3 research outputs found
Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy
Objective:To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology.Methods:We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes.Results:We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families.Conclusions:De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders.Johannes R. Lemke (32EP30_136042/1) and Peter De Jonghe (G.A.136.11.N and FWO/ESF-ECRP) received financial support within the EuroEPINOMICS-RES network (www.euroepinomics.org) within the Eurocores framework of the European Science Foundation (ESF). Saskia Biskup and Henrike Heyne received financial support from the German Federal Ministry for Education and Research (BMBF IonNeurONet: 01 GM1105A and FKZ: 01EO1501). Katia Hardies is a PhD fellow of the Institute for Science and Technology (IWT) Flanders. Ingo Helbig was supported by intramural funds of the University of Kiel, by a grant from the German Research Foundation (HE5415/3-1) within the EuroEPINOMICS framework of the European Science Foundation, and additional grants of the German Research Foundation (DFG, HE5415/5-1, HE 5415/6-1), German Ministry for Education and Research (01DH12033, MAR 10/012), and grant by the German chapter of the International League against Epilepsy (DGfE). The project also received infrastructural support through the Institute of Clinical Molecular Biology in Kiel, supported in part by DFG Cluster of Excellence "Inflammation at Interfaces" and "Future Ocean." The project was also supported by the popgen 2.0 network (P2N) through a grant from the German Ministry for Education and Research (01EY1103) and by the International Coordination Action (ICA) grant G0E8614N. Christel Depienne, Caroline Nava, and Delphine Heron received financial support for exome analyses by the Centre National de Genotypage (CNG, Evry, France)
Mild pyelectasis: evaluating the relationship between gestational age and renal pelvic anterior-posterior diameter.
OBJECTIVE: To determine the relationship between gestational age and renal pelvic anterior-posterior diameter and the feasibility of developing gestational age-specific thresholds for the diagnosis of mild pyelectasis.
METHODS: Cross-sectional study of 420 singleton fetuses between 16 and 39 weeks\u27 gestation. The mean renal AP diameter as a function of gestational age was determined using fractional polynomial regression models and centile plots were generated. Assessment of goodness of fit for each regression model was performed.
RESULTS: There was a positive correlation between gestational age and renal pelvic AP diameter (Pearson\u27s Correlation Coefficient 0.65). Using the derived mean and standard deviations of renal AP diameter, gestational-age specific 95% reference levels were generated. The sensitivity, specificity, positive, and negative predictive values of using the gestational age-specific cutoffs for predicting persistent postnatal renal anomaly were 80%; 99%; 29%; and 99% respectively.
CONCLUSION: There is a positive correlation between gestational age and renal pelvic AP diameters. Reliable gestational age-specific renal AP thresholds for diagnosis of pyelectasis are provided