Hostname: page-component-8448b6f56d-c47g7 Total loading time: 0 Render date: 2024-04-25T01:16:35.962Z Has data issue: false hasContentIssue false
  • English
  • Français

Biological markers of intellectual disability in tuberous sclerosis

Published online by Cambridge University Press:  05 March 2007

ARMIN RAZNAHAN ,
NICHOLAS P. HIGGINS ,
PAUL D. GRIFFITHS ,
AYLA HUMPHREY ,
JOHN R. W. YATES  and
PATRICK F. BOLTON
ARMIN RAZNAHAN*
Affiliation:
Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King's College London, UK
NICHOLAS P. HIGGINS
Affiliation:
Addenbrooke's Hospital Neuroradiology Department, University of Cambridge, UK
PAUL D. GRIFFITHS
Affiliation:
Section of Academic Radiology, University of Sheffield, UK
AYLA HUMPHREY
Affiliation:
Section of Developmental Psychiatry, University of Cambridge, UK
JOHN R. W. YATES
Affiliation:
Department of Medical Genetics, University of Cambridge, UK
PATRICK F. BOLTON
Affiliation:
Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King's College London, UK Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, UK
*
*Address for correspondence: Dr Armin Raznahan, Clinical Research Worker, Institute of Psychiatry, Department of Child and Adolescent Psychiatry, PO85, 16 De Crespigny Park, LondonSE5 8AF, UK. (Email: armin.raznahan@iop.kcl.ac.uk)
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Intellectual disability (ID) is highly prevalent in tuberous sclerosis (TS). Putative neurobiological risk factors include indices of cortical tuber (CT) load and epilepsy. We have used univariate and multivariate analyses, including both CT and epilepsy measures as predictors, in an attempt to clarify the pattern of cross-sectional associations between these variables and ID in TS.

Method

Forty-eight children, adolescents and young adults with TS were identified through regional specialist clinics. All subjects underwent thorough history taking and examination, and had brain magnetic resonance imaging (MRI) scans. The number and regional distribution of CTs was recorded. Subjects were assigned to one of nine ordered intellectual quotient (IQ) categories (range <25 to >130) using age-appropriate tests of intelligence.

Results

On univariate analyses, ID was significantly associated with both a history of infantile spasm (IS) (Z=−2·49, p=0·01) and total CT count (Spearman's ρ=−0·30, p=0·04). When controlling for total CT count, the presence of CTs in frontal (regression coefficient=−2·43, p=0·02) and temporal (regression coefficient=−1·60, p=0·02) lobes was significantly associated with ID. In multivariate analyses the association between IS and ID was rendered insignificant by the inclusion of the presence of CTs in temporal and frontal lobes, both of which remained associated (p=0·05 and p=0·06 respectively) with ID.

Conclusions

The presence of CTs in specific brain regions as opposed to a history of IS was associated with ID in TS. The significance of these findings is discussed in relation to previous work in TS, and the neural basis of intelligence.

