Abstract
Background
Tuberous sclerosis complex (TSC) is a genetic multisystem disorder that affects the
brain in almost every patient. It is caused by a mutation in the TSC1 or TSC2 genes, which regulate mammalian target of rapamycin (mTOR), a key player in control of cellular growth and protein synthesis. The most
frequent neurological symptoms are seizures, which occur in up to 90% of patients
and often are intractable, followed by autism spectrum disorders, intellectual disability,
attention deficit-hyperactivity disorder, and sleep problems. Conventional treatment
has frequently proven insufficient for neurological and behavioral symptoms, particularly
seizure control. This review focuses on the role of TSC/mTOR in neuronal development
and network formation and recent mechanism-based treatment approaches.
Methods
We performed a literature review to identify ongoing therapeutic challenges and novel
strategies.
Results
To achieve a better quality of life for many patients, current therapy approaches
are directed at restoring dysregulated mTOR signaling. Studies in animals have provided
insight into aberrant neuronal network formation caused by constitutive activation
of the mTOR pathway, and initial studies in TSC patients using magnetic resonance
diffusion tensor imaging and electroencephalogram support a model of impaired neuronal
connectivity in TSC. Rapamycin, an mTOR inhibitor, has been used successfully in Tsc-deficient mice to prevent and treat seizures and behavioral abnormalities. There
is recent evidence in humans of improved seizure control with mTOR inhibitors.
Conclusions
Current research provides insight into aberrant neuronal connectivity in TSC and the
role of mTOR inhibitors as a promising therapeutic approach.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Pediatric NeurologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 international tuberous sclerosis complex consensus conference.Pediatr Neurol. 2013; 49: 243-254
- Identification and characterization of the tuberous sclerosis gene on chromosome 16.Cell. 1993; 75: 1305-1315
- Identification of the Tuberous Sclerosis Gene TSC1 on Chromosome 9q34.Science. 1997; 277: 805-808
- Tuberous sclerosis.Lancet. 2008; 372: 657-668
- Tuberous sclerosis complex: disease modifiers and treatments.Curr Opin Pediatr. 2008; 20: 628-633
- Pathology of tuberous sclerosis.Ann N Y Acad Sci. 1991; 615: 128-139
- Neuropathology of tuberous sclerosis.Brain Dev. 2001; 23: 508-515
- Developmental origin of subependymal giant cell astrocytoma in tuberous sclerosis complex.Neurology. 2005; 64: 1446-1449
- Cerebral tuber count and its impact on mental outcome of patients with tuberous sclerosis complex.Epilepsia. 2011; 52: 22-27
- Tsc1 mutant neural stem/progenitor cells exhibit migration deficits and give rise to subependymal lesions in the lateral ventricle.Genes Dev. 2011; 25: 1595-1600
- Management of epilepsy associated with tuberous sclerosis complex (TSC): Clinical recommendations.Eur J Paediatr Neurol. 2012; 16: 582-586
- Tuberous sclerosis complex and epilepsy: recent developments and future challenges.Epilepsia. 2007; 48: 617-630
- Are cortical tubers epileptogenic? Evidence from electrocorticography.Epilepsia. 2009; 50: 147-154
- Associations between electroencephalographic and magnetic resonance imaging findings in tuberous sclerosis complex.Epilepsy Res. 2009; 87: 197-202
- Vigabatrin for tuberous sclerosis complex.Brain Dev. 2001; 23: 649-653
- Vigabatrin inhibits seizures and mTOR pathway activation in a mouse model of tuberous sclerosis complex.PLoS ONE. 2013; 8: e57445
- Consensus clinical guidelines for the assessment of cognitive and behavioural problems in tuberous sclerosis.Eur Child Adolesc Psychiatry. 2005; 14: 183-190
- Autistic behaviour and attention deficits in tuberous sclerosis: a population-based study.Dev Med Child Neurol. 1994; 36: 50-56
