Skip to main content
SpringerLink
Log in

The diagnosis of autism in a female: could it be Rett syndrome?

  • Original Paper
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

The overlap between autism and Rett syndrome clinical features has led to many cases of Rett syndrome being initially diagnosed with infantile autism or as having some autistic features. Both conditions seriously disrupt social and language development and are often accompanied by repetitive, nonpurposeful stereotypic hand movements. The aims of this study were to compare the early and subsequent clinical courses of female subjects with Rett syndrome categorised by whether or not a diagnosis of autism had been proposed before Rett syndrome had been diagnosed and compare the spectrum of methyl-CpG binding protein 2 (MECP2) mutations identified among the two groups. This study made use of a total of 313 cases recorded in two databases: the Australian Rett Syndrome Database (ARSD) and the International Rett Syndrome Phenotype Database (InterRett). Cases with an initial diagnosis of autism had significantly milder Rett syndrome symptoms and were more likely to remain ambulant, to have some functional hand use and not to have developed a scoliosis. Females with the p.R306C or p.T158M mutations in the MECP2 gene were more likely to have an initial diagnosis of autism, and the specific Rett syndrome symptoms were noted at a later age. We recommend that females who are initially considered to have autism be carefully monitored for the evolution of the signs and symptoms of Rett syndrome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2. Nat Genet 23:185–188

    Article  PubMed  CAS  Google Scholar 

  2. Association AP (1994) Diagnostic and statistical manual of mental disorders IV TR, 4th edn. American Psychiatric Association, Washington DC

    Google Scholar 

  3. Beyer KS, Blasi F, Bacchelli E, Klauck SM, Maestrini E, Poustka A (2002) Mutation analysis of the coding sequence of the MECP2 gene in infantile autism. Hum Genet 111:305–309

    Article  PubMed  CAS  Google Scholar 

  4. Carney RM, Wolpert CM, Ravan SA, Shahbazian M, Ashley-Koch A, Cuccaro ML, Vance JM, Pericak-Vance MA (2003) Identification of MECP2 mutations in a series of females with autistic disorder. Pediatr Neurol 28:205–211

    PubMed  Google Scholar 

  5. Charman T, Neilson TC, Mash V, Archer H, Gardiner MT, Knudsen GP, McDonnell A, Perry J, Whatley SD, Bunyan DJ, Ravn K, Mount RH, Hastings RP, Hulten M, Orstavik KH, Reilly S, Cass H, Clarke A, Kerr AM, Bailey ME (2005) Dimensional phenotypic analysis and functional categorisation of mutations reveal novel genotype-phenotype associations in Rett syndrome. Eur J Hum Genet 13:1121–1130

    Article  PubMed  CAS  Google Scholar 

  6. Christodoulou J, Grimm A, Maher T, Bennetts B (2003) RettBASE: the IRSA MECP2 variation database-a new mutation database in evolution. Hum Mutat 21:466–472

    Article  PubMed  CAS  Google Scholar 

  7. Colvin L, Fyfe S, Leonard S, Schiavello T, Ellaway C, de Klerk N, Christodoulou J, Msall M, Leonard H (2003) Describing the phenotype in Rett syndrome using a population database. Arch Dis Child 88:38–43

    Article  PubMed  CAS  Google Scholar 

  8. Colvin L, Leonard H, de Klerk N, Davis M, Weaving L, Williamson S, Christodoulou J (2004) Refining the phenotype of common mutations in Rett syndrome. J Med Genet 41:25–30

    Article  PubMed  CAS  Google Scholar 

  9. Fyfe S, Cream A, de Klerk N, Christodoulou J, Leonard H (2003) InterRett and RettBASE: International Rett Syndrome Association databases for Rett syndrome. J Child Neurol 18:709–713

    Article  PubMed  Google Scholar 

  10. Gillberg C (1986) Autism and Rett syndrome: some notes on differential diagnosis. Am J Med Gen (Part A) 24:127–131

    Article  Google Scholar 

  11. Grether JK (2006) Epidemiology of autism: current controversies and research directions. Clin Neurosci Res 6:119–126

    Article  Google Scholar 

  12. Gupta AR, State MW (2007) Recent advances in the genetics of autism. Biol Psychiatry 61:429–437

    Article  PubMed  Google Scholar 

  13. Hagberg B (1985) Rett syndrome: prevalence and impact on progressive severe mental retardation in girls. Acta Paediatr Scand 74:405–408

    Article  PubMed  CAS  Google Scholar 

  14. Hagberg B, Aicardi J, Dias K, Ramos O (1983) A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: report of 35 cases. Ann Neurol 14:471–479

