RESUMO
BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.
Assuntos
Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/fisiopatologia , Doenças do Desenvolvimento Ósseo/epidemiologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Anormalidades Craniofaciais/epidemiologia , Anormalidades Craniofaciais/fisiopatologia , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/fisiopatologia , Transtornos Mentais/epidemiologia , Displasia Septo-Óptica/epidemiologia , Displasia Septo-Óptica/fisiopatologia , Distúrbios da Fala/epidemiologia , Adaptação Psicológica , Adolescente , Adulto , Criança , Pré-Escolar , Comorbidade , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Transtornos Mentais/fisiopatologia , Países Baixos/epidemiologia , Fenótipo , Distúrbios da Fala/fisiopatologia , Síndrome , Adulto JovemRESUMO
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/genéticaRESUMO
INTRODUCTION: Zonisamide is a new-generation anticonvulsant antiepileptic drug metabolized primarily in the liver, with subsequent elimination via the renal route. OBJECTIVES: Our objective was to evaluate the utility of pharmacometabolomics in the detection of zonisamide metabolites that could be related to its disposition and therefore, to its efficacy and toxicity. METHODS: This study was nested to a bioequivalence clinical trial with 28 healthy volunteers. Each participant received a single dose of zonisamide on two separate occasions (period 1 and period 2), with a washout period between them. Blood samples of zonisamide were obtained from all patients at baseline for each period, before volunteers were administered any medication, for metabolomics analysis. RESULTS: After a Lasso regression was applied, age, height, branched-chain amino acids, steroids, triacylglycerols, diacyl glycerophosphoethanolamine, glycerophospholipids susceptible to methylation, phosphatidylcholines with 20:4 FA (arachidonic acid) and cholesterol ester and lysophosphatidylcholine were obtained in both periods. CONCLUSION: To our knowledge, this is the only research study to date that has attempted to link basal metabolomic status with pharmacokinetic parameters of zonisamide.
Assuntos
Metabolômica/métodos , Zonisamida/metabolismo , Zonisamida/farmacocinética , Adulto , Anticonvulsivantes/sangue , Anticonvulsivantes/metabolismo , Área Sob a Curva , Feminino , Voluntários Saudáveis , Humanos , Isoxazóis/sangue , Masculino , Fenômenos Farmacológicos/fisiologia , Equivalência Terapêutica , Adulto JovemRESUMO
The original version of this article contains a mistake.