Selenium from dietary sources and motor functions in the Brazilian Amazon

Selenium (Se) is a well-known anti-oxidant with a critical role in the proper functioning of nervous and muscle functions. Se deficiency has been associated with both cognitive and neuromotor impairment, while sensory and motor deficits have been attributed to excess Se. In the Lower Tapajós Region of the Brazilian Amazon, riverside populations present a wide range of Se levels. These fish-eating communities have among the highest mercury (Hg) exposures reported in the world today, and recently, lead (Pb) exposure has been identified. Some studies suggest that Se intake can be protective for Hg and/or Pb toxicity, however, data from animal and human studies are inconsistent. The objective of the present study was to examine the relations between biomarkers of Se and motor functions, taking into account co-variables and biomarkers of exposure to Hg and Pb. Participants (n=448), aged 15-87 y, were recruited from 12 communities along the Tapajós River. Se concentrations were measured in whole blood (B-Se), plasma (P-Se), hair (H-Se) and urine (U-Se) by ICP-MS. Whole blood Hg (B-Hg) and Pb (B-Pb) were also measured by ICP-MS. Interview-administered questionnaires served to collect information on socio-demographics and medical history. All participants underwent a complete visual examination and performed tests of motor functions (Branches Alternate Movement Task, Santa Ana Test, Dynamometer and Grooved Pegboard Test). B-Se varied from 103 to 1500 μg/L (median 228 μg/L), P-Se from 53.6 to 913 μg/L (median 135 μg/L), H-Se from 0.4 to 3.8 μg/g (median 0.7 μg/g) and U-Se from 2.3 to 1375 μg/g cr. (median 33.6 μg/g cr.). Median B-Hg and B-Pb levels were 42.5 μg/L and 113 μg/L respectively. In multivariable analysis, Se biomarkers (log-transformed) were positively related to better performance on all motor tests, taking into account socio-demographic co-variables and B-Hg and B-Pb levels. P-Se consistently showed stronger associations to motor performance compared to the other Se biomarkers. Regression estimates for Se biomarkers were considerably stronger when controlling for B-Hg. When stratifying at the median for B-Hg concentrations, P-Se consistently presented associations with the outcomes only at high B-Hg concentrations. This is the first human study to report beneficial effects of high Se status on motor functions. For this population with elevated Hg exposure, high dietary Se intake may be critical for brain and muscle functions. However, these findings are not necessarily applicable to populations with lower Hg exposure and/or Se status, which is the case for people who do not rely heavily on fish consumption, be they in Brazil, the United States or elsewhere. The associations were mostly observed with P-Se, suggesting that P-Se or plasma selenoproteins may be good biomarkers for these outcomes.     

Perinatal and childhood morbidity and mortality in congenital analbuminemia

Albumin, a serum transport protein, provides 80% of colloid osmotic pressure. Congenital analbuminemia (CAA) is an autosomal recessive disorder characterized by absence of serum albumin. Fifty cases of CAA have been reported throughout the world; however, little is known about its clinical impact. Most reported cases have few clinical signs and symptoms. Twelve local cases from the northwestern central plains region in Saskatchewan were identified and reviewed to ascertain morbidity and mortality related with CAA. All the cases are from two remote First Nations communities. Cases had frequent hospital admissions and recurrent respiratory tract infections. Placental abnormalities included hydropic placentas, placental infarcts and microcalcifications. One-half of the cases were born preterm and one-quarter were small for their gestational age. There were three mortalities in the case series. The present case series suggests increased morbidity and mortality during infancy in patients with CAA. The long-term risks of CAA in this population are unknown and a longitudinal study is recommended.     

A common variant of the PAX2 gene is associated with reduced newborn kidney size

Congenital nephron number ranges widely in the human population. Suboptimal nephron number may be associated with increased risk for essential hypertension and susceptibility to renal injury, but the factors that set nephron number during kidney development are unknown. In renal-coloboma syndrome, renal hypoplasia and reduced nephron number are due to heterozygous mutations of the PAX2 gene. This study tested for an association between a common haplotype of the PAX2 gene and subtle renal hypoplasia in normal newborns. A PAX2 haplotype was identified to occur in 18.5% of the newborn cohort, which was significantly associated with a 10% reduction in newborn kidney volume adjusted for body surface area. This haplotype was also associated with reduced allele-specific PAX2 mRNA level in a human renal cell carcinoma cell line. Subtle renal hypoplasia in normal newborns may be partially due to a common variant of the PAX2 gene that reduces mRNA expression during kidney development.     

The implementation of an enhanced clinical model to improve the diagnostic yield of exome sequencing for patients with a rare genetic disease: A Canadian experience

The introduction of clinical exome sequencing (ES) has provided a unique opportunity to decrease the diagnostic odyssey for patients living with a rare genetic disease (RGD). ES has been shown to provide a diagnosis in 29%–57% of patients with a suspected RGD, with as many as 70% remaining undiagnosed. There is a need to advance the clinical model of care by more formally integrating approaches that were previously considered research into an enhanced diagnostic workflow. We developed an Exome Clinic, which set out to evaluate a workflow for improving the diagnostic yield of ES for patients with an undiagnosed RGD. Here, we report the outcomes of 47 families who underwent clinical ES in the first year of the clinic. The diagnostic yield from clinical ES was 40% (19/47). Families who remained undiagnosed after ES had the opportunity for follow-up studies that included phenotyping and candidate variant segregation in relatives, genomic matchmaking, and ES reanalysis. This enhanced diagnostic workflow increased the diagnostic yield to 55% (26/47), predominantly through the resolution of variants and genes of uncertain significance. We advocate that this approach be integrated into mainstream clinical practice and highlight the importance of a coordinated translational approach for patients with RGD.