RESUMO
Hemimegalencephaly (HME) is a rare hamartomatous congenital malformation of the brain characterized by dysplastic overgrowth of either one of the cerebral hemispheres. HME is associated with early onset seizures, abnormal neurological findings, and with subsequent cognitive and behavioral disabilities. Seizures associated with HME are often refractory to antiepileptic medications. Hemispherectomy is usually necessary to provide effective seizure control. The exact etiology of HME is not fully understood, but involves a disturbance in early brain development and likely involves genes responsible for patterning and symmetry of the brain. We present a female newborn who had refractory seizures due to HME. Whole genome sequencing revealed a novel, likely pathogenic, maternally inherited, 3Kb deletion encompassing exon 5 of the NPRL3 gene (chr16:161898-164745x1). The NPRL3 gene encodes for a nitrogen permease regulator 3-like protein, a subunit of the GATOR complex, which regulates the mTOR signaling pathway. A trial of mTOR inhibitor drug, Sirolimus, did not improve her seizure control. Functional hemispherectomy at 3 months of age resulted in total abatement of clinical seizures.
Assuntos
Epilepsia/genética , Proteínas Ativadoras de GTPase/genética , Hemimegalencefalia/genética , Convulsões/genética , Serina-Treonina Quinases TOR/genética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Epilepsia/patologia , Feminino , Predisposição Genética para Doença , Hemimegalencefalia/tratamento farmacológico , Hemimegalencefalia/patologia , Humanos , Recém-Nascido , Convulsões/patologia , Sirolimo/administração & dosagem , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
A term newborn presented with widespread cutaneous erythematous to bluish lesions since birth. He had extensive lesions in the gastrointestinal tract, brain, retina, heart, and bones. He also developed an intestinal perforation due to erosion of an intestinal lesion. Due to his critical status and clinical presentation, he was initially diagnosed with multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT), and sirolimus treatment was initiated. Sirolimus was given by buccal route in this nonfeeding patient. Therapeutic serum levels were obtained comparable to enteral administration. Buccal mucosa was an effective novel route of sirolimus administration in this patient.
Assuntos
Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/metabolismo , Sirolimo/administração & dosagem , Sirolimo/sangue , Vias de Administração de Medicamentos , Eritema/sangue , Eritema/diagnóstico , Eritema/tratamento farmacológico , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Recém-Nascido , MasculinoRESUMO
We investigated the effects of betamethasone on oxidative stress and impaired vasodilation in a lamb model of persistent pulmonary hypertension (PPHN). We treated pregnant ewes following fetal ductal ligation with betamethasone or saline for 48 h before delivery. Response of fetal pulmonary arteries to nitric oxide synthase (NOS) agonist adenosine triphosphate (ATP) and nitric oxide (NO) donor, s-nitroso-n-acetyl-penicillamine (SNAP) was determined in tissue bath. Pulmonary artery endothelial cells (PAEC) from fetal lambs with ductal ligation or sham ligation were treated with betamethasone or its vehicle for 48 h. Expression of endothelial NOS (eNOS), endothelin, endothelin-B (ET-B) receptor, and CuZn- and Mn-superoxide dismutase (SOD) in PAEC was studied. Intracellular cGMP and superoxide levels and interaction of eNOS with heat shock protein 90 (Hsp90) were determined in PAEC. Antenatal betamethasone improved the relaxation response of pulmonary arteries to ATP and SNAP in PPHN. PPHN was associated with decreases in eNOS and ET-B receptor and increase in prepro-endothelin mRNA levels. Betamethasone decreased prepro-endothelin mRNA and ET-1 pro-peptide levels and increased eNOS and MnSOD protein levels in PPHN. Betamethasone reversed the increased superoxide/decreased cGMP levels and restored Hsp90-eNOS interactions in PPHN. Betamethasone reduces oxidative stress and improves response of pulmonary arteries to vasodilators in lambs with PPHN.