- Attention-deficit hyperactivity disorder (ADHD) and tuberous sclerosis complex.J Child Neurol. 2009; 24: 1282-1287
- Seizure risk in patients with attention-deficit-hyperactivity disorder treated with atomoxetine.Dev Med Child Neurol. 2007; 49: 498-502
- Psychiatric comorbid conditions in a clinic population of 241 patients with tuberous sclerosis complex.Epilepsy Behav. 2007; 11: 506-513
- Psychological profile of adults with tuberous sclerosis complex.Epilepsy Behav. 2007; 10: 402-406
- Psychopathology in tuberous sclerosis: an overview and findings in a population-based sample of adults with tuberous sclerosis.J Intellect Disab Res. 2006; 50: 561-569
- Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex.Psychol Med. 2003; 33: 335-344
- Characterizing sleep disorders of adults with tuberous sclerosis complex: a questionnaire-based study and review.Epilepsy Behav. 2012; 20: 68-74
- The natural history of epilepsy in tuberous sclerosis complex.Epilepsia. 2011; 51: 1236-1241
- Sleep disorder and epilepsy in children with tuberous sclerosis: a questionnaire-based study.Dev Med Child Neurol. 1994; 36: 108-115
- Sleep disorders in tuberous sclerosis: a polysomnographic study.Brain Devel. 1995; 17: 52-56
- Autism spectrum disorders: developmental disconnection syndromes.Curr Opin Neurobiol. 2007; 17: 103-111
- Autism and abnormal development of brain connectivity.J Neurosci. 2004; 24: 9228-9231
- mTOR signaling: at the crossroads of plasticity, memory and disease.Trends Neurosci. 2010; 33: 67-75
- Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E.Genes Dev. 2002; 16: 1472-1487
- mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events.Cell. 2005; 123: 569-580
- Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1.Dev Cell. 2006; 11: 859-871
- Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors.Cancer Res. 2009; 69: 6107-6114
- mTOR signaling in growth control and disease.Cell. 2012; 149: 274-293
- Differential Pi3K-pathway activation in cortical tubers and focal cortical dysplasias with balloon cells.Brain Pathol. 2007; 17: 165-173
- Differential localization of hamartin and tuberin and increased S6 phosphorylation in a tuber.Neurology. 2004; 63: 1293-1295
- mTOR cascade activation distinguishes tubers from focal cortical dysplasia.Ann Neurol. 2004; 56: 478-487
- The TSC1 tumor suppressor hamartin interacts with neurofilament-L and possibly functions as a novel integrator of the neuronal cytoskeleton.J Biol Chem. 2002; 277: 44180-44186
- Tuberous sclerosis complex proteins control axon formation.Genes Dev. 2008; 22: 2485-2495
- The small GTPase Rheb affects central brain neuronal morphology and memory formation in Drosophila.PLoS ONE. 2012; 7: e44888
- Local protein synthesis during axon guidance and synaptic plasticity.Curr Opin Neurobiol. 2004; 14: 305-310
- Tsc2-Rheb signaling regulates EphA-mediated axon guidance.Nat Neurosci. 2010; 13: 163-172
- Mechanisms of TSC-mediated control of synapse assembly and axon guidance.PloS One. 2007; 2: e375
- Increased brain apparent diffusion coefficient in tuberous sclerosis.Radiology. 2004; 232: 461-465
- Cerebral diffusion tensor images in children with tuberous sclerosis: a preliminary report.Pediatr Radiol. 2004; 34: 387-392
- Neuroimaging in tuberous sclerosis complex.Curr Opin Neurol. 2007; 20: 142-150
- Magnetic resonance imaging and diffusion-weighted imaging of normal-appearing white matter in children and young adults with tuberous sclerosis complex.Neuroradiology. 2009; 51: 781-786
- Diffusion tensor imaging identifies changes in normal-appearing white matter within the epileptogenic zone in tuberous sclerosis complex.Epilepsy Res. 2010; 89: 246-253
- Diffusion features of white matter in tuberous sclerosis with tractography.Pediatr Neurol. 2010; 42: 101-106
