Autism and Tuberous Sclerosis

Abstract

Autism and pervasive developmental disorders (PDD) are common in tuberous sclerosis (TSC). The frequency of autism is about 25%, with 40–45% of TSC cases meeting criteria for autism or PDD. Among autistic populations, the frequency of TSC is 1–4% and perhaps as high as 8–14% among the subgroup of autistic individuals with a seizure disorder. Mental retardation (MR) and seizures, particularly infantile spasms, are significant risk factors in the development of autism/PDD in TSC; however, neither are sufficient or necessary for the development of these behaviors. The mechanism underlying the association of autism and TSC is as yet unclear but clinical features and neuroimaging investigations suggest that an abnormal TSC gene may directly influence the development of autism rather than it being a secondary effect of seizures or MR. The presence of autism/PDD may arise if the TSC gene mutations occur at critical stages of neural development in neural tissue of brain regions critical in the development of autism.

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

REFERENCES

  1. Bailey, A., Phillips, W., & Rutter, M. (1996). Autism: Towards an integration of clinical, genetic, neuropsychological, and neurobiological perspectives. Journal of Child Psychology and Psychiatry, 37, 89–126.

    Google Scholar 

  2. Bolton, P. F., & Griffiths, P. D. (1997). Association of tuberous sclerosis of temporal lobes with autism and atypical autism. Lancet, 349, 392–395.

    Google Scholar 

  3. Carbonara, C., Longa, L., Grosso, E., Borrone, C., Garre, M. G., Brisigotti, M., & Migone, N. (1994). 9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene. Human Molecular Genetics, 10, 1829–1832.

    Google Scholar 

  4. Curatolo, P. (1996). Neurological manifestations of tuberous sclerosis complex. Children's Nervous System, 9, 515–521.

    Google Scholar 

  5. Curatolo, P., & Cusmai, R. (1987). Autism and infantile spasms in children with tuberous sclerosis. Developmental Medicine and Child Neurology, 29, 550–551.

    Google Scholar 

  6. European Chromosome 16 Tuberous Sclerosis Consortium. (1993). Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell, 75, 1305–1315.

    Google Scholar 

  7. Fryer, A. E., Chalmers, A., Connor, J. M., Fraser, I., Povey, S., Yates, A. D., Yates, J. R., & Osborne, J. P. (1987). Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet, 8534, 659–661.

    Google Scholar 

  8. Geist, R. T., & Gutmann, D. H. (1995). The tuberous sclerosis 2 gene is expressed at high levels in the cerebellum and developing spinal cord. Cell Growth & Differentiation, 6, 1477–1483.

    Google Scholar 

  9. Gillberg, C. (1991). The treatment of epilepsy in autism. Journal of Autism and Developmental Disorders, 21, 61–77.

    Google Scholar 

  10. Gillberg, C., & Coleman, M. (1992). The biology of the autistic syndromes (2nd ed.). Clinics in Developmental Medicine No. 126. London/New York: Mac Keith with Cambridge University Press.

    Google Scholar 

  11. Gillberg, I. C., Gillberg, C., & Ahlsen, G. (1994). Autistic behavior and attention deficits in tuberous sclerosis: A population-based study. Developmental Medicine and Child Neurology, 36, 50–56.

    Google Scholar 

  12. Gomez, M. R. (1988). Tuberous sclerosis (2nd ed.). New York: Raven.

    Google Scholar 

  13. Gonzalez, R. C., Welsh, J. T., & Sepulveda, A. C. (1993, November 3). Autismo en la esclerosis tuberosa. Leido, pp. 374–379.

  14. Green, A. J., Smith, M., & Yates, J. R. (1994). Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. Nature Genetics, 2, 193–196.

    Google Scholar 

  15. Green, A. J., & Yates, J. R. W. (1993). Loss of heterozygosity and chromosome 16p and harmatomata from patients with tuberous sclerosis. American Journal of Human Genetics, 53, 244.

    Google Scholar 

  16. Gutierrez, G. C., Smalley, S. L., & Tanguay, P. E. (1998). Autism in tuberous sclerosis complex. Journal of Autism and Developmental Disorders, 28, 97–103.