    Article  PubMed  CAS  Google Scholar 

  15. Hagberg B, Witt-Engerström I (1987) Rett syndrome: epidemiology and nosology-progress in knowledge 1986-a conference communication. Brain Dev 9:451–457

    PubMed  CAS  Google Scholar 

  16. Ham AL, Kumar A, Deeter R, Schanen NC (2005) Does genotype predict phenotype in Rett syndrome? J Child Neurol 20:768–778

    PubMed  Google Scholar 

  17. Huppke P, Held M, Handefeld F, Engel W, Laccone F (2002) Influence of mutation type and location on phenotype in 123 patients with Rett syndrome. Neuropediatrics 33:63–68

    Article  PubMed  CAS  Google Scholar 

  18. Huppke P, Laccone F, Kramer N, Engel W, Hanefeld F (2000) Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum Mol Genet 9:1369–1375

    Article  PubMed  CAS  Google Scholar 

  19. Jian L, Nagarajan L, de Klerk N, Ravine D, Bower C, Anderson A, Williamson S, Christodoulou J, Leonard H (2006) Predictors of seizure onset in Rett syndrome. J Pediatr 149:542–547

    Article  PubMed  Google Scholar 

  20. Kerr AM, Archer HL, Evans JC, Prescott RJ, Gibbon F (2006) People with MECP2 mutation-positive Rett disorder who converse. J Intellect Disabil Res 50:386–394

    Article  PubMed  CAS  Google Scholar 

  21. Kerr AM, Nomura Y, Armstrong D, Anvret M, Belichenko PV, Budden S, Cass H, Christodoulou J, Clarke A, Ellaway C, d’Esposito M, Francke U, Hulten M, Julu P, Leonard H, Naidu S, Schanen C, Webb T, Engerstrom IW, Yamashita Y, Segawa M (2001) Guidelines for reporting clinical features in cases with MECP2 mutations. Brain Dev 23:208–211

    Article  PubMed  CAS  Google Scholar 

  22. Laccone F, Huppke P, Hanefeld F, Meins M (2001) Mutation spectrum in patients with Rett syndrome in the German population: evidence of hot spot regions. Hum Mutat 17:183–190

    Article  PubMed  CAS  Google Scholar 

  23. Lam CW, Yeung WL, Ko CH, Poon PM, Tong SF, Chan KY, Lo IF, Chan LY, Hui J, Wong V, Pang CP, Lo YM, Fok TF (2000) Spectrum of mutations in the MECP2 gene in patients with infantile autism and Rett syndrome. J Med Genet 37:E41

    Article  PubMed  CAS  Google Scholar 

  24. Leonard H, Bower C (1998) Is the girl with Rett syndrome normal at birth? Dev Med Child Neurol 40:115–121

    PubMed  CAS  Google Scholar 

  25. Leonard H, Colvin L, Christodoulou J, Schiavello T, Williamson S, Davis M, Ravine D, Fyfe S, de Klerk N, Matsuishi T, Kondo I, Clarke A, Hackwell S, Yamashita Y (2003) Patients with the R133C mutation: is their phenotype different from patients with Rett syndrome with other mutations? J Med Genet 40:E52

    Article  PubMed  CAS  Google Scholar 

  26. Li H, Yamagata T, Mori M, Yasuhara A, Momoi MY (2005) Mutation analysis of methyl-CpG binding protein family genes in autistic patients. Brain Dev 27:321–325

    Article  PubMed  CAS  Google Scholar 

  27. Lobo-Menendez F, Sossey-Alaoui K, Bell JM, Copeland-Yates SA, Plank SM, Sanford SO, Skinner C, Simensen RJ, Schroer RJ, Michaelis RC (2003) Absence of MECP2 mutations in patients from the South Carolina autism project. Am J Med Gen (Part B) 117:97–101

    Article  Google Scholar 

  28. MacDermott S, Williams K, Ridley G, Glasson E, Wray J (2007) The prevalence of autism in Australia: can it be established from existing data? Autism Council of Australia Ltd., Perth, Western Australia

    Google Scholar 

  29. Monros E, Armstrong J, Aibar E, Poo P, Canos I, Pineda M (2001) Rett syndrome in Spain: mutation analysis and clinical correlations. Brain Dev 23:S251–S253

    Article  PubMed  Google Scholar 

  30. Moore H, Leonard H, Fyfe S, de Klerk N, Leonard N (2005) InterRett: the application of bioinformatics to International Rett syndrome research. Ann Hum Biol 32:228–236

