Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore Syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures. A few dozen individuals are reported in the literature. Here, we report a cohort of 28 individuals with SKS that represent 9 new MTOR pathogenic variants, including p.R1480_C1483del or Δ(R1480-C1483). We conducted a detailed natural history study on these patients and found prevalent pathophysiological deficits among SKS individuals, in addition to the common neurodevelopmental symptoms. The new symptoms include sleep-wake disturbance, hyperphagia, and hyperactivity, which are indicative of homeostatic imbalance. To better characterize SKS variants, we developed MTOR mutant cellular models and performed biochemical and cellular circadian rhythm assays to study the variants. We showed that these SKS alleles display a range of MTOR activities under nutrient-deficient basal conditions and respond to MTOR inhibitors differently. For example, Δ(R1480-C1483) is more active than the classic SKS variant C1483F and less responsive to MTOR inhibition by rapamycin. Further, we showed that optimal MTOR activity, important for metabolic and protein homeostasis, is required for normal circadian function. These data can help guide treatment strategies. As SKS is caused by gain of function mutations in MTOR, we used rapamycin to treat several patients. While higher doses caused delayed sleep-wake phase disorder, lower doses improved not only sleep but also aggression and repetitive behaviors. Thus, our study expands both the clinical and molecular spectrum of SKS and offers treatment options guided by molecular and sleep/wake data to improve both cognitive and non-cognitive homeostatic functions.