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Intellectual abilities in tuberous sclerosis complex: risk factors and correlates from the Tuberous Sclerosis 2000 Study

Published online by Cambridge University Press:  01 April 2015

P. F. Bolton ,
M. Clifford ,
C. Tye ,
C. Maclean ,
A. Humphrey ,
K. le Maréchal ,
J. N. P. Higgins ,
B. G. R. Neville ,
F. Rijsdjik  and
J. R. W. Yates
...Show all authors
P. F. Bolton*
Affiliation:
MRC Centre for Social Genetic & Developmental Psychiatry & Department of Child Psychiatry, The Institute of Psychiatry, Kings College London, London, UK
M. Clifford
Affiliation:
MRC Centre for Social Genetic & Developmental Psychiatry & Department of Child Psychiatry, The Institute of Psychiatry, Kings College London, London, UK
C. Tye
Affiliation:
MRC Centre for Social Genetic & Developmental Psychiatry & Department of Child Psychiatry, The Institute of Psychiatry, Kings College London, London, UK
C. Maclean
Affiliation:
Department of Medical Genetics, University of Cambridge, Cambridge, UK
A. Humphrey
Affiliation:
Section of Developmental Psychiatry, University of Cambridge, Cambridge, UK
K. le Maréchal
Affiliation:
MRC Centre for Social Genetic & Developmental Psychiatry & Department of Child Psychiatry, The Institute of Psychiatry, Kings College London, London, UK
J. N. P. Higgins
Affiliation:
Department of Radiology, Addenbrooke's Hospital, Cambridge, UK
B. G. R. Neville
Affiliation:
Institute of Child Health, University College London UK and National Centre for Young People with Epilepsy, Lingfield, UK
F. Rijsdjik
Affiliation:
MRC Centre for Social Genetic & Developmental Psychiatry & Department of Child Psychiatry, The Institute of Psychiatry, Kings College London, London, UK
J. R. W. Yates
Affiliation:
Department of Medical Genetics, University of Cambridge, Cambridge, UK East Anglian Medical Genetics Service, Addenbrooke's Hospital, Cambridge, UK
*
*Address for correspondence: P. F. Bolton, Professor of Child Psychiatry, MRC Centre for Social Genetic & Developmental Psychiatry & Department of Child Psychiatry, The Institute of Psychiatry, Kings College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK. The South London & Maudsley NHS Trust Biomedical Research Centre in Mental Health. (Email: [email protected])
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Abstract

Background

Tuberous sclerosis complex (TSC) is associated with intellectual disability, but the risk pathways are poorly understood.

Method

The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of the natural history of TSC. One hundred and twenty-five UK children age 0–16 years with TSC and born between January 2001 and December 2006 were studied. Intelligence was assessed using standardized measures at ≥2 years of age. The age of onset of epilepsy, the type of seizure disorder, the frequency and duration of seizures, as well as the response to treatment was assessed at interview and by review of medical records. The severity of epilepsy in the early years was estimated using the E-Chess score. Genetic studies identified the mutations and the number of cortical tubers was determined from brain scans.

Results

TSC2 mutations were associated with significantly higher cortical tuber count than TSC1 mutations. The extent of brain involvement, as indexed by cortical tuber count, was associated with an earlier age of onset and severity of epilepsy. In turn, the severity of epilepsy was strongly associated with the degree of intellectual impairment. Structural equation modelling supported a causal pathway from genetic abnormality to cortical tuber count to epilepsy severity to intellectual outcome. Infantile spasms and status epilepticus were important contributors to seizure severity.

Conclusions

The findings support the proposition that severe, early onset epilepsy may impair intellectual development in TSC and highlight the potential importance of early, prompt and effective treatment or prevention of epilepsy in tuberous sclerosis.