    Article  PubMed  CAS  Google Scholar 

  31. Mount RH, Charman T, Hastings RP, Reilly S, Cass H (2003) Features of autism in Rett syndrome and severe mental retardation. J Autism Dev Disord 33:435–442

    Article  PubMed  Google Scholar 

  32. Olsson B, Rett A (1987) Autism and Rett syndrome: behavioural investigations and differential diagnosis. Dev Med Child Neurol 29:429–441

    PubMed  CAS  Google Scholar 

  33. Olsson B, Rett A (1985) Behavioral observations concerning differential diagnosis between the Rett syndrome and autism. Brain Dev 7:281–289

    PubMed  CAS  Google Scholar 

  34. Percy A, Gillberg C, Hagberg B, Witt Engerström I (1990) Rett syndrome and the autistic disorders. [Review]. Neurol Clin 8:659–676

    PubMed  CAS  Google Scholar 

  35. Percy AK, Zoghbi HY, Lewis KR, Jankovic J (1988) Rett syndrome: qualitative and quantitative differentiation from autism. J Child Neurol 3:S65–S67

    Article  PubMed  Google Scholar 

  36. Samaco RC, Hogart A, LaSalle JM (2005) Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum Mol Genet 14:483–492

    Article  PubMed  CAS  Google Scholar 

  37. Samaco RC, Nagarajan RP, Braunschweig D, LaSalle JM (2004) Multiple pathways regulate MECP2 expression in normal brain development and exhibit defects in autism-spectrum disorders. Hum Mol Genet 13:629–639

    Article  PubMed  CAS  Google Scholar 

  38. Schanen C, Houwink EJ, Dorrani N, Lane J, Everett R, Feng A, Cantor RM, Percy A (2004) Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome. Am J Med Gen (Part A) 126:129–140

    Article  Google Scholar 

  39. Smeets E, Schollen E, Moog U, Matthijs G, Herbergs J, Smeets H, Curfs L, Schrander-Stumpel C, Fryns JP (2003) Rett syndrome in adolescent and adult females: clinical and molecular genetic findings. Am J Med Gen (Part A) 122:227–233

    Article  CAS  Google Scholar 

  40. Smeets E, Terhal P, Casaer P, Peters A, Midro A, Schollen E, van Roozendaal K, Moog U, Matthijs G, Herbergs J, Smeets H, Curfs L, Schrander-Stumpel C, Fryns JP (2005) Rett syndrome in females with CTS hot spot deletions: a disorder profile. Am J Med Gen (Part A) 132:117–120

    Article  CAS  Google Scholar 

  41. Smith T, Klevstrand M, Lovaas OI (1995) Behavioral treatment of Rett’s disorder: ineffectiveness in three cases. Am J Ment Retard 100:317–322

    PubMed  CAS  Google Scholar 

  42. Stata (1996–2006) Stata Statistical Software, 9th edn. StataCorp LP, College Station, TX, USA

  43. Thatcher KN, Peddada S, Yasui DH, Lasalle JM (2005) Homologous pairing of 15q11-13 imprinted domains in brain is developmentally regulated but deficient in Rett and autism samples. Hum Mol Genet 14:785–797

    Article  PubMed  CAS  Google Scholar 

  44. Trevathan E, Moser HW, Opitz JM, Percy AK, Naidu S, Holm VA, Boring CC, Janssen RS, Yeargin-Allsopp M, Adams MJ, Gillberg C (1988) Diagnostic criteria for Rett syndrome. The Rett Syndrome Diagnostic Criteria Work Group. Ann Neurol 23:425–428

    Article  Google Scholar 

  45. Trevathan E, Naidu S (1988) The clinical recognition and differential diagnosis of Rett syndrome. J Child Neurol 3:S6–S16

    PubMed  Google Scholar 

  46. Tsai LY (1992) Is Rett syndrome a subtype of pervasive developmental disorders? J Autism Dev Disord 22:551–561

    Article  PubMed  CAS  Google Scholar 

  47. van Buuren S, Boshuizen HC, Knook DL (1999) Multiple imputation of missing blood pressure covariates in survival analysis. Stat Med 18:681–694

    Article  PubMed  Google Scholar 

  48. Vourc’h P, Bienvenu T, Beldjord C, Chelly J, Barthelemy C, Muh JP, Andres C (2001) No mutations in the coding region of the Rett syndrome gene MECP2 in 59 autistic patients. Eur J Hum Genet 9:556–558

