Eén op de vijftig kinderen wordt geboren met een verstandelijke beperking. Van oudsher wordt zo’n aangeboren verstandelijke beperking gezien als een onomkeerbaar probleem van de hersenontwikkeling. Echter, recent onderzoek laat zien dat veelal een genetisch defect ten grondslag ligt aan een ernstige verstandelijke handicap. Met het groeiende inzicht in de rol van deze genen in het functioneren van de hersenen, beginnen we ons ook te realiseren dat de visie van onomkeerbaarheid mogelijk niet altijd opgaat. Deze hypothese wordt besproken aan de hand van de genetische syndromen neurofibromatose type 1 (NF1) en tubereuze sclerose complex (TSC). Veel patiënten met NF1 hebben een lichte verstandelijke beperking, waarvoor ze bijvoorbeeld extra hulp nodig hebben op school. Bij TSC is de variatie van de verstandelijke ontwikkeling veel groter. Sommige patiënten hebben een normaal IQ, anderen hebben extra hulp nodig of zitten op speciaal onderwijs, terwijl weer anderen nooit leren praten of lopen.
Literatuur
Bissler, J.J., Kingswood, J.C., Radzikowska, E., Zonnenberg, B.A., Frost, M., Belousova, E., Sauter, M., Nonomura, N., Brakemeier, S., Vries, P.J. de, Whittemore, V.H., Chen, D., Sahmoud, T., Shah, G., Lincy, J., Lebwohl, D. & Budde, K. (2013). Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST –2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet, Jan 10. pii: S0140–6736(12)61767–X. doi: 10.1016/S0140–6736(12)61767-X
Costa, R.M., Federov, N.B., Kogan, J.H., Murphy, G.G., Stern, J., Ohno, M., Kucherlapati, R., Jacks, T. & Silva, A.J. (2002). Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature, 415, 6871, 526–530.
Cui, Y., Costa, R.M., Murphy, G.G., Elgersma, Y., Zhu, Y., Gutmann, D.H., Parada, L.F., Mody, I. & Silva, A.J. (2008). Neurofibromin Regulation of ERK Signaling Modulates GABA Release and Learning. Cell, 135, 3, 549–560. doi: 10.1016/j.cell.2008.09.060
Davies, D.M., Vries, P.J. de, Johnson, S.R., McCartney, D.L., Cox, J.A., Serra, A.L., Watson, P.C., Howe, C.J., Doyle, T., Pointon, K., Cross, J.J., Tattersfield, A.E., Kingswood, J.C. & Sampson, J.R. (2011). Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial. Clinical Cancer Research, 17, 12, 4071–4081. doi: 10.1158/1078–0432.CCR –11–0445
Descheemaeker, M.J., Plasschaert, E., Frijns, J.P. & Legius, E. (2012). Neuropsychological profile in adults with neurofibromatosis type 1 compared to a control group. Journal of Intellectual Disability Research, Epub Oct 24. doi: 10.1111/j.1365–2788.2012.01648
Eeghen, A.M. van, Black, M.E., Pulsifer, M.B., Kwiatkowski, D.J. & Thiele, E.A. (2012). Genotype and cognitive phenotype of patients with tuberous sclerosis complex. European Journal of Human Genetics, 20, 5, 510–515.
Ehninger, D. & Silva, A.J. (2011). Increased levels of anxiety-related behaviors in a Tsc2 dominant negative transgenic mouse model of tuberous sclerosis. Behavior Genetics, 41, 3, 357–363. doi:10.1007/s10519–010-9398–1
Ehninger, D., Han, S., Shilyansky, C., Zhou, Y., Li, W., Kwiatkowski, D.J., Ramesh, V. & Silva, A.J. (2008). Reversal of learning deficits in a Tsc2 + /- mouse model of tuberous sclerosis. Nature medicine, 14, 8, 843–848. doi:10.1038/nm1788
Ferner, R.E., Huson, S.M., Thomas, N., Moss, C., Willshaw, H., Evans, D.G., Upadhyaya, M., Towers, R., Gleeson, M., Steiger, C. & Kirby, A. (2007). Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. Journal of Medical Genetics, 44, 2, 81–88.