Type
Original Article
Information
Psychological Medicine , Volume 37 , Issue 9 , September 2007 , pp. 1293 - 1304
Copyright
Copyright © Cambridge University Press 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Asato, M. R. & Hardan, A. Y. (2004). Neuropsychiatric problems in tuberous sclerosis complex. Journal of Child Neurology 19, 241–249.CrossRefGoogle ScholarPubMed
Blair, C. (2006). How similar are fluid cognition and general intelligence? A developmental neuroscience perspective on fluid cognition as an aspect of human cognitive ability. Behavioral and Brain Sciences 29, 109–160.CrossRefGoogle ScholarPubMed
Bolton, P. F., Park, R. J., Higgins, J. N., Griffiths, P. D. & Pickles, A. (2002). Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain 125, 1247–1255.CrossRefGoogle ScholarPubMed
De Vries, P. J. & Bolton, P. F. (1999). Neuropsychological attentional deficits in children with tuberous sclerosis. Molecular Psychiatry 4, S51.Google Scholar
Devlin, L. A., Shepherd, C., Crawford, H. & Morrison, P. (2006). Tuberous sclerosis complex: clinical features, diagnosis, and prevalence within Northern Ireland. Developmental Medicine and Child Neurology 48, 495–499.CrossRefGoogle ScholarPubMed
Doherty, C., Goh, S., Young, P. T., Erdag, N. & Thiele, E. A. (1920). Prognostic significance of tuber count and location in tuberous sclerosis complex. Journal of Child Neurology 10, 837–841.Google Scholar
Duncan, J. (2005). Frontal lobe function and general intelligence: why it matters. Cortex 41, 215–217.CrossRefGoogle ScholarPubMed
Duncan, J., Seitz, R. J., Kolodny, J., Bor, D., Herzog, H., Ahmed, A., Newell, F. N. & Emslie, H. (2000). A neural basis for general intelligence. Science 289, 457–460.CrossRefGoogle ScholarPubMed
Duvernoy, H. M. (1999). The Human Brain (2nd edn). Springer: Vienna.CrossRefGoogle Scholar
Goh, S., Butler, W. & Thiele, E. A. (2004). Subependymal giant cell tumors in tuberous sclerosis complex. Neurology 63, 1457–1461.CrossRefGoogle ScholarPubMed
Goh, S., Kwiatkowski, D. J., Dorer, D. J. & Thiele, E. A. (2005). Infantile spasms and intellectual outcomes in children with tuberous sclerosis complex. Neurology 65, 235–238.CrossRefGoogle ScholarPubMed
Gomez, M. R. (1979). Tuberous Sclerosis (1st edn). Raven Press: New York.Google Scholar
Goodman, M., Lamm, S. H., Engel, A., Shepherd, C. W., Houser, O. W. & Gomez, M. R. (1997). Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex. Journal of Child Neurology 12, 85–90.CrossRefGoogle Scholar
Guerreiro, M. M., Andermann, F., Andermann, E., Palmini, A., Hwang, P., Hoffman, H. J., Otsubo, H., Bastos, A., Dubeau, F., Snipes, G. J., Olivier, A. & Rasmussen, T. (1998). Surgical treatment of epilepsy in tuberous sclerosis: strategies and results in 18 patients. Neurology 51, 1263–1269.CrossRefGoogle ScholarPubMed
Haier, R. J., Jung, R. E., Yeo, R. A., Head, K. & Alkire, M. T. (2004). Structural brain variation and general intelligence. Neuroimage 23, 425–433.CrossRefGoogle ScholarPubMed
Haier, R. J., Jung, R. E., Yeo, R. A., Head, K. & Alkire, M. T. (2005). The neuroanatomy of general intelligence: sex matters. Neuroimage 25, 320–327.CrossRefGoogle ScholarPubMed
Harrison, J. E., O'Callaghan, F. J., Hancock, E., Osborne, J. P. & Bolton, P. F. (1999). Cognitive deficits in normally intelligent patients with tuberous sclerosis. American Journal of Medical Genetics 88, 642–646.3.0.CO;2-O>CrossRefGoogle ScholarPubMed
Henske, E. P., Scheithauer, B. W., Short, M. P., Wollmann, R., Nahmias, J., Hornigold, N., van Slegtenhorst, M., Welsh, C. T. & Kwiatkowski, D. J. (1996). Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. American Journal of Human Genetics 59, 400–406.Google ScholarPubMed
Hosoya, M., Naito, H. & Nihei, K. (1999). Neurological prognosis correlated with variations over time in the number of subependymal nodules in tuberous sclerosis. Brain and Development 21, 544–547.CrossRefGoogle ScholarPubMed
