RESUMO
Cytosolic PEPCK deficiency (PCKDC) is a rare autosomal recessive inborn error of metabolism, which can present with hypoglycemia, lactic acidosis, and liver failure. It is caused by biallelic pathogenic variants in the PCK1 gene. Only four PCK1 variants have been previously reported in seven patients with PCKDC, and their clinical course of this condition has not been well characterized. Here, we report a Hispanic male with novel biallelic PCK1 variants, p.(Gly430Asp) and p.(His496Gln), who had a unique clinical presentation. He presented with a new onset of growth failure, elevated blood lactate, transaminitis, and abnormal urine metabolites profile, but he has not had documented hypoglycemia. Growth restriction happened due to insufficient caloric intake, and it was improved with nutritional intervention. PCKDC is a manageable disorder and therefore appropriate nutritional and clinical suspicion from typical lab abnormalities which lead to molecular confirmation tests are essential to prevent poor clinical outcomes.
Assuntos
Códon sem Sentido , Ingestão de Energia/genética , Insuficiência de Crescimento/genética , Transtornos do Crescimento/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Sequência de Aminoácidos , Peso ao Nascer , Pré-Escolar , Ciclo do Ácido Cítrico , Citosol/enzimologia , Insuficiência de Crescimento/sangue , Insuficiência de Crescimento/urina , Feminino , Preferências Alimentares , Genótipo , Transtornos do Crescimento/sangue , Transtornos do Crescimento/urina , Humanos , Alimentos Infantis , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Masculino , Microcefalia/genética , Linhagem , Fosfoenolpiruvato Carboxiquinase (GTP)/deficiência , Gravidez , Complicações na Gravidez , Convulsões , Alinhamento de Sequência , Homologia de Sequência de AminoácidosRESUMO
RBM10, is an RNA binding protein that is important for development by regulating the expression of multiple genes. RBM10 is on the X chromosome, and nonsense and frameshift RBM10 variants cause TARP syndrome in males. In a 4-year-old male, we identified a novel maternally inherited missense RBM10 variant in the RRM2 RNA binding domain, c.965C>T, p.Pro322Leu. His clinical features included intellectual disability, developmental delay, growth restriction, hypotonia, and craniofacial malformations. These features were much milder than those described in previously reported cases of TARP syndrome. By in vitro assays, we found that the mutant p.Pro322Leu RBM10 protein retained its specific RNA binding capacity, while gaining a low-affinity nonspecific RNA binding. It was normally localized to the nucleus, but its expression level was significantly reduced with a significantly short half-life. These results indicated that the p.Pro322Leu missense variant causes a developmental disorder in humans through a unique loss-of-function mechanism.