Smith-Kingsmore syndrome – MTOR gene.

The Smith-Kingsmore syndrome (SKS), also known as MINDS syndrome, is a neurological process characterized by macrocephaly, intellectual disability and seizures.

Other signs related to this process may include delay or absence of language development, attention deficit hyperactivity disorder (ADHD) or autism spectrum alterations; Cerebral structural abnormalities such as hemimegalencephaly or megalencephaly, polymicrogyria, and/or ventriculomegaly. In addition, some affected individuals have unusual facial features, such as a triangular face with a pointed chin, frontal bump, hypertelorism with descending palpebral fissures, flat nasal bridge and long filtrum.

This process is due to mutations in the MTOR (mechanistic target of rapamycin kinase) gene, located on the short arm of chromosome 1 (1p36.22), which encodes the mTOR protein. This protein forms two groups together with other proteins, known as the mTORC1 and mTORC2 complex. Signaling through mTORC1 and mTORC2 regulates protein synthesis, and influences cell growth, division and survival. This mTOR signaling is especially important for brain growth and development, and plays a role in synaptic plasticity, which is critical for learning and memory.

The mutations on MTOR gene responsible for the development of Smith-Kingsmore syndrome affect the germ line, which means that they are present in cells throughout the body. The most frequent mutation, found in almost half of the affected individuals, consist on the change of the amino acid glutamic for to the amino acid lysine at position 1799 of the protein (Glu1799Lys or E1799K). This and other mutations of the MTOR gene increase the activity of the mTOR protein and, consequently, mTOR signaling. Thus, the production of proteins normally regulated by mTORC1 or mTORC2 is not controlled, thus affecting growth, division and other cellular processes. Excessive mTOR signaling in brain cells and other parts of the body results in the signs related to this process.

This syndrome is transmitted with an autosomal dominant inheritance pattern, which means that one copy of the altered gene in each cell is sufficient to express the process. Most cases are due to new mutations in the gene, which occur during the formation of reproductive cells or early embryonic development. Rarely people with Smith-Kingsmore syndrome inherit the altered gene due to germline mosaicism.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with the Smith-Kingsmore syndrome, by means of the complete PCR amplification of the exons of the MTOR gene, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).