Smith-Kingsmore syndrome (SKS) (MIM 616638) is a rare condition, first described by Smith et al (2013). It is caused by mutations in the mechanistic target of rapamycin (MTOR, MIM 601231) gene on chromosome 1p36. The specific genetic changes may vary, so the symptoms vary too, and can cause a wide range of medical, intellectual, and behavioral challenges. The most consistent findings in Smith-Kingsmore syndrome are intellectual disability (ID), developmental delay, large brain size (megalencephaly) and seizures.
MTOR Gene and the mTOR Pathway
The MTOR gene is a key regulator of cell growth, cell proliferation, protein synthesis and synaptic plasticity. MTOR is a protein coding gene, which encodes mTOR, a serine/threonine protein kinase. mTOR is a core component of two protein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The mTOR pathway (PI3K-AKT-mTOR) is highly regulated and critical for cell survival and apoptosis. Many genetic changes in this pathway underlying neurodevelopmental disorders cause the pathway to become hyperactive (i.e. gain of function). As a result of pathway hyperactivation, the affected neurons grow unusually large and misshapen, leading to brain malformations, cognitive delays and epilepsy.
Mutations in different genes in this pathway result in many other neurodevelopmental disorders including PIK3CA related overgrowth disorders, Tuberous Sclerosis, PTEN-related disorders (including the macrocephaly-autism syndrome), among many others, with possible clinical overlap between these disorders and MTOR related disorders.
Changes in MTOR
Current research shows that children with MTOR mutations have different and variable clinical outcomes, depending largely on the type of mutation and its distribution in the body. So far, children with genetic changes in MTOR segregate into three clinical groups or disorders, including Smith-Kingsmore syndrome. The first group includes children with generalized brain overgrowth (megalencephaly), intellectual disability, autism and hypotonia (aka. Smith-Kingsmore syndrome). The second group includes children with diffuse brain overgrowth, abnormalities of the surface of the brain (polymicrogyria), and skin pigmentation abnormalities. The third group includes children with focal changes in the brain (focal cortical dysplasia or hemimegalencephaly) causing early onset epilepsy.
The distribution and levels of MTOR genetic changes in these three groups vary. The mutations in MTOR in patients with Smith-Kingsmore syndrome are usually present in all cells of the body, and there is great phenotypic variability within patients showing the same mutation. For a current list of the features that have been documented or reported by parents, please see the Common Features page. In contrast, genetic changes in MTOR in the second and third groups can be more localized or restricted to certain tissues (mosaic). This may cause these mutations to escape detection if a child has genetic testing on a peripheral (blood or saliva) sample.
To date the majority of disease-causing mutations identified in MTOR in patients with Smith-Kingsmore syndrome are missense changes, however at least one case of microdeletion is also known. Mutations in the focal adhesion targeting (FAT) domain are frequent, especially the recurrent variant p.Glu1799Lys. Other changes that have been found include: p.Arg1480_Cys1483del, p.Cys1483Phe, p.Cys1483Tyr, p.Trp1490Arg, p.Met1595Ile, p. Ala1832Thr, p.Phe1888Cys, p.Phe2202Cys, p.Met2327Ile, p.Ile2501Val.
Researchers are continuing to learn more about Smith-Kingsmore syndrome and other conditions caused by MTOR mutations. The aim is to better understand the characteristics and the differences of MTOR conditions like Smith-Kingsmore syndrome to be able to design well-informed treatment plans. Different MTOR mutations could have different effects on the pathway, especially if it is already differentially modulated by other variant/s in other gene/s. Clarifying these aspects could be of great importance for the use of mTOR inhibitors such as rapamycin, as it efficiently inhibits mTORC1 but not mTORC2, two complexes with different downstream functions. For more information on current research and treatments, please see the SKS Research page.
 Smith, L. D., Saunders, C. J., Dinwiddie, D. L., et al. Exome sequencing reveals de novo germline mutation of mammalian target of rapamycin (MTOR) in a patient with megalencephaly and intractable seizures. Genomes Exomes 2: 63-72, 2013.
 Mirzaa GM, Campbell CD, Solovieff N, et al. Association of MTOR mutations with developmental brain disorders, including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism. JAMA Neurol. 2016;73:836–845.