RESUMO
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.
Assuntos
Encéfalo/metabolismo , Megalencefalia/genética , Síndrome de Smith-Lemli-Opitz/genética , Serina-Treonina Quinases TOR/genética , Adolescente , Encéfalo/fisiopatologia , Proliferação de Células/genética , Criança , Classe I de Fosfatidilinositol 3-Quinases/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Megalencefalia/diagnóstico por imagem , Megalencefalia/fisiopatologia , Mutação , Plasticidade Neuronal/genética , Proteínas Proto-Oncogênicas c-akt/genética , Síndrome de Smith-Lemli-Opitz/diagnóstico por imagem , Síndrome de Smith-Lemli-Opitz/fisiopatologia , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genéticaAssuntos
Anormalidades Múltiplas/genética , Coloboma/genética , Cardiopatias Congênitas/genética , Mutação , Fatores de Processamento de RNA/genética , Proteínas Repressoras/genética , Anormalidades Múltiplas/metabolismo , Pré-Escolar , Coloboma/metabolismo , Feminino , Cardiopatias Congênitas/metabolismo , Humanos , Masculino , Análise de Sequência de DNARESUMO
INTRODUCTION: Stargardt's disease is the most frequent form of inherited macular dystrophy in children and adults. It is a genetic eye disorder caused by mutations in ABCA4 gene with an autosomal recessive inheritance. ABCA4 is a very polymorphic and large gene containing 50 exons. The development of next generation sequencing (NGS) can be used for the genetic diagnosis of this disease. PATIENTS AND METHODS: A report is presented on two patients with a clinical diagnosis of Stargardt's disease whose genetic confirmation was performed by a NGS panel of 298 genes. RESULTS: Clinically, the patients showed bull's eye maculopathy and absence of flecks, and genetically they shared the Gly1961Glu mutation that could explain their common phenotype, together with c.C3056T:p.T1019M for case 1, and c.287del:p.Asn96Thrfs*19 for case 2. CONCLUSIONS: NGS is particularly useful in the diagnosis of Stargardt's disease as ABCA4 is a large gene with a high allelic heterogeneity that causes a wide range of clinical manifestations.