Keywords

Braincortical tuberepilepsyintelligenceIQtuberous sclerosis
Type
Original Articles
Information
Psychological Medicine , Volume 45 , Issue 11 , August 2015 , pp. 2321 - 2331
Copyright
Copyright © Cambridge University Press 2015 

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References

Au, KS, Williams, AT, Roach, ES, Batchelor, L, Sparagana, SP, Delgado, MR, Wheless, JW, Baumgartner, JE, Roa, BB, Wilson, CM, Smith-Knuppel, TK, Cheung, MY, Whittemore, VH, King, TM, Northrup, H (2007). Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genetic Medicine 9, 88–100.CrossRefGoogle ScholarPubMed
Bolton, PF (2004). Neuroepileptic correlates of autistic symptomatology in tuberous sclerosis. Mental Retardation & Developmental Disability Research Review 10, 126–131.CrossRefGoogle ScholarPubMed
Bolton, PF, Griffiths, PD (1997). Association of tuberous sclerosis of temporal lobes with autism and atypical autism. Lancet 349, 392–395.CrossRefGoogle ScholarPubMed
Bolton, PF, Park, RJ, Higgins, JN, Griffiths, PD, Pickles, A (2002). Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain 125, 1247–1255.CrossRefGoogle ScholarPubMed
Bombardieri, R, Pinci, M, Moavero, R, Cerminara, C, Curatolo, P (2010). Early control of seizures improves long-term outcome in children with tuberous sclerosis complex. European Journal of Paediatric Neurology 14, 146–149.CrossRefGoogle ScholarPubMed
Cappellano, A, Senerchia, A, Adolfo, F, Paiva, P, Pinho, R, Covic, A, Cavalheiro, S, Saba, N (2013). Successful everolimus therapy for SEGA in pediatric patients with tuberous sclerosis complex. Child's Nervous System 29, 2301–2305.CrossRefGoogle ScholarPubMed
Crino, PB, Aronica, E, Baltuch, G, Nathanson, KL (2010). Biallelic TSC gene inactivation in tuberous sclerosis complex. Neurology 74, 1716–1723.CrossRefGoogle ScholarPubMed
Curatolo, P, Józwiak, S, Nabbout, R (2012). TSC Consensus Meeting for SEGA and Epilepsy Management. Management of epilepsy associated with tuberous sclerosis complex (TSC): clinical recommendations. European Journal Paediatric Neurology 16, 582–586.CrossRefGoogle ScholarPubMed
Curatolo, P, Verdecchia, M, Bombardieri, R (2002). Tuberous sclerosis complex: a review of neurological aspects. Europena Journal Paediatric Neurology 6, 15–23.CrossRefGoogle ScholarPubMed
Dabora, SL, Jozwiak, S, Franz, DN, Roberts, PS, Nieto, A, Chung, J, Choy, YS, Reeve, MP, Thiele, E, Egelhoff, JC, Kasprzyk-Obara, J, Domanska-Pakiela, D, Kwiatkowski, DJ (2001). Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. American Journal Human Genetics 68, 64–80.CrossRefGoogle Scholar
de Vries, PJ, Howe, CJ (2007). The tuberous sclerosis complex proteins – a GRIPP on cognition and neurodevelopment. Trends in Molecular Medicine 13, 319–326.CrossRefGoogle ScholarPubMed
Doherty, C, Goh, S, Poussaint, TY, Erdag, N, Thiele, EA (2005). Prognostic significance of tuber count and location in tuberous sclerosis complex. Journal of Child Neurology 20, 837–841.CrossRefGoogle ScholarPubMed
Ehninger, D, Han, S, Shilyansky, C, Zhou, Y, Li, W, Kwiatkowski, DJ, Ramesh, V, Silva, AJ (2008). Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nature Medicine 14, 843–848.CrossRefGoogle Scholar
