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.
G Gordo  1  2  3 ,  J Tenorio  1  2 ,  P Arias  1  2 ,  F Santos-Simarro  1  4 ,  S García-Miñaur  1  4 ,  J C Moreno  1  2 ,  J Nevado  1  5 ,  E Vallespin  1  5 ,  L Rodriguez-Laguna  1  3 ,  R de Mena  1  5 ,  I Dapia  1  2 ,  M Palomares-Bralo  1  5 ,  Á Del Pozo  1  6 ,  K Ibañez  1  6 ,  J C Silla  1  6 ,  E Barroso  1  2 ,  V L Ruiz-Pérez  1  7 ,  V Martinez-Glez  1  3  4 ,  P Lapunzina  1  2  4
Affiliations
  • 1. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
  • 2. Molecular Endocrinology Section, Overgrowth Syndromes Laboratory, Instituto de Genética Médica y Molecular (INGEMM), IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
  • 3. Vascular Malformations Section, Instituto de Genética Médica y Molecular (INGEMM), IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
  • 4. Clinical Genetics Section, Instituto de Genética Médica y Molecular (INGEMM), IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
  • 5. Structural and Functional Genomics Section, Instituto de Genética Médica y Molecular (INGEMM), IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
  • 6. Bioinformatics Section, Instituto de Genética Médica y Molecular (INGEMM), IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
  • 7. IIB, Instituto de Investigación "Alberto Sols", Universidad Autónoma de Madrid (UAM), Madrid, Spain.
PMID: 28892148 DOI: 10.1111/cge.13135
Abstract

Smith-Kingsmore syndrome (SKS) OMIM #616638, also known as MINDS syndrome (ORPHA 457485), is a rare autosomal dominant disorder reported so far in 23 patients. SKS is characterized by intellectual disability, macrocephaly/hemi/megalencephaly, and seizures. It is also associated with a pattern of facial dysmorphology and other non-neurological features. Germline or mosaic mutations of the mTOR gene have been detected in all patients. The mTOR gene is a key regulator of cell growth, cell proliferation, protein synthesis and synaptic plasticity, and the mTOR pathway (PI3K-AKT-mTOR) is highly regulated and critical for cell survival and Apoptosis. Mutations in different genes in this pathway result in known rare diseases implicated in hemi/megalencephaly with Epilepsy, as the tuberous sclerosis complex caused by mutations in TSC1 and TSC2, or the PIK3CA-related overgrowth spectrum (PROS). We here present 4 new cases of SKS, review all clinical and molecular aspects of this disorder, as well as some characteristics of the patients with only brain mTOR somatic mutations.

Keywords
MINDS syndrome; Smith-Kingsmore syndrome; constitutive mosaicism; germline mosaicism; gonadal mosaicism; mTOR; macrocephaly; megalencephaly; somatic mosaicism.