Goorden, S.M., Woerden, G.M. van, Weerd, L. van der, Cheadle, J.P. & Elgersma, Y. (2007). Cognitive deficits in Tsc1 + /- mice in the absence of cerebral lesions and seizures. Annals of Neurology, 62, 6, 648–655. doi:10.1002/ana.21317
Goto, J., Talos, D.M., Klein, P., Qin, W., Chekaluk, Y.I., Anderl, S., Malinowska, I.A., Di Nardo, A., Bronson, R.T., Chan, J.A., Vinters, H.V., Kernie, S.G., Jensen, F.E., Sahin, M. & Kwiatkowski, D.J. (2011). Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex. Proceedings of the National Academy of Sciences of the USA, 108, 45, E1070–1079. doi:10.1073/pnas.1106454108
Hunt, A. & Shepherd, C. (1993). A prevalence study of autism in tuberous sclerosis. Journal of Autism and Developmental Disorders, 23, 2, 323–339.
Inoki, K., Li, Y., Zhu, T., Wu, J., Guan, K.L. (2002). TSC2 is phosphorylated and inhibited by Akt and suppressess mTOR signalling. Nature Cell Biology, 4, 9, 648–657.
Jansen, F.E., Vincken, K.L., Algra, A., Anpeek, P., Braams, O., Nellist, M., Zonnenberg, B.A., Jennekens-Schinkel, A., Ouweland, A. van den, Halley, D., Huffelen, A.C. van & Nieuwenhuizen, O. van (2008). Cognitive impairment in tuberous sclerosis complex is a multifactorial condition. Neurology, 70, 12, 916–923.
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, 2, 335–344.
Kotulska, K., Chmielewski, D., Borkowska, J., Jurkiewicz, E., Kuczyński, D., Kmieć, T., Lojszczyk, B., Dunin-Wasowicz, D. & Jozwiak, S. (2013). Long-term effect of everolimus on epilepsy and growth in children under 3 years of age treated for subependymal giant cell astrocytoma associated with tuberous sclerosis complex. European Journal of Paediatric Neurology, Apr 6. pii: S1090–3798(13)00028–7. doi: 10.1016/j.ejpn.2013.03.002
Krab, L.C., Aarsen, F.K., Goede-Bolder, A. de, Catsman-Berrevoets, C.E., Arts, W.F., Moll, H.A. & Elgersma, Y. (2008). Impact of neurofibromatosis type 1 on school performance. Journal of Child Neurology, 23, 9, 1002–1010. doi: 10.1177/0883073808316366
Krab, L.C., Goede-Bolder, A. de, Aarsen, F.K., Pluijn, S.M., Bouman, M.J., Geest, J.N. van der, Lequin, M., Catsman, C.E., Arts, W.F., Kushner, S.A., Silva, A.J., Zeeuw, C.I. de, Moll, H.A. & Elgersma, Y. (2008). Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. JAMA, 300, 3, 287–294. doi: 10.1001/jama.300.3.287
Krab, L.C., Goorden, S.M.I. & Elgersma, Y. (2008). Oncogenes on my mind: ERK and MTOR signaling in cognitive diseases. Trends in Genetics, 24, 10, 498–510. doi: 10.1016/j.tig.2008.07.005
Krueger, D.A., Care, M.M., Holland, K., Agricola, K., Tudor, C., Mangeshkar, P., Wilson, K.A., Byars, A., Sahmoud, T. & Franz, D.N. (2010). Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. New England Journal of Medicine, 363, 19, 1801–1811. doi: 10.1056/NEJMoa1001671
Li, W., Cui, Y., Kushner, S.A., Brown, R.A., Jentsch, J.D., Frankland, P.W., Cannon, T.D. & Silva, A.J. (2005). The HMG-CoA Reductase Inhibitor Lovastatin Reverses the Learning and Attention Deficits in a Mouse Model of Neurofibromatosis Type 1. Current Biology, 15, 21, 1961–1967.
