sirolimus and Intellectual-Disability

Local translation of dendritic mRNAs is a key aspect of dendrite and spine morphogenesis and synaptic plasticity, two phenomena generally compromised in intellectual disability disorders. Mammalian target of rapamycin (mTOR) is a protein kinase involved in a plethora of functions including dendritogenesis, plasticity and the regulation of local translation. Hence, this kinase may well be implicated in intellectual disability. Hyperactivation of mTOR has been recently reported in mouse models of Fragile X and tuberous sclerosis, two important causes of intellectual disability. Moreover, local dendritic translation seems to be increased in Fragile X syndrome. Recent findings show that the mTOR pathway is also deregulated in murine models of Rett's syndrome and Down's syndrome. As in Fragile X, local dendritic translation seems to be abnormally active in Down's syndrome mice, while rapamycin, a Food and Drug Administration-approved mTOR inhibitor, restores normal rates of translation. Rapamycin administration in tuberous sclerosis mice rescues deficits in behavior and synaptic plasticity. Indeed, mTOR-dependent deregulation of local translation may be a common trait in different intellectual deficiencies, suggesting that mTOR inhibitors may have significant therapeutic potential for the treatment of diverse forms of cognitive impairment.

Topics: Animals; Dendrites; Down Syndrome; Fragile X Syndrome; Intellectual Disability; Neuronal Plasticity; Protein Biosynthesis; Rett Syndrome; RNA, Messenger; Sirolimus; Synapses; TOR Serine-Threonine Kinases; Tuberous Sclerosis

Tuberous sclerosis complex is an autosomal dominant disease, with variable expressivity and multisystemic involvement, which is characterised by the growth of benign tumours called hamartomas. The organs that are most commonly affected are the brain, skin, kidneys, eyes, heart and lungs. Of all the children with this disease, 85% present neurological manifestations that, due to their severity, are the main cause of morbidity and mortality. The most significant neurological manifestations are epilepsy, autism spectrum disorders and mental retardation. It has been shown that in tuberous sclerosis complex the genes TSC1 and TSC2 alter the mTOR enzyme cascade, which sets off inhibition of this pathway. The possibility of resorting to treatments applied at the origin, thus inhibiting this pathway, is currently being evaluated.

Topics: Anticonvulsants; Astrocytoma; Autistic Disorder; Brain Diseases; Brain Neoplasms; Drug Design; Epilepsy; Everolimus; Glioma, Subependymal; Hamartoma; Humans; Intellectual Disability; Learning Disabilities; Molecular Targeted Therapy; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Topics: Abnormalities, Multiple; Autophagosomes; Autophagy; Chromosome Deletion; Chromosomes, Human, Pair 17; Epigenesis, Genetic; Humans; Intellectual Disability; Lysine; Lysosomes; Reactive Oxygen Species; Sirolimus; Superoxide Dismutase-1; TOR Serine-Threonine Kinases

Topics: Cognition; Epilepsy; Humans; Intellectual Disability; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis

De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.

Topics: Animals; Brain; Cell Movement; Cell Size; Cells, Cultured; Humans; Intellectual Disability; Megalencephaly; Mutation; Neurons; Organ Size; Ras Homolog Enriched in Brain Protein; Seizures; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Zebrafish

Tuberous sclerosis complex (TSC) is frequently accompanied by difficult-to-treat epilepsy, which conditions these patients' quality of life and cognitive level. AIM. To describe the epidemiological and clinical characteristics, as well as the treatment of patients affected by TSC with epilepsy.. A retrospective review was carried out of the medical records of 30 patients aged under 18 registered in our database, who had been diagnosed with TSC and epilepsy.. The age at onset of epilepsy in the patients with TSC in our series ranged from one month to four years. All of them began with partial crises. Two presented West's syndrome and four others had infantile spasms without hypsarrhythmia. In 19 of the patients, the epilepsy was medication resistant. As regards treatment with antiepileptic drugs, 11 are in monotherapy, 10 in bitherapy, seven in tritherapy and one with four drugs. Two were given ACTH, two carry an implanted vagal nerve stimulator, four receive treatment with everolimus and eight have undergone surgery.. Epilepsy is a very common problem and begins in the early years of life in TSC. There are currently a large number of therapeutic options available, although 63.3% of patients have non-controlled epilepsy and most of them present crises on a daily basis. Poor control of their crises is correlated with mental retardation and autism spectrum disorder. The positive response obtained with other therapeutic possibilities, such as mTOR pathway inhibitors, surgery and vagal nerve stimulator, should be noted.. Posibilidades terapeuticas en la epilepsia refractaria en el complejo esclerosis tuberosa.. Introduccion. El complejo esclerosis tuberosa (CET) cursa frecuentemente con epilepsia de dificil control, lo que condiciona la calidad de vida y el nivel cognitivo de estos pacientes. Objetivo. Describir las caracteristicas epidemiologicas, clinicas y el tratamiento de los pacientes afectos de CET con epilepsia. Pacientes y metodos. Se han revisado retrospectivamente las historias clinicas de 30 pacientes menores de 18 años, diagnosticados de CET y epilepsia registrados en nuestra base de datos. Resultados. La edad de inicio de la epilepsia en los pacientes con CET en nuestra serie esta comprendida entre el primer mes de vida y los 4 años. Todos comenzaron con crisis parciales. Dos presentaron sindrome de West y cuatro, espasmos infantiles sin hipsarritmia. En 19 de los pacientes, la epilepsia se comporto como farmacorresistente. Respecto al tratamiento con farmacos antiepilepticos, 11 estan en monoterapia, 10 en biterapia, siete en triterapia y uno con cuatro farmacos. Dos recibieron ACTH, dos tienen implantado un estimulador del nervio vago, cuatro reciben tratamiento con everolimus y ocho han sido sometidos a cirugia. Conclusiones. La epilepsia es un problema muy frecuente y de inicio en los primeros años de vida en el CET. Las opciones terapeuticas actuales son muchas, sin embargo el 63,3% de los pacientes tiene una epilepsia no controlada y la mayoria de ellos presenta crisis diarias. El mal control de las crisis se correlaciona con retraso mental y trastorno del espectro autista. Señalar la respuesta positiva obtenida con otras posibilidades terapeuticas: inhibidores de la via mTOR, cirugia y el estimulador del nervio vago.

Topics: Adrenocorticotropic Hormone; Age of Onset; Anticonvulsants; Astrocytoma; Brain Neoplasms; Child; Child Development Disorders, Pervasive; Child, Preschool; Combined Modality Therapy; Drug Resistance; Drug Therapy, Combination; Epilepsies, Partial; Everolimus; Female; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Retrospective Studies; Sirolimus; Spasms, Infantile; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Vagus Nerve Stimulation