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. 1996 Feb;33(2):107–112. doi: 10.1136/jmg.33.2.107

Clinical features in 27 patients with Angelman syndrome resulting from DNA deletion.

A Smith 1, C Wiles 1, E Haan 1, J McGill 1, G Wallace 1, J Dixon 1, R Selby 1, A Colley 1, R Marks 1, R J Trent 1
PMCID: PMC1051834  PMID: 8929945

Abstract

We report the clinical features in 27 Australasian patients with Angelman syndrome (AS), all with a DNA deletion involving chromosome 15(q11-13), spanning markers from D15S9 to D15S12, about 3 center dot 5 Mb of DNA. There were nine males and 18 females. All cases were sporadic. The mean age at last review (end of 1994) was 11 center dot 2 years (range 3 to 34 years). All patients were ataxic, severely retarded, and lacking recognisable speech. In all patients, head circumference (HC) at birth was normal but skewed in distribution, with 62 center dot 5% at the 10th centile. At last review HC was around the 50th centile in three patients (12 center dot 5%) while 15 had poor postnatal head growth. Short stature was not invariable, 5/26 (19%) were on or above the 50th centile. Hypotonia at birth was recorded in 15/24 (63%) and neonatal feeding difficulties were recorded in 20/26 (77%). Epilepsy was present in 26/27 (96%) with onset by the third year of life in 20 patients (83%). Improvement in epilepsy was reported in 11/16 patients (69%) with age. An abnormal EEG was reported in 25/25 patients. Hypopigmentation was present in 19/26 (73%). One patient had oculocutaneous albinism. Five patients could not walk independently. Of the remaining 22 who could walk, age of onset of walking ranged from 2 to 8 years. Disrupted sleep patterns were present in 18/21 patients (86%), with improvement in 9/12 patients (75%) over 10 years of age. The clinical features in this group of deletional AS patients were similar to previous reports, but these have not separated patients into subgroups based on DNA studies. In our group of deletional cases, 100% showed severe mental retardation, ataxic movements, absent language, abnormal EEG, happy disposition (noted in infancy in 95%), normal birth weight and head circumference at birth, and a large, wide mouth. These features occurred with a higher frequency than in AS patients as a whole. Our study also provided information on the evolution of the phenotype. The data can act as a benchmark for comparisons of AS resulting from other genetic mechanisms.

