Smith-Kingsmore syndrome

Smith-Kingsmore syndrome is a neurological disorder characterized by a head that is larger than normal (macrocephaly), intellectual disability, and seizures. In some people with this condition, the ability to speak is delayed or never develops. Some children with Smith-Kingsmore syndrome have neurodevelopmental conditions known as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder, which is characterized by impaired communication and social interaction. Structural brain abnormalities may also be present in affected individuals. For example, one or both sides of the brain may be enlarged (hemimegalencephaly or megalencephaly) or have too many ridges on the surface (polymicrogyria), or the fluid-filled spaces near the center of the brain (ventricles) may be bigger than normal (ventriculomegaly).

Many people with Smith-Kingsmore syndrome have unusual facial features, such as a triangular face with a pointed chin, a protruding forehead (frontal bossing), widely spaced eyes (hypertelorism) with outside corners that point downward (downslanting palpebral fissures), a flat nasal bridge, or a long space between the nose and upper lip (long philtrum). However, not everyone with Smith-Kingsmore syndrome has distinctive facial features.

Smith-Kingsmore syndrome is a rare condition with an unknown prevalence.

Mutations in a gene called MTOR cause Smith-Kingsmore syndrome. The protein produced from this gene, called mTOR, is a key piece of two groups of proteins, known as mTOR complex 1 (mTORC1) and mTOR complex2 (mTORC2). These two complexes relay signals inside cells that regulate protein production and control several cellular processes, including growth, division, and survival. This mTOR signaling is especially important for growth and development of the brain, and it plays a role in a process called synaptic plasticity, which is the ability of the connections between nerve cells (synapses) to change and adapt over time in response to experience. Synaptic plasticity is critical for learning and memory.

MTOR gene mutations that cause Smith-Kingsmore syndrome increase the activity of the mTOR protein and, consequently, mTOR signaling. As a result, protein production normally regulated by these complexes is uncontrolled, which impacts cell growth and division and other cellular processes. Too much mTOR signaling in brain cells disrupts brain growth and development and synaptic plasticity, leading to macrocephaly, intellectual disability, seizures, and other neurological problems in people with Smith-Kingsmore syndrome. Excessive mTOR signaling in other parts of the body likely underlies the unusual facial features and other less common signs and symptoms of the condition. It is unclear why the brain is particularly affected in people with Smith-Kingsmore syndrome.

Genetic Testing Information

• Genetic Testing Registry: Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome

Genetic and Rare Diseases Information Center

• Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• SMITH-KINGSMORE SYNDROME; SKS

Scientific Articles on PubMed

• PubMed

• Gordo G, Tenorio J, Arias P, Santos-Simarro F, Garcia-Minaur S, Moreno JC, Nevado J, Vallespin E, Rodriguez-Laguna L, de Mena R, Dapia I, Palomares-Bralo M, Del Pozo A, Ibanez K, Silla JC, Barroso E, Ruiz-Perez VL, Martinez-Glez V, Lapunzina P. mTOR mutations in Smith-Kingsmore syndrome: Four additional patients and a review. Clin Genet. 2018 Apr;93(4):762-775. doi: 10.1111/cge.13135. Epub 2018 Feb 13. Citation on PubMed
• Hoeffer CA, Klann E. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 2010 Feb;33(2):67-75. doi: 10.1016/j.tins.2009.11.003. Epub 2009 Dec 4. Citation on PubMed or Free article on PubMed Central
• Jhanwar-Uniyal M, Amin AG, Cooper JB, Das K, Schmidt MH, Murali R. Discrete signaling mechanisms of mTORC1 and mTORC2: Connected yet apart in cellular and molecular aspects. Adv Biol Regul. 2017 May;64:39-48. doi: 10.1016/j.jbior.2016.12.001. Epub 2017 Jan 4. Citation on PubMed
• Mirzaa GM, Campbell CD, Solovieff N, Goold C, Jansen LA, Menon S, Timms AE, Conti V, Biag JD, Adams C, Boyle EA, Collins S, Ishak G, Poliachik S, Girisha KM, Yeung KS, Chung BHY, Rahikkala E, Gunter SA, McDaniel SS, Macmurdo CF, Bernstein JA, Martin B, Leary R, Mahan S, Liu S, Weaver M, Doerschner M, Jhangiani S, Muzny DM, Boerwinkle E, Gibbs RA, Lupski JR, Shendure J, Saneto RP, Novotny EJ, Wilson CJ, Sellers WR, Morrissey M, Hevner RF, Ojemann JG, Guerrini R, Murphy LO, Winckler W, Dobyns WB. Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism. JAMA Neurol. 2016 Jul 1;73(7):836-845. doi: 10.1001/jamaneurol.2016.0363. Citation on PubMed or Free article on PubMed Central
• Moller RS, Weckhuysen S, Chipaux M, Marsan E, Taly V, Bebin EM, Hiatt SM, Prokop JW, Bowling KM, Mei D, Conti V, de la Grange P, Ferrand-Sorbets S, Dorfmuller G, Lambrecq V, Larsen LH, Leguern E, Guerrini R, Rubboli G, Cooper GM, Baulac S. Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy. Neurol Genet. 2016 Oct 31;2(6):e118. doi: 10.1212/NXG.0000000000000118. eCollection 2016 Dec. Citation on PubMed or Free article on PubMed Central
• Moosa S, Bohrer-Rabel H, Altmuller J, Beleggia F, Nurnberg P, Li Y, Yigit G, Wollnik B. Smith-Kingsmore syndrome: A third family with the MTOR mutation c.5395G>A p.(Glu1799Lys) and evidence for paternal gonadal mosaicism. Am J Med Genet A. 2017 Jan;173(1):264-267. doi: 10.1002/ajmg.a.37999. Epub 2016 Oct 18. Citation on PubMed