Franz, DN, Leonard, J, Tudor, C, Chuck, G, Care, M, Sethuraman, G, Dinopoulos, A, Thomas, G, Crone, KR (2006). Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Annals of Neurology 59, 490–498.CrossRefGoogle ScholarPubMed
Gillberg, IC, Gillberg, C, Ahlsen, G (1994). Autisic behaviour and attention deficits in tuberous sclerosis: a population-based study. Developmental Medicine and Child Neurology 36, 50–56.CrossRefGoogle Scholar
Goodman, M, Lamm, SH, Engel, A, Shepherd, CW, Houser, OW, Gomez, MR (1997). Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex. Journal of Child Neurology 12, 85–90.CrossRefGoogle Scholar
Green, AJ, Smith, M, Yates, JR (1994). Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. Nature Genetics 6, 193–196.CrossRefGoogle ScholarPubMed
Harrison, JE, Bolton, PF (1997). Annotation: tuberous sclerosis. Journal of Child Psychology & Psychiatry 38, 603–614. Issn: 0021–9630.CrossRefGoogle ScholarPubMed
Harrison, JE, O'Callaghan, FJ, Hancock, E, Osborne, JP, Bolton, PF (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
Holmes, GL (2009). The long-term effects of neonatal seizures. Clinical Perinatology 36, 901–914, vii–viii.CrossRefGoogle ScholarPubMed
Holmes, GL, Stafstrom, CE (2007). Tuberous sclerosis complex and epilepsy: recent developments and future challenges. Epilepsia 48, 617–630.CrossRefGoogle ScholarPubMed
Huang, J, Dibble, CC, Matsuzaki, M, Manning, BD (2008). The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Molecular Cell Biology 28, 4104–4115.CrossRefGoogle ScholarPubMed
Humphrey, A, MacLean, C, Ploubidis, GB, Granader, Y, Clifford, M, Haslop, M, Neville, BG, Yates, JR, Bolton, PF, TS 2000 Study Group (2014). Intellectual development before and after the onset of infantile spasms: a controlled prospective longitudinal study in tuberous sclerosis. Epilepsia 55, 108–116.CrossRefGoogle ScholarPubMed
Humphrey, A, Neville, BG, Clarke, A, Bolton, PF (2006). Autistic regression associated with seizure onset in an infant with tuberous sclerosis. Developmental Medicine & Child Neurology 48, 609–611.CrossRefGoogle Scholar
Humphrey, A, Ploubidis, GB, Yates, JR, Steinberg, T, Bolton, PF (2008). The Early Childhood Epilepsy Severity Scale (E-Chess). Epilepsy Research 79, 139–145.CrossRefGoogle ScholarPubMed
Humphrey, A, Williams, J, Pinto, E, Bolton, PF (2004). A prospective longitudinal study of early cognitive development in tuberous sclerosis – a clinic based study. European Child & Adolescent Psychiatry 13, 159–165.CrossRefGoogle ScholarPubMed
Jambaque, I, Chiron, C, Dumas, C, Mumford, J, Dulac, O (2000). Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in tuberous sclerosis patients. Epilepsy Research 38, 151–160.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 & Child Neurology 33, 698–705.CrossRefGoogle ScholarPubMed
Jansen, FE, Braams, O, Vincken, KL, Algra, A, Anbeek, P, Jennekens-Schinkel, A, Halley, D, Zonnenberg, BA, van den Ouweland, A, van Huffelen, AC, van Nieuwenhuizen, O, Nellist, M (2008 a). Overlapping neurologic and cognitive phenotypes in patients with TSC1 or TSC2 mutations. Neurology 70, 908–915.CrossRefGoogle ScholarPubMed
Jansen, FE, Vincken, KL, Algra, A, Anbeek, P, Braams, O, Nellist, M, Zonnenberg, BA, Jennekens-Schinkel, A, van den Ouweland, A, Halley, D, van Huffelen, AC, van Nieuwenhuizen, O (2008 b). Cognitive impairment in tuberous sclerosis complex is a multifactorial condition. Neurology 70, 916–923.CrossRefGoogle ScholarPubMed
