RESUMEN
Introduction: Our knowledge of X-linked Alport Syndrome [AS] comes mostly from selected cohorts with more severe disease. Methods: We examined the phenotypic spectrum of X-linked AS in males and females with a genotype-based approach using data from the Geisinger MyCode DiscovEHR study, an unselected health system-based cohort with exome sequencing and electronic health records. Patients with COL4A5 variants reported as pathogenic (P) or likely pathogenic (LP) in ClinVar, or protein-truncating variants (PTVs), were each matched with up to 5 controls without COL4A3/4/5 variants by sociodemographics, diabetes diagnosis, and year of first outpatient encounter. AS-related phenotypes included dipstick hematuria, bilateral sensorineural hearing loss (BSHL), proteinuria, decreased eGFR, and ESKD. Results: Out of 170,856 patients, there were 29 hemizygous males (mean age 52.0 y [SD 20.0]) and 55 heterozygous females (mean age 59.3 y [SD 18.8]) with a COL4A5 P/LP variant, including 48 with the hypomorphic variant p.Gly624Asp. Overall, penetrance (having any AS phenotypic feature) was highest for non-p.Gly624Asp P/LP variants (males: 94%, females: 85%), intermediate for p.Gly624Asp (males: 77%, females: 69%), compared to controls (males: 32%; females: 50%). The proportion with ESKD was highest for males with P/LP variants (44%), intermediate for males with p.Gly624Asp (15%) and females with P/LP variants (10%), compared to controls (males: 3%, females 2%). Only 47% of individuals with COL4A5 had completed albuminuria screening, and a minority were taking renin-angiotensin aldosterone system (RAAS) inhibitors. Only 38% of males and 16% of females had a known diagnosis of Alport syndrome or thin basement membrane disease. Conclusion: In an unselected cohort, we show increased risks of AS-related phenotypes in men and women compared to matched controls, while showing a wider spectrum of severity than has been described previously and variability by genotype. Future studies are needed to determine whether early genetic diagnosis can improve outcomes in Alport Syndrome.
RESUMEN
The effects of alcohol are multifaceted, involving brain circuits regulating reward, motivation, and stress, frequently via the endogenous opioid, beta-endorphin (ß-E). It is currently unknown how alcohol affects neural circuit activation in females and how ß-E affects ethanol's ability to induce neuronal activation. Therefore, we investigated the impact of acute alcohol treatment on neuronal activation in reward- and stress-related brain circuitry in a sex- and ß-E dependent manner. In this study, male and female control (C57BL/6J; ß-E+/+) and ß-E null (-/-) mice were injected intraperitoneally with 2 g/kg ethanol (EtOH) or saline. Post-injection, animals were sacrificed using ketamine/xylazine and perfused with saline followed by 4% paraformaldehyde. Brain sections (35 µm) were immunohistochemically processed for tyrosine hydroxylase (TH), dopamine's rate-limiting enzyme, and c-fos, a neuronal activation marker. The number of c-fos immunoreactive cell nuclei, TH-immunoreactivity, and TH/c-fos-ir cells were quantified in the nucleus accumbens (NAc), ventral tegmental area (VTA), paraventricular nucleus (PVN), central nucleus of the amygdala (CeA), paraventricular thalamic nucleus (PVA) and Edinger-Westphal nucleus (EW). In females, EtOH increased c-fos expression in the CeA, PVN, EW and NAc shell, while c-fos expression in the VTA, and TH expression in the VTA and NAc, depended on a genotype and treatment interaction. In males, EtOH increased c-fos in the CeA and PVN. EtOH also increased the number of double-labeled cells in the Arc, but only in females. These results suggest that the neurons in females are inherently more sensitive to EtOH, emphasizing the importance of studying the relationship between sex and alcohol addiction.