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Selected References

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  1. Bottani A., Robinson W. P., DeLozier-Blanchet C. D., Engel E., Morris M. A., Schmitt B., Thun-Hohenstein L., Schinzel A. Angelman syndrome due to paternal uniparental disomy of chromosome 15: a milder phenotype? Am J Med Genet. 1994 May 15;51(1):35–40. doi: 10.1002/ajmg.1320510109. [DOI] [PubMed] [Google Scholar]
  2. Bower B. D., Jeavons P. M. The "happy puppet" syndrome. Arch Dis Child. 1967 Jun;42(223):298–302. doi: 10.1136/adc.42.223.298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Buiting K., Saitoh S., Gross S., Dittrich B., Schwartz S., Nicholls R. D., Horsthemke B. Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15. Nat Genet. 1995 Apr;9(4):395–400. doi: 10.1038/ng0495-395. [DOI] [PubMed] [Google Scholar]
  4. Chan C. T., Clayton-Smith J., Cheng X. J., Buxton J., Webb T., Pembrey M. E., Malcolm S. Molecular mechanisms in Angelman syndrome: a survey of 93 patients. J Med Genet. 1993 Nov;30(11):895–902. doi: 10.1136/jmg.30.11.895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chu C. E., Cooke A., Stephenson J. B., Tolmie J. L., Clarke B., Parry-Jones W. L., Connor J. M., Donaldson M. D. Diagnosis in Prader-Willi syndrome. Arch Dis Child. 1994 Nov;71(5):441–442. doi: 10.1136/adc.71.5.441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Clayton-Smith J. Clinical research on Angelman syndrome in the United Kingdom: observations on 82 affected individuals. Am J Med Genet. 1993 Apr 1;46(1):12–15. doi: 10.1002/ajmg.1320460105. [DOI] [PubMed] [Google Scholar]
  7. Clayton-Smith J., Pembrey M. E. Angelman syndrome. J Med Genet. 1992 Jun;29(6):412–415. doi: 10.1136/jmg.29.6.412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Clayton-Smith J., Webb T., Cheng X. J., Pembrey M. E., Malcolm S. Duplication of chromosome 15 in the region 15q11-13 in a patient with developmental delay and ataxia with similarities to Angelman syndrome. J Med Genet. 1993 Jun;30(6):529–531. doi: 10.1136/jmg.30.6.529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Delach J. A., Rosengren S. S., Kaplan L., Greenstein R. M., Cassidy S. B., Benn P. A. Comparison of high resolution chromosome banding and fluorescence in situ hybridization (FISH) for the laboratory evaluation of Prader-Willi syndrome and Angelman syndrome. Am J Med Genet. 1994 Aug 1;52(1):85–91. doi: 10.1002/ajmg.1320520117. [DOI] [PubMed] [Google Scholar]
  10. Deng Z. M., Woodage T., Smart R., Smith A., Trent R. J. Novel patterns of inheritance of genetic disease are illustrated by the Angelman syndrome. Med J Aust. 1993 Jun 21;158(12):813–816. doi: 10.5694/j.1326-5377.1993.tb137668.x. [DOI] [PubMed] [Google Scholar]
  11. Dittrich B., Robinson W. P., Knoblauch H., Buiting K., Schmidt K., Gillessen-Kaesbach G., Horsthemke B. Molecular diagnosis of the Prader-Willi and Angelman syndromes by detection of parent-of-origin specific DNA methylation in 15q11-13. Hum Genet. 1992 Nov;90(3):313–315. doi: 10.1007/BF00220089. [DOI] [PubMed] [Google Scholar]
  12. Donaldson M. D., Chu C. E., Cooke A., Wilson A., Greene S. A., Stephenson J. B. The Prader-Willi syndrome. Arch Dis Child. 1994 Jan;70(1):58–63. doi: 10.1136/adc.70.1.58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fisher J. A., Burn J., Alexander F. W., Gardner-Medwin D. Angelman (happy puppet) syndrome in a girl and her brother. J Med Genet. 1987 May;24(5):294–298. doi: 10.1136/jmg.24.5.294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Freeman S. B., May K. M., Pettay D., Fernhoff P. M., Hassold T. J. Paternal uniparental disomy in a child with a balanced 15;15 translocation and Angelman syndrome. Am J Med Genet. 1993 Mar 1;45(5):625–630. doi: 10.1002/ajmg.1320450522. [DOI] [PubMed] [Google Scholar]
  15. Gu X. F., de Rooij F., Voortman G., Te Velde K., Deybach J. C., Nordmann Y., Grandchamp B. Detection of eleven mutations causing acute intermittent porphyria using denaturing gradient gel electrophoresis. Hum Genet. 1994 Jan;93(1):47–52. doi: 10.1007/BF00218912. [DOI] [PubMed] [Google Scholar]
  16. Hamabe J., Fukushima Y., Harada N., Abe K., Matsuo N., Nagai T., Yoshioka A., Tonoki H., Tsukino R., Niikawa N. Molecular study of the Prader-Willi syndrome: deletion, RFLP, and phenotype analyses of 50 patients. Am J Med Genet. 1991 Oct 1;41(1):54–63. doi: 10.1002/ajmg.1320410116. [DOI] [PubMed] [Google Scholar]
  17. Imaizumi K., Takada F., Kuroki Y., Naritomi K., Hamabe J., Niikawa N. Cytogenetic and molecular study of Angelman syndrome. Am J Med Genet. 1990 Mar;35(3):314–318. doi: 10.1002/ajmg.1320350305. [DOI] [PubMed] [Google Scholar]
  18. Jauch A., Robson L., Smith A. Investigations with fluorescence in situ hybridization (FISH) demonstrate loss of the telomeres on the reciprocal chromosome in three unbalanced translocations involving chromosome 15 in the Prader-Willi and Angelman syndromes. Hum Genet. 1995 Sep;96(3):345–349. doi: 10.1007/BF00210421. [DOI] [PubMed] [Google Scholar]