    Google Scholar 

  17. Halley, D. J. (1996). Tuberous sclerosis: Between genetic and physical analysis. Acta Geneticae Medicae et Gemellologiae (Rome), 45, 63–75.

    Google Scholar 

  18. Henske, E., Neumann, H. P. H., Scheithauer, B. W., Herbst, E. W., Short, M. P., & Kwiatkowski, D. J. (1995). Loss of heterozygosity in the tuberous sclerosis (TSC2) region of chromosome band I6pI3 occurs in sporadic as well as TSC-associated renal angiomyolipomas. Genes, Chromosomes & Cancer, 13, 295–298.

    Google Scholar 

  19. Hunt, A. (1983). Tuberous sclerosis: A survey of 97 cases, I: Seizures, pertussis immunization and handicap. Developmental Medicine and Child Neurology, 25, 346–349.

    Google Scholar 

  20. Hunt, A., & Shepherd, C. (1993). A prevalence study of autism in tuberous sclerosis. Journal of Autism and Developmental Disorders, 23, 323–339.

    Google Scholar 

  21. Hunt, A., & Dennis, J. (1987). Psychiatric disorder among children with tuberous sclerosis. Developmental Medicine and Child Neurology, 29, 190–198.

    Google Scholar 

  22. Hunt, A. (1993). Development, behavior and seizures in 300 cases of tuberous sclerosis. Journal of Intellectual Disability Research, 37, 41–51.

    Google Scholar 

  23. International Molecular Genetic Study of Autism Consortium (1998, March). Human Molecular Genetics, 7, 571–578.

    Google Scholar 

  24. Jambaque, I., Cusmai, R., Curatolo, P., & Cortesi, F. (1991). Neuropsychological aspects of tuberous sclerosis in relation to epilepsy and MRI findings. Developmental Medicine and Child Neurology, 33, 698–705.

    Google Scholar 

  25. Janssen, B., Sampson, J., van der Est, M., Deelen, W., Verhoef, S., Daniels, I., Hesseling, A., Brock-Carter, P., Nellist, M., Lindhout, D., Sandkuijl, L., & Halley, D. (1994). Refined localization of TSC1 by combined analysis of 9q34 and 16p13 data in tuberous sclerosis families. Human Genetics, 94, 437–440.

    Google Scholar 

  26. Kandt, R. S., Haines, J. L., Smith, M., Northrup, H., Gardner, R. J. M., Short, M. P., Dumars, K., Roach, E. S., Steingold, S., Wall, S., Blanton, S., Flodman, P., Kwiatkowski, D. J., Jewell, A., Weber, J. L., Roses, A. D., & Pericak-Vance, M. A. (1992). Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. Nature Genetics, 2, 37–41.

    Google Scholar 

  27. Kanner, L. (1943). Autistic disturbances of affective contact. Nervous Child, 2, 217–250.

    Google Scholar 

  28. Kobayashi, T., Hirayama, Y., Kobayashi, E., Yoshiaki, K., & Hino, O. (1995). A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer. Nature Genetics, 9, 70–74.

    Google Scholar 

  29. Le Couteur, A., Rutter, M., Lord, C., Rios, P., Robertson, S., Holdgrafer, M., & McLennan, J. (1989). Autism Diagnostic interview: A standardized investigator-based instrument. Journal of Autism and Developmental Disorders, 19, 363–386.

    Google Scholar 

  30. Lord, C., Rutter, M., Goode, S., Heemsbergen, S., Jordan, J., Mawhood, L., & Schopler, E. (1989). Autism diagnostic observation schedule: A standardized observation of communicative and social behavior. Journal of Autism and Developmental Disorders, 19, 185–212.

    Google Scholar 

  31. Lord, C., Rutter, M., & Le Couteur, A. (1994). Autism Diagnostic Interview—Revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of Autism and Developmental Disorders, 24, 659–685.

    Google Scholar 

  32. Osborne, J. P., Fryer, A., & Webb, D. (1991). Epidemiology of Tuberous Sclerosis. In W. G. Johnson & M. R. Gomez (Eds.), Tuberous sclerosis and allied disorders (pp. 125–139). New York: New York Academy of Sciences.

