RESUMEN
Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). On the basis of the decreased galactosylation in glycan chains, galactose was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-related laboratory abnormalities. The disease and treatment mechanisms, however, have remained largely elusive. Here, we confirm the clinical benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights into the functional and biochemical regulation of glycosylation. We report here that, by using tracer-based metabolomics, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metabolism, and as such replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER- and GA-linked glycosylation, respectively. To this end, we further show that the galactose in UDP-galactose is incorporated into mature, de novo glycans. Our results also allude to the potential of monosaccharide therapy for several other CDG.
Asunto(s)
Trastornos Congénitos de Glicosilación/metabolismo , Fibroblastos/metabolismo , Galactosa/administración & dosificación , Fosfoglucomutasa/deficiencia , Uridina Difosfato Galactosa/metabolismo , Uridina Difosfato Glucosa/metabolismo , Células Cultivadas , Estudios de Cohortes , Trastornos Congénitos de Glicosilación/tratamiento farmacológico , Trastornos Congénitos de Glicosilación/patología , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Glicosilación , HumanosRESUMEN
Mitochondrial diseases are associated with defects of adenosine triphosphate production and energy supply to organs as a result of dysfunctions of the mitochondrial respiratory chain. Biallelic mutations in the YARS2 gene encoding mitochondrial tyrosyl-tRNA synthetase cause myopathy, lactic acidosis, and sideroblastic anemia 2 (MLASA2), a type of mitochondrial disease. Here, we report a consanguineous Turkish family with two siblings showing severe metabolic decompensation including recurrent hypoglycemia, lactic acidosis, and transfusion-dependent anemia. Using whole-exome sequencing of the proband and his parents, we identified a novel YARS2 mutation (c.1303A>G, p.Ser435Gly) that was homozygous in the patient and heterozygous in his parents. This mutation is located at the ribosomal protein S4-like domain of the gene, while other reported YARS2 mutations are all within the catalytic domain. Interestingly, the proband showed more severe symptoms and an earlier onset than previously reported patients, suggesting the functional importance of the S4-like domain in tyrosyl-tRNA synthetase.
Asunto(s)
Acidosis Láctica/genética , Anemia Sideroblástica/genética , Enfermedades Musculares/genética , Mutación , Tirosina-ARNt Ligasa/genética , Acidosis Láctica/complicaciones , Adolescente , Adulto , Anemia Sideroblástica/complicaciones , Niño , Preescolar , Resultado Fatal , Femenino , Homocigoto , Humanos , Lactante , Recién Nacido , Masculino , Enfermedades Musculares/complicaciones , Linaje , Adulto JovenRESUMEN
BACKGROUND: The aim of this study was to investigate the quality of life (QoL) of a group of patients with inherited metabolic diseases (IMD) who were treated with restrictive diet. METHOD: A total of 68 patients (35 boys, 51.5%; 33 girls, 48.5%) with IMD (organic acidemia [OA], n = 14; disorder of carbohydrate metabolism [CMD], n = 33; and disorder of amino acid metabolism [AMD], n = 21) and their parents were inteviewed. Both parents completed a QoL Scale for Metabolic Diseases-Parent Form, a KINDL parent questionnaire, and a depression form. All patients aged ≥4 years completed a questionnaire themselves, including the KINDL-Kid and KINDL-Kiddo self-reports. The semi-standardized interviews were carried out with patients and their parents in a clinical setting. RESULTS: The patients with bad diet compliance had lower scores for school labeling and perception of disease on both the parent and child questionnaire forms (P < 0.05). The patients were then divided into three groups (OA, CMD, AMD) for further analysis. Differences were seen between groups with regard to scores of physical function and school performance according to QoL Scale for Metabolic Diseases-Parent Form (P < 0.01). According to parent perceptions, the CMD patients had better QoL with regard to emotional wellbeing. CONCLUSION: As negative effects of the disease increased, the QoL of IMD patients and their parents decreased in terms of emotional, physical, and cognitive function. Application of expanded newborn scanning programs, early diagnosis, regular follow up, and family education would lessen the effects of the disease and improve the QoL of both families and children.