Humphrey, A., Williams, J., Pinto, E. & Bolton, P. F. (2004). A prospective longitudinal study of early cognitive development in tuberous sclerosis – a clinic-based study. European Child and Adolescent Psychiatry 13, 159–165.CrossRefGoogle ScholarPubMed
Hunt, A. (1983). Tuberous sclerosis: a survey of 97 cases. II: Physical findings. Developmental Medicine and Child Neurology 25, 350–352.CrossRefGoogle ScholarPubMed
Hunt, A. (1993). Development, behaviour and seizures in 300 cases of tuberous sclerosis. Journal of Intellectual Disability Research 37, 41–51.CrossRefGoogle ScholarPubMed
Jambaque, I., Cusmai, R., Curatolo, P., Cortesi, F., Perrot, C. & Dulac, O. (1991). Neuropsychological aspects of tuberous sclerosis in relation to epilepsy and MRI findings. Developmental Medicine and Child Neurology 33, 698–705.CrossRefGoogle ScholarPubMed
Johnson, M. H., Halit, H., Grice, S. J. & Karmiloff-Smith, A. (2002). Neuroimaging of typical and atypical development: a perspective from multiple levels of analysis. Development and Psychopathology 14, 521–536.CrossRefGoogle ScholarPubMed
Joinson, C., O'Callaghan, F. J., Osborne, J. P., Martyn, C., Harris, T. & Bolton, P. F. (2003). Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Psychological Medicine 33, 335–344.CrossRefGoogle Scholar
Jozwiak, J. (2006). Hamartin and tuberin: working together for tumour suppression. International Journal of Cancer 118, 1–5.CrossRefGoogle ScholarPubMed
Jozwiak, S., Goodman, M. & Lamm, S. H. (1998). Poor mental development in patients with tuberous sclerosis complex: clinical risk factors. Archives of Neurology 55, 379–384.CrossRefGoogle ScholarPubMed
Jozwiak, J. & Jozwiak, S. (2005). Giant cells: contradiction to two-hit model of tuber formation? Cellular and Molecular Neurobiology 25, 795–805.CrossRefGoogle ScholarPubMed
Knudson, A. G. Jr. (1971). Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the United States of America 68, 820–823.CrossRefGoogle ScholarPubMed
Lewis, J. C., Thomas, H. V., Murphy, K. C. & Sampson, J. R. (2004). Genotype and psychological phenotype in tuberous sclerosis. Journal of Medical Genetics 41, 203–207.CrossRefGoogle ScholarPubMed
Menor, F., Marti-Bonmati, L., Mulas, F., Poyatos, C. & Cortina, H. (1992). Neuroimaging in tuberous sclerosis: a clinicoradiological evaluation in pediatric patients. Pediatric Radiology 22, 485–489.CrossRefGoogle ScholarPubMed
O'Callaghan, F. J., Harris, T., Joinson, C., Bolton, P., Noakes, M., Presdee, D., Renowden, S., Shiell, A., Martyn, C. N. & Osborne, J. P. (2004). The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex. Archives of Disease in Childhood 89, 530–533.CrossRefGoogle ScholarPubMed
O'Callaghan, F. J., Shiell, A. W., Osborne, J. P. & Martyn, C. N. (1998). Prevalence of tuberous sclerosis estimated by capture–recapture analysis. Lancet 351, 1490.CrossRefGoogle ScholarPubMed
Raznahan, A., Joinson, C., O'Callaghan, F., Osborne, J. P. & Bolton, P. F. (2006). Psychopathology in tuberous sclerosis: an overview and findings in a population-based sample of adults with tuberous sclerosis. Journal of Intellectual Disability Research 50, 561–569.CrossRefGoogle Scholar
Ridler, K., Bullmore, E. T., De Vries, P. J., Suckling, J., Barker, G. J., Meara, S. J., Williams, S. C. & Bolton, P. F. (2001). Widespread anatomical abnormalities of grey and white matter structure in tuberous sclerosis. Psychological Medicine 31, 1437–1446.CrossRefGoogle ScholarPubMed
Ridler, K., Suckling, J., Higgins, N., Bolton, P. & Bullmore, E. (2004). Standardized whole brain mapping of tubers and subependymal nodules in tuberous sclerosis complex. Journal of Child Neurology 19, 658–665.CrossRefGoogle ScholarPubMed
Ridler, K., Suckling, J., Higgins, N. J., De Vries, P. J., Stephenson, C. M. E., Bolton, P. F. & Bullmore, E. T. (2007). Neuroanatomical correlates of memory deficits in tuberous sclerosis complex. Cerebral Cortex 17, 261–271.CrossRefGoogle ScholarPubMed