    Article  PubMed  CAS  Google Scholar 

  49. Watson P, Black G, Ramsden S, Barrow M, Super M, Kerr B, Clayton-Smith J (2001) Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein. J Med Genet 38:224–228

    Article  PubMed  CAS  Google Scholar 

  50. Weaving LS, Williamson SL, Bennetts B, Davis M, Ellaway CJ, Leonard H, Thong MK, Delatycki M, Thompson EM, Laing N, Christodoulou J (2003) Effects of MECP2 mutation type, location and X-inactivation in modulating Rett syndrome phenotype. Am J Med Gen (Part A) 118:103–114

    Article  Google Scholar 

  51. Witt-Engerström I, Gillberg C (1987) Rett syndrome in Sweden. J Autism Dev Disord 17:149–150

    Article  PubMed  Google Scholar 

  52. Zappella M (1992) The Rett girls with preserved speech. Brain Dev 14:98–101

    PubMed  CAS  Google Scholar 

  53. Zappella M, Gillberg C, Ehlers S (1998) The preserved speech variant: a subgroup of the Rett complex: a clinical report of 30 cases. J Autism Dev Disord 28:519–526

    Article  PubMed  CAS  Google Scholar 

  54. Zappella M, Meloni I, Longo I, Canitano R, Hayek G, Rosaia L, Mari F, Renieri A (2003) Study of MECP2 gene in Rett syndrome variants and autistic girls. Am J Med Gen (Part B) 119:102–107

    Article  Google Scholar 

  55. Zappella M, Meloni I, Longo I, Hayek G, Renieri A (2001) Preserved speech variants of the Rett syndrome: molecular and clinical analysis. Am J Med Gen (Part A) 104:14–22

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge the National Institute of Child Health and Human Development (USA) for its current funding of the Australian Rett Syndrome Study under NIH grant number 1 R01 HD 43100-01A1. We would also like to acknowledge the International Rett Syndrome Association for its funding of InterRett. DJY is funded by NIH grant R01 HD 43100-01A1, HL and NDK are funded by NHMRC program grant number 003209 and WEK by NIH grant P01 HD 24448. We would like to thank the Australian clinicians who have reported cases and particularly the families for their ongoing support and participation in our study. We would also like to acknowledge the support of the Rett Syndrome Association of Australia, the Australian Paediatric Surveillance Unit and the Rett Syndrome Australian Research Fund. The authors are also grateful for the genotyping of the Australian Rett syndrome cases by Dr. Mark Davis, Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, WA, Australia, and Dr. John Christodoulou, Dr. Linda Weaving and Ms. Sarah Williamson, Western Sydney Genetics Program, the Children’s Hospital at Westmead, Sydney, NSW, Australia.

Ethics Statement

All data collected for the purposes of the Australian Rett Syndrome Register and the International Rett Syndrome Study Register have been monitored and approved by the Princess Margaret Hospital for Children Human Ethics Committee and performed in accordance with the ethical standards laid down by the Declaration of Helsinki, Fifth Revision, http://www.bmj.com/cgi/content/full/321/7266/913.

Author information

Authors and Affiliations

  1. Centre for Child Health Research, Telethon Institute for Child Health Research, University of Western Australia, Perth, WA, Australia

    Deidra J. Young, Ami Bebbington, Alison Anderson, Nick de Klerk & Helen Leonard

  2. Western Australian Institute for Medical Research, Centre for Medical Research, University of Western Australia, Perth, WA, Australia

    David Ravine

  3. School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia

    David Ravine

  4. School of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia

    Carolyn Ellaway

  5. The Children’s Hospital at Westmead, Sydney, NSW, Australia

    Carolyn Ellaway

  6. Princess Margaret Hospital for Children, Perth, WA, Australia

    Alpana Kulkarni

  7. Kennedy Krieger Institute, Baltimore, MD, USA

    Walter E. Kaufmann

  8. School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Walter E. Kaufmann

  9. Telethon Institute for Child Health Research, P.O. Box 855, West Perth, WA, 6872, Australia

    Deidra J. Young

Authors
  1. Deidra J. Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ami Bebbington
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alison Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Ravine
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carolyn Ellaway
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alpana Kulkarni
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nick de Klerk
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Walter E. Kaufmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Helen Leonard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Deidra J. Young.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Young, D.J., Bebbington, A., Anderson, A. et al. The diagnosis of autism in a female: could it be Rett syndrome?. Eur J Pediatr 167, 661–669 (2008). https://doi.org/10.1007/s00431-007-0569-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-007-0569-x

Keywords

Search

Navigation