Abnormal Cellular/Synaptic Growth Hypothesis
Abnormal Cellular/Synaptic Growth Hypothesis
This hypothesis came about from studies on single gene disorders like fragile X where patients with the disorder have a high incidence rate. Fragile X Syndrome, for example, has a ASD prevalence rate of 15% and Tuberous sclerosis has an ASD prevalence of 25-60 percent.
Studies of Tuberouse Schlerosis and Cowden/Lhermitte-Cuclos Syndromes found that the two syndromes associate susceptibility to Autism Spectrum Disorders with macrocephaly. Macrocephaly is relatively common among ASD patients with an estimated prevalence rate of 20%.
Tuberouse Schlerosis and Cowden/Lhermitte-Cuclos Syndrome are caused by NF1, TSC1/TSC2, and PTEN. These proteins act as negative effectors of mTORC1, which is a major regulator of cellular growth in mitotic cells. It is thought that mutations enhance the MTORC1 complex which is activated by a sequential kinase cascade downstream of the phosphoinositide-3 kinase pathway. This pathway can be modulated by serotonin.1
The tuberous schlerosis complex has GAP activity against GTP binding protein Rheb which results in the inhibition of rapamycin kinase (mTOR).