Skip to main content

Behandelingen voor genetische neurocognitieve aandoeningen

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.

This is a preview of subscription content, access via your institution.

Figuur 1
Figuur 2
Figuur 3

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.

    PubMed  CAS  Article  Google Scholar 

  • 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

    PubMed  CAS  Article  Google Scholar 

  • 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

    PubMed  CAS  Article  Google Scholar 

  • 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.

    PubMed  Article  Google Scholar 

  • 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

    PubMed  Article  Google Scholar 

  • 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

    PubMed  CAS  Article  Google Scholar 

  • 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.

    PubMed  CAS  Article  Google Scholar 

  • 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

    PubMed  Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • Hunt, A. & Shepherd, C. (1993). A prevalence study of autism in tuberous sclerosis. Journal of Autism and Developmental Disorders, 23, 2, 323–339.

    PubMed  CAS  Article  Google Scholar 

  • 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.

    PubMed  CAS  Article  Google Scholar 

  • 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.

    PubMed  CAS  Article  Google Scholar 

  • 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.

    PubMed  CAS  Article  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • 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

    PubMed  CAS  Article  Google Scholar 

  • 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

    PubMed  CAS  Article  Google Scholar 

  • 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

    PubMed  CAS  Article  Google Scholar 

  • 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.

    PubMed  CAS  Article  Google Scholar 

  • 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

    PubMed  CAS  Article  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    PubMed  CAS  Article  Google Scholar 

  • 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.

    PubMed  CAS  Article  Google Scholar 

  • Prather, P. & Vries, P.J. de (2004). Behavioral and cognitive aspects of tuberous sclerosis complex. Journal of Child Neurology, 19, 9, 666–674.

    Google Scholar 

  • 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.

    PubMed  CAS  Article  Google Scholar 

  • 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.

    PubMed  CAS  Article  Google Scholar 

  • 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

    CAS  Article  Google Scholar 

  • 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

    PubMed  Article  Google Scholar 

  • 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

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

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.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12474-013-0025-9