MTOR mutations in Smith-Kingsmore syndrome: Four additional patients and a review.

G Gordo,P Lapunzina,K Ibañez,V.L Ruiz‐Pérez,E Barroso,E Vallespin,P Arias,Á Del Pozo,L Rodriguez‐Laguna,R De Mena,F Santos‐Simarro,J.C Moreno,I Dapia,S García‐Miñaur,J Tenorio,M Palomares‐Bralo,J Nevado,J.C Silla,V Martinez‐Glez

doi:10.1111/cge.13135

G Gordo, P Lapunzina + Show 17 more

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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.

Highlights

Smith-Kingsmore syndrome (SKS) (MIM 616638), known as MINDS (ORPHA 457485), is a rare syndrome, first described by Smith et al[1] and caused by mutations in the mammalian target of rapamycin gene
SKS belongs to the group of “mTORopathies,” a term introduced to describe neurological disorders characterized by altered cortical architecture, abnormal neuronal morphology and intractable epilepsy as a consequence of mTOR signalling hyperactivation, providing probably a histopathological substrate for epileptogenesis.[2,3]
Glu1799Lys gain-of-function (GOF) variant affecting the FRAP– ATM–TTRAP (FAT) domain of the protein has been detected in 48.1% (13/27) of SKS patients (Figure 2, Table 2), and in cases with brain somatic mTOR variants the most frequently affected amino acid is the serine at position 2215 (p.Ser2215Phe and p.Ser2215Tyr), found in 37% (10/27) of the patients (Table 3)

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| INTRODUCTION

Smith-Kingsmore syndrome (SKS) (MIM 616638), known as MINDS (ORPHA 457485), is a rare syndrome, first described by Smith et al[1] and caused by mutations in the mammalian target of rapamycin (mTOR, MIM 601231) gene. To update the phenotype in SKS, we performed a retrospective review of the clinical characteristics including the 4 patients described and the 23 patients previously reported to date (Table 2). These patients were ascertained from a series of patients with focal epilepsy, ID, brain anomalies and megalencephaly or hemimegalencephaly.[1,12,17,18,19,20,21,22] Reported patients with only brain somatic mutations of mTOR were reviewed.[10,17,23,24,25]. Primers were designed with the PyroMark software, and pyrosequencing was performed with the PyroMark Q96 MD instrument (Qiagen, Hilden, Germany), according to manufacturer’s protocol

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