- Diffusion tensor imaging of commissural and projection white matter in tuberous sclerosis complex and correlation with tuber load.AJNR Am J Neuroradiol. 2010; 31: 1273-1277
- Loss of white matter microstructural integrity is associated with adverse neurological outcome in tuberous sclerosis complex.Acad Radiol. 2012; 19: 17-25
- A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival.J Neurosci. 2007; 27: 5546-5558
- Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse.Human Mol Genet. 2009; 18: 1252-1265
- Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin.Neurobiol Dis. 2012; 45: 369-380
- A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus.Proc Natl Acad Sci of USA. 2002; 99: 467-472
- Impaired synaptic plasticity in a rat model of tuberous sclerosis.Eur J Neurosci. 2006; 23: 686-692
- Epilepsy and Tsc2 haploinsufiiciency lead to autistic-like social deficit behaviors on rats.Behav Genet. 2011; 41: 364-372
- Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function.J Neurosci. 2011; 31: 8862-8869
- Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis.Nat Med. 2008; 14: 843-848
- Cognitive deficits in Tsc1+/− mice in the absence of cerebral lesions and seizures.Ann Neurol. 2007; 62: 648-655
- Impaired social interactions and motor learning skills in tuberous sclerosis complex model mice expressing a dominant/negative form of tuberin.Neurobiol Dis. 2012; 45: 156-164
- Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice.Nature. 2012; 488: 647-651
- Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex.Neurobiol Dis. 2013; 51: 93-103
- Brain functional networks in syndromic and non-syndromic autism: a graph theoretical study of EEG connectivity.BMC Med. 2013; 11: 54
- Solving the autism puzzle a few pieces at a time.Neuron. 2011; 70: 806-808
- Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function.J Neurosci. 2008; 28: 5422-5432
- The differential effects of prenatal and/or postnatal rapamycin on neurodevelopmental defects and cognition in a neuroglial mouse model of tuberous sclerosis complex.Human Mol Genet. 2012; 21: 3226-3236
- Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex.Ann Neurol. 2008; 63: 444-453
- Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex.Proc Natl Acad Sci USA. 2011; 108: E1070-E1079
- Behavioural and EEG effects of chronic rapamycin treatment in a mouse model of tuberous sclerosis complex.Neuropharmacology. 2012; 67C: 1-7
- Rapamycin causes regression of astrocytomas in tuberous sclerosis complex.Ann Neurol. 2006; 59: 490-498
- Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis.N Engl J Med. 2008; 358: 140-151
- Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis.N Engl J Med. 2010; 363: 1801-1811
- Everolimus alters white matter diffusion in tuberous sclerosis complex.Neurology. 2012; 78: 526-531
- Everolimus treatment of refractory epilepsy in tuberous sclerosis complex.Ann neurol. 2013; 74: 679-687
Article info
Publication history
Published online: December 06, 2013
Accepted:
November 27,
2013
Identification
Copyright
© 2014 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Mechanism-Based Treatments in Neurodevelopmental Disorders: Fragile X SyndromePediatric NeurologyVol. 50Issue 4
- PreviewFragile X syndrome (FXS) is the most common identifiable genetic cause of intellectual disability and autistic spectrum disorders. Recent major advances have been made in the understanding of the neurobiology and functions of fragile X mental retardation protein, the FMR1 gene product, which is absent or reduced in FXS, largely based on work in the fmr1 knockout mouse model. FXS has emerged as a disorder of synaptic plasticity associated with abnormalities of long-term depression and long-term potentiation and immature dendritic spine architecture, related to dysregulation of dendritic translation typically activated by group I mGluR and other receptors.
- Full-Text
- Preview