Meikle, L., Talos, D.M., Onda, H., Pollizzi, K., Rotenberg, A., Sahin, M., Jensen, F.E. & Kwiatkowski, D.J. (2007). A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. Journal of Neuroscience, 27, 21, 5546–5558. doi:10.1523/JNEUROSCI.5540–06.2007
Muzykewicz, D.A., Newberry, P., Danforth, N., Halpern, E.F. & Thiele, E.A. (2007). Psychiatric comorbid conditions in a clinic population of 241 patients with tuberous sclerosis complex. Epilepsy & Behavior, 11, 4, 506–513.
Nellist, M., Brook-Carter, P.T., Connor, J.M., Kwiatkowski, D.J., Johnson, P. & Sampson, J.R. (1993). Identification of markers flanking the tuberous sclerosis locus on chromosome 9 (TSC1). Journal of Medical Genetics, 30, 3, 224–227.
Povey, S., Burley, M.W., Attwood, J., Benham, F., Hunt, D., Jeremiad, S.J., Franklin, D., Gillett, G., Malas, S. & Robson, E.B. (1994). Two loci for tuberous sclerosis: one on 9q34 and one on 16p13. Annals of Human Genetics, 58, 2, 107–127.
Prather, P. & Vries, P.J. de (2004). Behavioral and cognitive aspects of tuberous sclerosis complex. Journal of Child Neurology, 19, 9, 666–674.
Shilyansky, C., Lee, Y.S. & Silva, A.J. (2010). Molecular and Cellular Mechanisms of Learning Disabilities: A Focus on NF1. Annual Review of Neuroscience, 33, 221–243. doi: 10.1146/annurevneuro –060909–153215.
Tang, S.J., Reis, G., Kang, H., Gingras, A.C., Sonenberg, N. & Schuman, E.M. (2002). A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proceedings of the National Academy of Sciences of the USA, 99,1, 467–472.
Tidyman, W.E. & Rauen, K.A. (2009). The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Current Opinion in Genetics & Development, 19, 3, 230–236. doi: 10.1016/j. gde.2009.04.001
Tierney, K.M., Mccartney, D.L., Serfontein, J.R. & Vries, P.J. de (2011). Neuropsychological Attention Skills and Related Behaviours in Adults with Tuberous Sclerosis Complex. Behavior Genetics, 41, 3, 437–444. doi: 10.1007/s10519–010-9423–4
Vries, P.J. de, Gardiner, J. & Bolton, P.F. (2009). Neuropsychological attention deficits in tuberous sclerosis complex (TSC). American Journal of Medical Genetics A, 149 A,3, 387–395. doi:10.1002/ajmg.a.32690
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Mw. drs. I.E. Overwater, onderzoeker, afdelingen Neurologie, Neurowetenschappen en ENCORE expertisecentrum voor erfelijke neurocognitieve ontwikkelingsstoornissen, Erasmus MC Universitair Medisch Centrum, Rotterdam;
drs. T. van der Vaart, onderzoeker, afdelingen Neurowetenschappen, Kindergeneeskunde en ENCORE expertisecentrum voor erfelijke neurocognitieve ontwikkelingsstoornissen, Erasmus MC Universitair Medisch Centrum, Rotterdam; m.vandervaart@erasmusmc.nl;
mw. dr. M.C.Y. de Wit, neuroloog-kinderneuroloog, afdelingen Neurologie en ENCORE expertisecentrum voor erfelijke neurocognitieve ontwikkelingsstoornissen, Erasmus MC Universitair Medisch Centrum, Rotterdam;
mw. dr. R. Oostenbrink, kinderarts, afdelingen kindergeneeskunde en ENCORE expertisecentrum voor erfelijke neurocognitieve ontwikkelingsstoornissen, Erasmus MC Universitair Medisch Centrum, Rotterdam;
prof. dr. Y. Elgersma, moleculair neurobioloog, afdelingen neurowetenschappen en ENCORE expertisecentrum voor erfelijke neurocognitieve ontwikkelingsstoornissen, Erasmus MC Universitair Medisch Centrum, Rotterdam.
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Overwater, I., van der Vaart, T., De Wit, MC. et al. Behandelingen voor genetische neurocognitieve aandoeningen. NEUROPRAXIS 17, 132–138 (2013). https://doi.org/10.1007/s12474-013-0025-9
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DOI: https://doi.org/10.1007/s12474-013-0025-9