Human COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes.

BACKGROUND: Human coenzyme Q4 (COQ4) is essential for coenzyme Q10 (CoQ10) biosynthesis. Pathogenic variants in COQ4 cause childhood-onset neurodegeneration. We aimed to delineate the clinical spectrum and the cellular consequences of COQ4 deficiency. METHODS: Clinical course and neuroradiological findings in a large cohort of paediatric patients with COQ4 deficiency were analysed. Functional studies in patient-derived cell lines were performed. RESULTS: We characterised 44 individuals from 36 families with COQ4 deficiency (16 newly described). A total of 23 different variants were identified, including four novel variants in COQ4. Correlation analyses of clinical and neuroimaging findings revealed three disease patterns: type 1: early-onset phenotype with neonatal brain anomalies and epileptic encephalopathy; type 2: intermediate phenotype with distinct stroke-like lesions; and type 3: moderate phenotype with non-specific brain pathology and a stable disease course. The functional relevance of COQ4 variants was supported by in vitro studies using patient-derived fibroblast lines. Experiments revealed significantly decreased COQ4 protein levels, reduced levels of cellular CoQ10 and elevated levels of the metabolic intermediate 6-demethoxyubiquinone. CONCLUSION: Our study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of COQ4 variants. Due to the insufficient clinical response to oral CoQ10 supplementation, alternative treatment strategies are warranted.

Maternal Overweight and Obesity during Pregnancy Are Associated with Neonatal, but Not Maternal, Hepcidin Concentrations.

BACKGROUND: Overweight or obesity among pregnant women may compromise maternal and neonatal iron status by upregulating hepcidin. OBJECTIVES: This study determined the association of 1) maternal and neonatal iron status with maternal and neonatal hepcidin concentrations, and 2) maternal prepregnancy weight status with maternal and neonatal hepcidin concentrations. METHODS: We examined hematologic data from 405 pregnant women and their infants from the placebo treatment group of a pregnancy iron supplementation trial in rural China. We measured hepcidin, serum ferritin (SF), soluble transferrin receptor (sTfR), and high-sensitivity C-reactive protein in maternal blood samples at mid-pregnancy and in cord blood at delivery. We used regression analysis to examine the association of maternal prepregnancy overweight or obese status with maternal hepcidin concentration in mid-pregnancy and cord hepcidin concentrations. We also used path analysis to examine mediation of the association of maternal prepregnancy overweight or obese status with maternal iron status by maternal hepcidin, as well as with neonatal hepcidin by neonatal iron status. RESULTS: Maternal iron status was positively correlated with maternal hepcidin at mid-pregnancy (SF: r = 0.63, P < 0.001; sTfR: r = -0.37, P < 0.001). Neonatal iron status was also positively correlated with cord hepcidin (SF: r = 0.61, P < 0.001; sTfR: r = -0.39, P < 0.001). In multiple linear regression models, maternal prepregnancy overweight or obese status was not associated with maternal hepcidin at mid-pregnancy but was associated with lower cord hepcidin (coefficient = -0.21, P = 0.004). Using path analysis, we observed a significant indirect effect of maternal prepregnancy overweight or obese status on cord hepcidin, mediated by neonatal iron status. CONCLUSIONS: In both pregnant women and neonates, hepcidin was responsive to iron status. Maternal prepregnancy overweight status, with or without including obese women, was associated with lower cord blood hepcidin, likely driven by lower iron status among the neonates of these mothers.

Serum trace element differences between Schizophrenia patients and controls in the Han Chinese population.

Little is known about the trace element profile differences between Schizophrenia patients and healthy controls; previous studies about the association of certain elements with Schizophrenia have obtained conflicting results. To identify these differences in the Han Chinese population, inductively coupled plasma-mass spectrometry was used to quantify the levels of 35 elements in the sera of 111 Schizophrenia patients and 110 healthy participants, which consisted of a training (61/61 for cases/controls included) and a test group including remaining participants. An orthogonal projection to latent structures model was constructed from the training group (R(2)Y = 0.465, Q(2)cum = 0.343) had a sensitivity of 76.0% and a specificity of 71.4% in the test group. Single element analysis indicated that the concentrations of cesium, zinc, and selenium were significantly reduced in patients with Schizophrenia in both the training and test groups. The meta-analysis including 522 cases and 360 controls supported that Zinc was significantly associated with Schizophrenia (standardized mean difference [SMD], -0.81; 95% confidence intervals [CI], -1.46 to -0.16, P = 0.01) in the random-effect model. Information theory analysis indicated that Zinc could play roles independently in Schizophrenia. These results suggest clear element profile differences between patients with Schizophrenia and healthy controls, and reduced Zn level is confirmed in the Schizophrenia patients.