(2):111-8. </li></ul>
  14. 18. Genotype-phenotype correlation in PWS <ul><li>GH therapy results </li></ul><ul><li>3-year retrospective study on 46 PWS patients indicates that benefit from GH therapy (0.1 IU/kg/day subcutaneously) in height increase and improved body composition </li></ul><ul><li>there is no significant gender or genotype pattern differences among the height, weight, body mass index before and after GH treatment. </li></ul>Lin HY et al J Chin Med Assoc. 2008 Jun;71(6):305-9.
  15. 19. Genotype-phenotype correlation in PWS <ul><li>Scoliosis </li></ul><ul><li>a retrospective longitudinal, clinical, and radiologic study performed on 145 patients with confirmed PWS (1980-2006), 64% received growth-hormone therapy </li></ul><ul><li>43.4% patients were afflicted with scoliosis </li></ul><ul><li>scoliosis frequency steadily rose with age, and a large majority of patients were affected at skeletal maturity (66.7%) </li></ul><ul><li>scoliosis prevalence was not affected by the genotype or by growth-hormone treatment. </li></ul><ul><li>patients with higher BMI values had an increased risk of developing a kyphotic deformity in association with scoliosis </li></ul><ul><li>Odent et all Pediatrics. 2008 Aug;122(2):e499-503 </li></ul>
  16. 20. Genotype-phenotype correlation in PWS <ul><li>C entral adrenal insufficiency </li></ul><ul><li>The high percentage (60%) of central adrenal insufficiency in PWS patients might explain, in the recent past, the high rate of sudden death, particularly during infection-related stress. </li></ul><ul><li>There was no significant difference reported in age, gender, genotype, and body mass index score between patients with central adrenal insufficiency and those without. </li></ul><ul><li>Dudley O et al. J Intellect Disabil Res. 2008 May;52(Pt 5):426-36 </li></ul>
  17. 21. Genotype-phenotype correlation in PWS <ul><li>Understanding the influence of gene expression on the particular phenotype of PWS, espeacelly on behavioral and cognitive characteristics is in the early stage of research development. </li></ul><ul><li>Additional research is needed to identify the function of these genes and their interaction with gene networks to clarify the potential role they play . </li></ul><ul><li>It is important to confirm the clinical diagnosis and to establish the genetic mechanism responsible for PWS, considering their consequences regarding the prognosis and genetic counseling. </li></ul>
  18. 22. T H A N K Y O U !!!

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