sirolimus and Child-Development-Disorders--Pervasive

Topics: Animals; Child Development Disorders, Pervasive; Disease Models, Animal; Eukaryotic Initiation Factors; Fragile X Mental Retardation Protein; Mice; Nerve Tissue Proteins; Neurofibromin 1; Oxytocin; PTEN Phosphohydrolase; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Tuberous sclerosis (TSC) is a genetic disorder caused by heterozygous mutations in the TSC1 or TSC2 genes and is associated with autism spectrum disorders (ASD) in 20-60% of cases. In addition, altered TSC/mTOR signaling is emerging as a feature common to a subset of ASD. Recent findings, in animal models, show that restoration of the underlying molecular defect can improve neurological dysfunction in several of these models, even if treatment is initiated in adult animals, suggesting that pathophysiological processes in the mature brain contribute significantly to the overall neurological phenotype in these models. These findings suggest that windows for therapeutic intervention in ASD could be wider than thought previously.

Topics: Animals; Child; Child Development Disorders, Pervasive; Humans; Mutation; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins

Overactivation of the mammalian target of rapamycin (mTOR) has been implicated in the pathogenesis of syndromic forms of autism spectrum disorders (ASDs), such as tuberous sclerosis complex, neurofibromatosis 1, and fragile X syndrome. Administration of mTORC1 (mTOR complex 1) inhibitors (e.g. rapamycin) in syndromic mouse models of ASDs improved behavior, cognition, and neuropathology. However, since only a minority of ASDs are due to the effects of single genes (∼10%), there is a need to explore inhibition of mTOR activity in mouse models that may be more relevant to the majority of nonsyndromic presentations, such as the genetically inbred BTBR T(+)Itpr3(tf)/J (BTBR) mouse model of ASDs. BTBR mice have social impairment and exhibit increased stereotypic behavior. In prior work, d-cycloserine, a partial glycineB site agonist that targets the N-methyl-d-aspartate (NMDA) receptor, was shown to improve sociability in both Balb/c and BTBR mouse models of ASDs. Importantly, NMDA receptor activation regulates mTOR signaling activity. The current study investigated the ability of rapamycin (10mg/kg, i.p.×four days), an mTORC1 inhibitor, to improve sociability and stereotypic behavior in BTBR mice. Using a standard paradigm to assess mouse social behavior, rapamycin improved several measures of sociability in the BTBR mouse, suggesting that mTOR overactivation represents a therapeutic target that mediates or contributes to impaired sociability in the BTBR mouse model of ASDs. Interestingly, there was no effect of rapamycin on stereotypic behaviors in this mouse model.

Topics: Animals; Behavior, Animal; Child Development Disorders, Pervasive; Disease Models, Animal; Enzyme Inhibitors; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Mutant Strains; Multiprotein Complexes; Sirolimus; Social Behavior; Stereotyped Behavior; TOR Serine-Threonine Kinases

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

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an unknown molecular pathogenesis. A recent molecular focus has been the mutated neuroligin 3, neuroligin 3(R451C), in gain-of-function studies and for its role in induced impairment of synaptic function, but endoplasmic reticulum (ER) stress induced by mutated molecules also deserves investigation. We previously found two missense mutations, H246N and Y251S, in the gene-encoding synaptic cell adhesion molecule-1 (CADM1) in ASD patients, including cleavage of the mutated CADM1 and its intracellular accumulation. In this study, we found that the mutated CADM1 showed slightly reduced homophilic interactions in vitro but that most of its interactions persist. The mutated CADM1 also showed morphological abnormalities, including shorter dendrites, and impaired synaptogenesis in neurons. Wild-type CADM1 was partly localized to the ER of C2C5 cells, whereas mutated CADM1 mainly accumulated in the ER despite different sensitivities toward 4-phenyl butyric acid with chemical chaperone activity and rapamycin with promotion activity for degradation of the aggregated protein. Modeling analysis suggested a direct relationship between the mutations and the conformation alteration. Both mutated CADM1 and neuroligin 3(R451C) induced upregulation of C/EBP-homologous protein (CHOP), an ER stress marker, suggesting that in addition to the trafficking impairment, this CHOP upregulation may also be involved in ASD pathogenesis.

Topics: Amino Acid Sequence; Amino Acid Substitution; Animals; Anti-Bacterial Agents; Cell Adhesion Molecule-1; Cell Adhesion Molecules; Cell Adhesion Molecules, Neuronal; Cells, Cultured; Child; Child Development Disorders, Pervasive; Child, Preschool; Endoplasmic Reticulum; Humans; Immunoglobulins; Membrane Proteins; Mice; Mutation, Missense; Nerve Tissue Proteins; Neurons; Phenylbutyrates; Protein Structure, Tertiary; Sirolimus; Transcription Factor CHOP; Up-Regulation