Jeste, SS, Wu, JY, Senturk, D, Varcin, K, Ko, J, McCarthy, B, Shimizu, C, Dies, K, Vogel-Farley, V, Sahin, M (2014). Early developmental trajectories associated with ASD in infants with tuberous sclerosis complex. Neurology 83, 160–168.CrossRefGoogle Scholar
Joinson, C, O'Callaghan, FJ, Osborne, JP, Martyn, C, Harris, T, Bolton, PF (2003). Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Psychological Medicine 33, 335–344.CrossRefGoogle Scholar
Jóźwiak, S, Goodman, M, Lamm, SH (1998). Poor mental development in patients with tuberous sclerosis complex: clinical risk factors. Archives of Neurology 55, 379–384.CrossRefGoogle ScholarPubMed
Jóźwiak, S, Kotulska, K, Domanska-Pakiela, D, Lojszczyk, B, Syczewska, M, Chmielewski, D, Dunin-Wasowicz, D, Kmiec, T, Szymkiewicz-Dangel, J, Kornacka, M, Kawalec, W, Kuczynski, D, Borkowska, J, Tomaszek, K, Jurkiewicz, E, Respondek-Liberska, M (2011). Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. European Journal of Paediatric Neurology 15, 424–431.CrossRefGoogle ScholarPubMed
Kaczorowska, M, Jurkiewicz, E, Domańska-Pakieła, D, Syczewska, M, Lojszczyk, B, Chmielewski, D, Kotulska, K, Kuczyński, D, Kmieć, T, Dunin-Wąsowicz, D, Kasprzyk-Obara, J, Jóźwiak, S (2011). Cerebral tuber count and its impact on mental outcome of patients with tuberous sclerosis complex. Epilepsia 52, 22–27.CrossRefGoogle ScholarPubMed
Kassiri, J, Snyder, TJ, Bhargava, R, Wheatley, BM, Sinclair, DB (2010). Cortical tubers, cognition, and epilepsy in tuberous sclerosis. Pediatric Neurology 44, 328–332.CrossRefGoogle Scholar
Krueger, DA, Care, MM, Holland, K, Agricola, K, Tudor, C, Mangeshkar, P, Wilson, KA, Byars, A, Sahmoud, T, Franz, DN (2010). Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. New England Journal of Medicine 363, 1801–1811.CrossRefGoogle ScholarPubMed
Krueger, DA, Wilfong, AA, Holland-Bouley, K, Anderson, AE, Agricola, K, Tudor, C, Mays, M, Lopez, CM, Kim, MO, Franz, DN (2013). Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Annals of Neurology 74, 679–687.CrossRefGoogle ScholarPubMed
Kwiatkowski, DJ (2003). Tuberous sclerosis: from tubers to mTOR. Annals of Human Genetics 67, 87–96.CrossRefGoogle ScholarPubMed
Mullen, E (1995). Mullen Scales of Early Learning. American Guidance Service: Circle Pines, MN.Google Scholar
Muthén, LK, Muthén, BO (2010). MPlus 6, 6th edn. Los Angeles, CA: Muthén & Muthén.Google Scholar
Numis, A, Major, P, Montenegro, M, Muzykewicz, D, Pulsifer, M, Thiele, E (2011). Identification of risk factors for autism spectrum disorders in tuberous sclerosis complex. Neurology 76, 981–987.CrossRefGoogle ScholarPubMed
O'Callaghan, FJ, Harris, T, Joinson, C, Bolton, PF, Noakes, M, Presdee, D, Renowden, S, Shiell, A, Martyn, CN, Osborne, JP (2004). The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex. Archives of Diseases in Childhood 89, 530–533.CrossRefGoogle ScholarPubMed
Orlova, KA, Crino, PB (2010). The tuberous sclerosis complex. Annals of the New York Academy of Sciences 1184, 87–105.CrossRefGoogle ScholarPubMed
