RESUMO
N-Glycanase 1, encoded by NGLY1, catalyzes the deglycosylation of misfolded N-linked glycoproteins retrotranslocated into the cytosol. We identified nine cases with mutations in NGLY1. The patients show developmental delay, seizures, peripheral neuropathy, abnormal liver function and alacrima (absence of tears). The mutations in NGLY1 resulted in the absence of N-glycanase 1 protein in patient-derived fibroblasts. Applying a recently established cellular deglycosylation-dependent Venus fluorescence assay, we found that patient fibroblasts had dramatically reduced fluorescence, indicating a pronounced reduction in N-glycanase enzymatic activity. Using this assay, we could find no evidence of other related activities. Our findings reveal that NGLY1 mutations destroy both N-glycanase 1 protein and enzymatic activity.
Assuntos
Deficiências do Desenvolvimento/genética , Oftalmopatias Hereditárias/genética , Insuficiência Hepática/genética , Doenças do Aparelho Lacrimal/genética , Mutação , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/genética , Doenças do Sistema Nervoso Periférico/genética , Convulsões/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Deficiências do Desenvolvimento/patologia , Ensaios Enzimáticos , Éxons , Fibroblastos/enzimologia , Fibroblastos/patologia , Expressão Gênica , Genes Reporter , Insuficiência Hepática/congênito , Humanos , Doenças do Aparelho Lacrimal/congênito , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/deficiência , Doenças do Sistema Nervoso Periférico/congênito , Cultura Primária de Células , Convulsões/congênitoRESUMO
Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome (DS) is characterized by the transient appearance of blast cells, which resolves spontaneously. Approximately 20 % of patients with TAM die at an early age due to organ failure, including liver disease. We studied 25 DS-TAM patients retrospectively to clarify the correlation between clinical and laboratory characteristics and liver diseases. Early death (<6 months of age) occurred in four of the 25 patients (16.0 %), and two of those four patients died due to liver failure. Although physiologic jaundice improved gradually after a week, all DS patients had elevated D-Bil levels during the clinical course of TAM, except one who suffered early death. The median peak day of the WBC count, total bilirubin (T-Bil) and D-Bil levels was: day 1 (range day 0-57), day 8 (range day 1-55), and day 17 (range 1-53), respectively. Our results reveal that all patients with DS-TAM may develop liver disease irrespective of the absence or presence of symptoms and risk factors for early death. In patients of DS-TAM, careful observation of the level of D-Bil is needed by at least 1 month of age for the detection of liver disease risk.
Assuntos
Síndrome de Down/fisiopatologia , Insuficiência Hepática/etiologia , Reação Leucemoide/fisiopatologia , Fígado/fisiopatologia , Progressão da Doença , Feminino , Insuficiência Hepática/congênito , Insuficiência Hepática/epidemiologia , Insuficiência Hepática/fisiopatologia , Hospitais Pediátricos , Humanos , Recém-Nascido , Japão/epidemiologia , Masculino , Insuficiência de Múltiplos Órgãos/epidemiologia , Insuficiência de Múltiplos Órgãos/etiologia , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
We present a rare case of hydranencephaly with cholestasis and giant hepatitis. Studies for infectious agents were all negative including for the detection of virus in liver tissue by using polymerase chain reaction. Although the anterior pituitary functions (cortisol, thyroid stimulating hormone, free T4, human growth hormone) were normal, the patient revealed massive cholestasis and giant hepatitis.
