Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria

Primary hyperoxaluria (PH) is a rare autosomal recessive disease characterized by oxalate accumulation in the kidneys and other organs. Three loci have been identified: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3). Here, we compared genotype to phenotype in 355 patients in the Rare Kidney Stone Consortium PH registry and calculated prevalence using publicly available whole-exome data. PH1 (68.4% of families) was the most severe PH type, whereas PH3 (11.0% of families) showed the slowest decline in renal function but the earliest symptoms. A group of patients with disease progression similar to that of PH3, but for whom no mutation was detected (11.3% of families), suggested further genetic heterogeneity. We confirmed that the AGXT p.G170R mistargeting allele resulted in a milder PH1 phenotype; however, other potential AGXT mistargeting alleles caused more severe (fully penetrant) disease. We identified the first PH3 patient with ESRD; a homozygote for two linked, novel missense mutations. Population analysis suggested that PH is an order of magnitude more common than determined from clinical cohorts (prevalence, approximately 1:58,000; carrier frequency, approximately 1:70). We estimated PH to be approximately three times less prevalent among African Americans than among European Americans because of a limited number of common European origin alleles. PH3 was predicted to be as prevalent as PH1 and twice as common as PH2, indicating that PH3 (and PH2) cases are underdiagnosed and/or incompletely penetrant. These results highlight a role for molecular analyses in PH diagnostics and prognostics and suggest that wider analysis of the idiopathic stone-forming population may be beneficial.     

The Future of Polycystic Kidney Disease Research—As Seen By the 12 Kaplan Awardees

Polycystic kidney disease (PKD) is one of the most common life-threatening genetic diseases. Jared J. Grantham, M.D., has done more than any other individual to promote PKD research around the world. However, despite decades of investigation there is still no approved therapy for PKD in the United States. In May 2014, the University of Kansas Medical Center hosted a symposium in Kansas City honoring the occasion of Dr. Grantham''s retirement and invited all the awardees of the Lillian Jean Kaplan International Prize for Advancement in the Understanding of Polycystic Kidney Disease to participate in a forward-thinking and interactive forum focused on future directions and innovations in PKD research. This article summarizes the contributions of the 12 Kaplan awardees and their vision for the future of PKD research.     

Comparison of Marker-Based and Stereo Radiography Knee Kinematics in Activities of Daily Living

Movement of the marker positions relative to the body segments obscures in vivo joint level motion. Alternatively, tracking bones from radiography images can provide precise motion of the bones at the knee but is impracticable for measurement of body segment motion. Consequently, researchers have combined marker-based knee flexion with kinematic splines to approximate the translations and rotations of the tibia relative to the femur. Yet, the accuracy of predicting six degree-of-freedom joint kinematics using kinematic splines has not been evaluated. The objectives of this study were to (1) compare knee kinematics measured with a marker-based motion capture system to kinematics acquired with high speed stereo radiography (HSSR) and describe the accuracy of marker-based motion to improve interpretation of results from these methods, and (2) use HSSR to define and evaluate a new set of knee joint kinematic splines based on the in vivo kinematics of a knee extension activity. Simultaneous measurements were recorded from eight healthy subjects using HSSR and marker-based motion capture. The marker positions were applied to three models of the lower extremity to calculate tibiofemoral kinematics and compared to kinematics acquired with HSSR. As demonstrated by normalized RMSE above 1.0, varus–valgus rotation (1.26), medial–lateral (1.26), anterior–posterior (2.03), and superior–inferior translations (4.39) were not accurately measured. Using kinematic splines improved predictions in varus–valgus (0.81) rotation, and medial–lateral (0.73), anterior–posterior (0.69), and superior–inferior (0.49) translations. Using splines to predict tibiofemoral kinematics as a function knee flexion can lead to improved accuracy over marker-based motion capture alone, however this technique was limited in reproducing subject-specific kinematics.     

Lethal licorice

The human body's response to extreme stress is complex and this patient's experience illustrates just how traumatic it can be both physiologically and psychologically. While Alan's experience was extreme and unusual, it serves to emphasise the importance of diet and health maintenance particularly for the cardiac patient.     

A Two-to-Five Year Follow-Up of a Pediatric Acute-Onset Neuropsychiatric Syndrome Cohort

Child Psychiatry & Human Development - Little is known about the long-term prognosis of children with pediatric acute-onset neuropsychiatric syndrome (PANS). Out of the 46 eligible patients...