Asunto(s)
Dieta Reductora , Predisposición Genética a la Enfermedad , Enfermedades Metabólicas/psicología , Calidad de Vida , Adolescente , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Masculino , Salud Mental , Enfermedades Metabólicas/dietoterapia , Enfermedades Metabólicas/genética , Pronóstico , Psicometría , Estudios Retrospectivos , Encuestas y Cuestionarios , Adulto JovenRESUMEN
The most commonly encountered complications in familial hypercholesterolemia (FH) are mainly cardiovascular in origin and the majority of cases unfortunately die due to this problem. LDL-apheresis is a proven therapeutic method in lowering this mortal risk. In this study we aimed to demonstrate the efficiency of LDL-apheresis performed by DALI or Cascade filtration on four pediatric patients with the diagnosis of homozygous FH. Applied LDL-apheresis techniques, side effects, laboratory results and cardiovascular follow-up are discussed in the light of current literature. Our study has shown once again that lipid apheresis treatment in children with homozygous FH is the most effective treatment. The number of childhood subjects in whom lipid apheresis is performed is quite insufficient. There are no studies that compare DALI with cascade filtration in childhood subjects in our knowledge. The view of this aspect, this study will contribute to literature.
Asunto(s)
Eliminación de Componentes Sanguíneos , Hiperlipoproteinemia Tipo II/terapia , Lipoproteínas LDL , Adolescente , Niño , Femenino , Homocigoto , Hospitales Universitarios , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Estudios Retrospectivos , TurquíaRESUMEN
Very-long-chain acyl-coenzyme A (CoA) dehydrogenase deficiency (VLCADD) (OMIM #201475) is an autosomal recessive disorder of fatty acid oxidation. Major phenotypic expressions are hypoketotic hypoglycemia, hepatomegaly, cardiomyopathy, myopathy, rhabdomyolysis, elevated creatinine kinase, and lipid infiltration of liver and muscle. At the same time, it is a rare cause of Sudden Infant Death Syndrome (SIDS) or unexplained death in the neonatal period [1-4]. We report a patient with VLCADD whose parents were investigated for infanticide because her three previous siblings had suddenly died after normal deliveries.
Asunto(s)
Errores Innatos del Metabolismo/diagnóstico , Enfermedades Mitocondriales/diagnóstico , Enfermedades Musculares/diagnóstico , Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Síndromes Congénitos de Insuficiencia de la Médula Ósea , Consanguinidad , Diagnóstico Diferencial , Exones , Femenino , Genética Forense , Defectos de los Tabiques Cardíacos/diagnóstico por imagen , Defectos de los Tabiques Cardíacos/etiología , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/etiología , Recién Nacido , Infanticidio , Errores Innatos del Metabolismo Lipídico , Errores Innatos del Metabolismo/genética , Enfermedades Mitocondriales/genética , Enfermedades Musculares/genética , Mutación , Linaje , UltrasonografíaRESUMEN
BACKGROUND/AIMS: The incidence of non-alcoholic fatty liver disease has been increasing parallel to obesity in the pediatric age group. This study aimed to analyze the factors that are related to non-alcoholic fatty liver disease in obese children. METHODS: 101 obese children and 68 non-obese controls were included in the study. Liver steatosis was investigated by ultrasonography. The subjects were divided into three groups: 53 obese patients with fatty liver (Group I), 48 obese patients without steatosis (Group II), and 68 controls without steatosis (Group III). Group I was further divided into those with Grade 1 steatosis (44 patients, Group Ia) and higher grades of steatosis (9 patients, Group Ib). The relationships of body mass index, serum ALT, lipids, leptin, and insulin resistance index with steatosis were analyzed. RESULTS: 52.4% of obese children had fatty liver and 13.8% had high ALT levels. Additionally, all patients with elevated ALT levels were seen to have liver steatosis by ultrasonography. Leptin and insulin resistance index levels were higher in obese groups than controls; however, the difference disappeared when these levels were adjusted for body mass index. ALT levels were higher in Group I (31.5+/-30.2) than Group II (18.0+/-7.1) and Group III (14.5+/-5.2) (p<0.05). Group Ib showed higher VLDL and ALT levels than Group Ia (p<0.05). Multiple regression analysis revealed that body mass index was the most important determinant of liver steatosis, while body mass index and VLDL were the determinants of higher ALT levels. CONCLUSIONS: We suggest that body mass index and VLDL are the most important determinants of non-alcoholic fatty liver disease and elevated ALT levels in obese children. The contribution of leptin to this process could not be determined in our findings.