RESUMO
OBJECTIVE: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder. METHODS: Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type versus variant Nav1.3 subunits coexpressed with ß1 and ß2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293T cells). RESULTS: Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20, 75%). Many, but not all (15/19, 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4 to 6 of domains II to IV. Most pathogenic missense variants tested (10/11, 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function. INTERPRETATION: Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in >75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis. ANN NEUROL 2020;88:348-362.
Assuntos
Encéfalo/diagnóstico por imagem , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Canal de Sódio Disparado por Voltagem NAV1.3/genética , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/genética , Canais de Sódio/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Feto/diagnóstico por imagem , Variação Genética/genética , Células HEK293 , Humanos , Lactente , MasculinoRESUMO
Migrating partial seizures in infancy (MPSI) are an age-specific epilepsy syndrome characterized by migrating focal seizures, which are intractable to various antiepileptic drugs and cause severe developmental delay. We report a case of MPSI with heterozygous missense mutation in KCNT1, which was successfully managed by ketogenic diet. At age 2months, the patient developed epilepsy initially manifesting focal seizures with eye deviation and apnea, then evolving to secondarily generalized clonic convulsion. Various antiepileptic drugs including phenytoin, valproic acid, zonisamide, clobazam, levetiracetam, vitamin B6, and carbamazepine were not effective, but high-dose phenobarbital allowed discontinuation of midazolam infusion. Ictal scalp electroencephalogram showed migrating focal seizures. MPSI was suspected and she was transferred to our hospital for further treatment. Potassium bromide (KBr) was partially effective, but the effect was transient. High-dose KBr caused severe adverse effects such as over-sedation and hypercapnia, with no further effects on the seizures. At age 9months, we started a ketogenic diet, which improved seizure frequency and severity without obvious adverse effects, allowing her to be discharged from hospital. Ketogenic diet should be tried in patients with MPSI unresponsive to antiepileptic drugs. In MPSI, the difference in treatment response in patients with and those without KCNT1 mutation remains unknown. Accumulation of case reports would contribute to establish effective treatment options for MPSI.
Assuntos
Dieta Cetogênica , Epilepsias Parciais/dietoterapia , Anticonvulsivantes/uso terapêutico , Encéfalo/fisiopatologia , Terapia Combinada/métodos , Eletroencefalografia , Epilepsias Parciais/tratamento farmacológico , Epilepsias Parciais/genética , Epilepsias Parciais/fisiopatologia , Feminino , Seguimentos , Humanos , Lactente , Proteínas do Tecido Nervoso/genética , Canais de Potássio/genética , Canais de Potássio Ativados por Sódio , Resultado do TratamentoRESUMO
BACKGROUND/AIMS: Sialyl Lewis X (sLeX), one of the cancer-associated glycoproteins, has been reported to be expressed in both liver tissue from various types of liver disease and hepatocellular carcinoma. In order to clarify sLeX expression during the early stage of hepatocarcinogenesis, we examined sLeX expressions in either liver tissue specimens without any nodular lesions, dysplastic nodules or hepatocellular carcinomas. METHODOLOGY: Immunohistochemical observations were performed using a monoclonal antibody for sLeX. As for the liver tissue specimens, 8 livers without any chronic liver disease and 42 diseased livers were examined, while for the nodular lesions, 5 dysplastic nodules (borderline lesions) and 47 hepatocellular carcinomas were examined in this study. RESULTS: sLeX was not expressed in all 8 normal livers. sLeX was expressed membraneously in 8 of 15 (53%) chronic hepatitic liver tissue specimens, in 8 of 9 (89%) precirrhotic liver tissue specimens and in 16 of 18 (89%) cirrhotic liver tissue specimens. The incidence of sLeX expression on hepatocytes in both pre-cirrhotic and cirrhotic liver tissue was higher than that in chronic hepatitic liver tissue (P < 0.05). The sLeX expression in liver tissue was positive in all 14 liver tissue specimens containing multiple hepatocellular carcinomas, in which at least one of the nodules was a well-differentiated hepatocellular carcinoma regarded as multicentric hepatocellular carcinomas. In 18 of 28 (64%) liver tissue specimens without multicentric hepatocellular carcinomas, sLeX was positive and the difference was statistically significant (P < 0.05). In nodular lesions, sLeX was negative in 5 dysplastic nodules (borderline lesions). In hepatocellular carcinoma, 14 of 47 (30%) hepatocellular carcinoma nodules showed a positive expression. Six of 14 (43%) well-differentiated hepatocellular carcinomas were positive on the cell membrane. Four of 23 (17%) moderately differentiated hepatocellular carcinomas were positive on the cell membrane, while one of 23 (4%) moderately differentiated hepatocellular carcinoma was positive in the cytoplasm. In addition, 3 of 10 (30%) poorly differentiated hepatocellular carcinomas were positive in the cytoplasm. CONCLUSIONS: These results suggested that the sLeX-positive liver tissue specimens possessed a high degree of carcinogenicity and therefore sLeX expression in the diseased liver might be a good predictor for hepatocellular carcinoma emergence. At the same time, the suppression of sLeX occurred at a very early stage of hepatocarcinogenesis. In addition, the phenotype of sLeX was also considered to change during the progression of hepatocarcinogenesis.