Riikonen, R. & Simell, O. (1990). Tuberous sclerosis and infantile spasms. Developmental Medicine and Child Neurology 32, 203–209.CrossRefGoogle ScholarPubMed
Roach, E. S., Gomez, M. R. & Northrup, H. (1998). Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. Journal of Child Neurology 13, 624–628.CrossRefGoogle ScholarPubMed
Roach, E. S. & Sparagana, S. P. (2004). Diagnosis of tuberous sclerosis complex. Journal of Child Neurology 19, 643–649.CrossRefGoogle ScholarPubMed
Roach, E. S., Williams, D. P. & Laster, D. W. (1987). Magnetic resonance imaging in tuberous sclerosis. Archives of Neurology 44, 301–303.CrossRefGoogle ScholarPubMed
Rodenburg, R., Stams, G. J., Meijer, A. M., Aldenkamp, A. P. & Dekovic, M. (2005). Psychopathology in children with epilepsy: a meta-analysis. Journal of Pediatric Psychology 30, 453–468.CrossRefGoogle ScholarPubMed
Rutter, M., Tizard, J., Yule, W., Graham, P. & Whitmore, K. (1976). Research report: Isle of Wight Studies, 1964–1974. Psychological Medicine 6, 313–323.CrossRefGoogle ScholarPubMed
Shaw, P., Greenstein, D., Lerch, J., Clasen, L., Lenroot, R., Gogtay, N., Evans, A., Rapoport, J. & Giedd, J. (2006). Intellectual ability and cortical development in children and adolescents. Nature 440, 676–679.CrossRefGoogle ScholarPubMed
Shepherd, C. W., Houser, O. W. & Gomez, M. R. (1995). MR findings in tuberous sclerosis complex and correlation with seizure development and mental impairment. AJNR. American Journal of Neuroradiology 16, 149–155.Google ScholarPubMed
Shepherd, C. W. & Stephenson, J. B. (1992). Seizures and intellectual disability associated with tuberous sclerosis complex in the west of Scotland. Developmental Medicine and Child Neurology 34, 766–774.CrossRefGoogle ScholarPubMed
Spearman, C. (1927). The Abilities of Man. Macmillan: New York.Google Scholar
The European Chromosome 16 Tuberous Sclerosis Consortium (1993). Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75, 1305–1315.CrossRefGoogle Scholar
Thompson, P. M., Cannon, T. D., Narr, K. L., van Erp, T., Poutanen, V. P., Huttunen, M., Lonnqvist, J., Standertskjold-Nordenstam, C. G., Kaprio, J., Khaledy, M., Dail, R., Zoumalan, C. I. & Toga, A. W. (2001). Genetic influences on brain structure. Nature Neuroscience 4, 1253–1258.CrossRefGoogle ScholarPubMed
Toga, A. W. & Thompson, P. M. (2005). Genetics of brain structure and intelligence. Annual Review of Neuroscience 28, 1–23.CrossRefGoogle ScholarPubMed
van Slegtenhorst, M., de Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., Lindhout, D., van den Ouweland, A., Halley, D., Young, J., Burley, M., Jeremiah, S., Woodward, K., Nahmias, J., Fox, M., Ekong, R., Osborne, J., Wolfe, J., Povey, S., Snell, R. G., Cheadle, J. P., Jones, A. C., Tachataki, M., Ravine, D., Sampson, J. R., Reeve, M. P., Richardson, P., Wilmer, F., Munro, C., Hawkins, T. L., Sepp, T., Ali, J. B., Ward, S., Green, A. J., Yates, J. R., Kwiatkowska, J., Henske, E. P., Short, M. P., Haines, J. H., Jozwiak, S. & Kwiatkowski, D. J. (1997). Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277, 805–808.CrossRefGoogle ScholarPubMed
Vingerhoets, G. (2006). Cognitive effects of seizures. Seizure 15, 221–226.CrossRefGoogle ScholarPubMed
Vinters, H. V., Kerfoot, C., Catania, M., Emelin, J. K., Roper, S. N. & DeClue, J. E. (1998). Tuberous sclerosis-related gene expression in normal and dysplastic brain. Epilepsy Research 32, 12–23.CrossRefGoogle ScholarPubMed
Webb, D. W., Fryer, A. E. & Osborne, J. P. (1996). Morbidity associated with tuberous sclerosis: a population study. Developmental Medicine and Child Neurology 38, 146–155.CrossRefGoogle ScholarPubMed
Weber, A. M., Egelhoff, J. C., McKellop, J. M. & Franz, D. N. (2000). Autism and the cerebellum: evidence from tuberous sclerosis. Journal of Autism and Developmental Disorders 30, 511–517.CrossRefGoogle ScholarPubMed
Wong, V. & Khong, P. L. (2006). Tuberous sclerosis complex: correlation of magnetic resonance imaging (MRI) findings with comorbidities. Journal of Child Neurology 21, 99–105.CrossRefGoogle ScholarPubMed