  19. Malcolm S., Clayton-Smith J., Nichols M., Robb S., Webb T., Armour J. A., Jeffreys A. J., Pembrey M. E. Uniparental paternal disomy in Angelman's syndrome. Lancet. 1991 Mar 23;337(8743):694–697. doi: 10.1016/0140-6736(91)90278-w. [DOI] [PubMed] [Google Scholar]
  20. Matsumoto A., Kumagai T., Miura K., Miyazaki S., Hayakawa C., Yamanaka T. Epilepsy in Angelman syndrome associated with chromosome 15q deletion. Epilepsia. 1992 Nov-Dec;33(6):1083–1090. doi: 10.1111/j.1528-1157.1992.tb01763.x. [DOI] [PubMed] [Google Scholar]
  21. Nicholls R. D. Genomic imprinting and uniparental disomy in Angelman and Prader-Willi syndromes: a review. Am J Med Genet. 1993 Apr 1;46(1):16–25. doi: 10.1002/ajmg.1320460106. [DOI] [PubMed] [Google Scholar]
  22. Nicholls R. D. New insights reveal complex mechanisms involved in genomic imprinting. Am J Hum Genet. 1994 May;54(5):733–740. [PMC free article] [PubMed] [Google Scholar]
  23. Nicholls R. D., Pai G. S., Gottlieb W., Cantú E. S. Paternal uniparental disomy of chromosome 15 in a child with Angelman syndrome. Ann Neurol. 1992 Oct;32(4):512–518. doi: 10.1002/ana.410320406. [DOI] [PubMed] [Google Scholar]
  24. Pembrey M., Fennell S. J., van den Berghe J., Fitchett M., Summers D., Butler L., Clarke C., Griffiths M., Thompson E., Super M. The association of Angelman's syndrome with deletions within 15q11-13. J Med Genet. 1989 Feb;26(2):73–77. doi: 10.1136/jmg.26.2.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Robb S. A., Pohl K. R., Baraitser M., Wilson J., Brett E. M. The 'happy puppet' syndrome of Angelman: review of the clinical features. Arch Dis Child. 1989 Jan;64(1):83–86. doi: 10.1136/adc.64.1.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Saitoh S., Harada N., Jinno Y., Hashimoto K., Imaizumi K., Kuroki Y., Fukushima Y., Sugimoto T., Renedo M., Wagstaff J. Molecular and clinical study of 61 Angelman syndrome patients. Am J Med Genet. 1994 Aug 15;52(2):158–163. doi: 10.1002/ajmg.1320520207. [DOI] [PubMed] [Google Scholar]
  27. Smeets D. F., Hamel B. C., Nelen M. R., Smeets H. J., Bollen J. H., Smits A. P., Ropers H. H., van Oost B. A. Prader-Willi syndrome and Angelman syndrome in cousins from a family with a translocation between chromosomes 6 and 15. N Engl J Med. 1992 Mar 19;326(12):807–811. doi: 10.1056/NEJM199203193261206. [DOI] [PubMed] [Google Scholar]
  28. Smith A., Prasad M., Deng Z. M., Robson L., Woodage T., Trent R. J. Comparison of high resolution cytogenetics, fluorescence in situ hybridisation, and DNA studies to validate the diagnosis of Prader-Willi and Angelman's syndromes. Arch Dis Child. 1995 May;72(5):397–402. doi: 10.1136/adc.72.5.397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Smith J. C., Webb T., Pembrey M. E., Nichols M., Malcolm S. Maternal origin of deletion 15q11-13 in 25/25 cases of Angelman syndrome. Hum Genet. 1992 Feb;88(4):376–378. doi: 10.1007/BF00215668. [DOI] [PubMed] [Google Scholar]
  30. Stoll C., Alembik Y., Dott B., Fischbach M., Chognot D. Mental retardation, ataxia, seizures, dysmorphia, and hydrocephaly in two sibs. Angelman syndrome or new syndrome. Genet Couns. 1993;4(2):153–156. [PubMed] [Google Scholar]
  31. Van Lierde A., Atza M. G., Giardino D., Viani F. Angelman's syndrome in the first year of life. Dev Med Child Neurol. 1990 Nov;32(11):1011–1016. doi: 10.1111/j.1469-8749.1990.tb08125.x. [DOI] [PubMed] [Google Scholar]
  32. Wagstaff J., Knoll J. H., Glatt K. A., Shugart Y. Y., Sommer A., Lalande M. Maternal but not paternal transmission of 15q11-13-linked nondeletion Angelman syndrome leads to phenotypic expression. Nat Genet. 1992 Jul;1(4):291–294. doi: 10.1038/ng0792-291. [DOI] [PubMed] [Google Scholar]
  33. Williams C. A., Gray B. A., Hendrickson J. E., Stone J. W., Cantú E. S. Incidence of 15q deletions in the Angelman syndrome: a survey of twelve affected persons. Am J Med Genet. 1989 Mar;32(3):339–345. doi: 10.1002/ajmg.1320320313. [DOI] [PubMed] [Google Scholar]
  34. Woodage T., Deng Z. M., Prasad M., Smart R., Lindeman R., Christian S. L., Ledbetter D. H., Robson L., Smith A., Trent R. J. A variety of genetic mechanisms are associated with the Prader-Willi syndrome. Am J Med Genet. 1994 Sep 15;54(3):219–226. doi: 10.1002/ajmg.1320540308. [DOI] [PubMed] [Google Scholar]
  35. Yamada K. A., Volpe J. J. Angelman's syndrome in infancy. Dev Med Child Neurol. 1990 Nov;32(11):1005–1011. doi: 10.1111/j.1469-8749.1990.tb08124.x. [DOI] [PubMed] [Google Scholar]
  36. Zackowski J. L., Nicholls R. D., Gray B. A., Bent-Williams A., Gottlieb W., Harris P. J., Waters M. F., Driscoll D. J., Zori R. T., Williams C. A. Cytogenetic and molecular analysis in Angelman syndrome. Am J Med Genet. 1993 Apr 1;46(1):7–11. doi: 10.1002/ajmg.1320460104. [DOI] [PubMed] [Google Scholar]
  37. Zori R. T., Hendrickson J., Woolven S., Whidden E. M., Gray B., Williams C. A. Angelman syndrome: clinical profile. J Child Neurol. 1992 Jul;7(3):270–280. doi: 10.1177/088307389200700307. [DOI] [PubMed] [Google Scholar]

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