Peters, JM, Taquet, M, Prohl, AK, Scherrer, B, van Eeghen, AM, Prabhu, SP, Sahin, M, Warfield, SK (2013). Diffusion tensor imaging and related techniques in tuberous sclerosis complex: review and future directions. Future Neurology 8, 583–597.CrossRefGoogle ScholarPubMed
Raznahan, A, Higgins, NP, Griffiths, PD, Humphrey, A, Yates, JR, Bolton, PF (2007). Biological markers of intellectual disability in tuberous sclerosis. Psychological Medicine 37, 1293–1304.CrossRefGoogle ScholarPubMed
Raznahan, A, Joinson, C, O'Callaghan, F, Osborne, JP, Bolton, PF (2006). Psychopathology in tuberous sclerosis: an overview and findings in a population-based sample of adults with tuberous sclerosis. Journal of Intellectual Disabilities Research 50, 561–569.CrossRefGoogle Scholar
Ridler, K, Bullmore, E, De Vries, P, Suckling, J, Barker, G, Meara, S, Williams, S, Bolton, PF (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, De Vries, P, Stephenson, C, Bolton, PF, Bullmore, E (2007). Neuroanatomical correlates of memory deficits in tuberous sclerosis complex. Cerebral Cortex 17, 261–271.CrossRefGoogle ScholarPubMed
Roach, ES, DiMario, FJ, Kandt, RS, Northrup, H (1999). Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation. National Tuberous Sclerosis Association. Journal of Child Neurology 14, 401–407.CrossRefGoogle ScholarPubMed
Shepherd, CW, Houser, OW, Gomez, MR (1995 a). MR findings in tuberous sclerosis complex and correlation with seizure development and mental impairment. American Journal of Neuroradiology 16, 149–155.Google ScholarPubMed
Shepherd, CW, Houser, OW, Gomez, MR (1995 b). MR findings in tuberous sclerosis complex and correlation with seizure development and mental impairment. American Journal of Neuroradiology 16, 149–155.Google ScholarPubMed
Shepherd, CW, Stephenson, JBP (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
Sparrow, S, Balla, D, Cicchetti, D (1984). The Vineland Adaptive Behavior Scales: Interview Edition, Survey form. American Guidance Service: Circle Pines, MN.Google Scholar
Tillema, J-M, Leach, JL, Krueger, DA, Franz, DN (2012). Everolimus alters white matter diffusion in tuberous sclerosis complex. Neurology 78, 526–531.CrossRefGoogle ScholarPubMed
van Eeghen, AM, Chu-Shore, CJ, Pulsifer, MB, Camposano, SE, Thiele, EA (2012). Cognitive and adaptive development of patients with tuberous sclerosis complex: a retrospective, longitudinal investigation. Epilepsy & Behavior 23, 10–15.CrossRefGoogle ScholarPubMed
Winterkorn, EB, Pulsifer, MB, Thiele, EA (2007). Cognitive prognosis of patients with tuberous sclerosis complex. Neurology 68, 62–64.CrossRefGoogle ScholarPubMed
Yates, JR, Maclean, C, Higgins, JN, Humphrey, A, le Marechal, K, Clifford, M, Carcani-Rathwell, I, Sampson, JR, Bolton, PF (2011). The Tuberous Sclerosis 2000 Study: presentation, initial assessments and implications for diagnosis and management. Archives of Diseases in Childhood 96, 1020–1025.CrossRefGoogle ScholarPubMed
Zaroff, CM, Barr, WB, Carlson, C, LaJoie, J, Madhavan, D, Miles, DK, Nass, R, Devinsky, O (2006). Mental retardation and relation to seizure and tuber burden in tuberous sclerosis complex. Seizure 15, 558–562.CrossRefGoogle ScholarPubMed
Zeng, LH, Xu, L, Gutmann, DH, Wong, M (2008). Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Annals of Neurology 63, 444–453.CrossRefGoogle Scholar
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