    Google Scholar 

  33. Piven, J., Chase, G. A., Landa, R., Wzorek, M., Gayle, J., Cloud, D., & Folstein, S. (1991). Psychiatric disorders in the parents of autistic individuals. Journal of the American Academy of Adolescent Psychiatry, 30, 471–478.

    Google Scholar 

  34. Riikonen, R., & Simmell, O. (1990). Tuberous sclerosis and infantile spasms. Developmental Medicine and Child Neurology, 32, 203–209.

    Google Scholar 

  35. Riikonen, R., & Amnell, G. (1981). Psychiatric disorders in children with earlier infantile spasms. Developmental Medicine and Child Neurology, 23, 747–760.

    Google Scholar 

  36. Smalley, S. L. (1995). Autism and tuberous sclerosis. Psychiatric Genetics, 5, S88.

    Google Scholar 

  37. Smalley, S. L., Burger, F., & Smith, M. (1994). Phenotypic variation of tuberous sclerosis in a single extended kindred. Medical Genetics, 31, 761–765.

    Google Scholar 

  38. Smalley, S. L., Levitt, J., & Bauman, M. (1998). Autism: Diagnosis, Etiology, and Treatment. In C. E. Coffey & R. A. Brumback (Eds.), Textbook of pediatric neuropsychiatry. Washington, DC: American Psychiatric Press.

    Google Scholar 

  39. Smalley, S. L., McCracken, J., & Tanguay, P. (1995). Autism, affective disorders, and social phobia. American Journal of Medical Genetics, 60, 19–26.

    Google Scholar 

  40. Smalley, S. L., Tanguay, P. E., Smith, M., & Gutierrez, G. (1992). Autism and tuberous sclerosis. Journal of Autism and Developmental Disorders, 22, 339–355.

    Google Scholar 

  41. van Slegtenhorst, M., Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Berhoef, S., Lindhout, D., van den Ouweland, A., Halley, D., Young, J., Burley, M., Jeremiah, S., Woodward, K., Nahmias, J., Fox, M., Ekong, R., Wolfe, J., Povey, S., Osborne, J., Snell, R., Cheadle, J., Jones, A., Tachataki, M., Ravine, D., Sampson, J., Reeve, M., Richardson, P., Wilmer, F., Munro, C., Hawkins, T., Sepp, T., Ali, J., Ward, S., Green, A., Yates, J., Short, M., Haines, J., Jozwiak, S., Kwiatkowska, J., Henske E., & Kwiatkowski, D. (1997). Identification of the tuberous sclerosis gene TSC1 on Chromosome 9q34. Science, 277, 805–808.

    Google Scholar 

  42. Wienecke, R., Maize, J. C., Reed, J. A., de Gunzburg, J., Yeung, R. S., & DeClue, J. E. (1997). Expression of the TSC2 product tuberin and its target RAP 1 in normal human tissues. American Journal of Pathology, 150, 43–50.

    Google Scholar 

  43. Wilson, P. J., Ramesh, V., Kristiansen, A., Bove, C., Jozwiak, D., Kwiatkowski, D. J., Short, M. P., & Haines, J. L. (1996). Novel mutations detected in the TSC2 gene from both sporadic and familial TSC patients. Human Molecular Genetics, 5, 249–256.

    Google Scholar 

  44. Xiao, G.-H., Shoarinejad, F., Jin, F., Golemis, E. A., & Yeung, R. S. (1997). The tuberous sclerosis 2 gene product, tuberin, functions as a RabS GTPase activating protein (GAP) in modulating endocytosis. Journal of Biological Chemistry, 272, 6097–6100.

    Google Scholar 

  45. Yeung, R. S., Xiao, G.-H., Jin, F., Lee, W-C., Testa, J. R., & Knudson, A. G. (1994). Predisposition to renal cell carcinoma in the Eker rat is determined by germline mutation of the tuberous sclerosis 2 (TSC2) gene. Proceedings of the National Academy of Science (U.S.), 91, 11413–11416.

    Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Smalley, S.L. Autism and Tuberous Sclerosis. J Autism Dev Disord 28, 407–414 (1998). https://doi.org/10.1023/A:1026052421693

Download citation

  • Autism
  • tuberous sclerosis
  • seizure disorder
  • mental retardation