Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers’ questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clustered in exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K (26%) and 11 had G937R (8%) mutations. Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.
The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected communities of color. To dismantle these disparities, it is critical to promote COVID-19 vaccine equity, both through increasing vaccine access and addressing vaccine mistrust. This article describes a community–academic collaboration (the Community Vaccine Collaborative [CVC]), whose mission is to ensure COVID-19 vaccine equity among marginalized communities. Based in Pittsburgh, Pennsylvania, our group has focused on inclusion of marginalized groups into vaccine clinical trials, addressing vaccine mistrust, and building systems to ensuring equitable access to the COVID-19 vaccine. We review formation of the CVC, activities to-date, and recommendations for other communities interested in developing similar collaboratives.
BRCA1 and BRCA2 (BRCA1/2) testing is standard for individuals with personal and/or family history suggestive of hereditary breast and ovarian cancer syndrome. The indications for testing have been expanding. To accommodate the need, incorporation of cancer genetic services into the practice of non‐genetic healthcare providers should be considered. We carried out a survey to evaluate the knowledge and opinions regarding BRCA1/2 testing among primary care providers. The survey was sent to 245 Obstetrics/Gynecology and 97 Family Medicine physicians in the UPMC network. Eighty‐six completed the survey between July 2015 and September 2015. The average correct responses to knowledge questions was 73%. A few respondents reported being completely confident, and ~50% reported being somewhat confident, in providing BRCA1/2‐related information. Respondents selected genetic specialists and oncologists as the most qualified to provide cancer genetic services. Several perceived barriers and motivating factors to the implementation of BRCA1/2 testing in primary care were identified. The findings from this study suggested that primary care providers were not uniformly ready to provide BRCA1/2 genetic testing. Availability of professional society guidelines and evidence of testing's usefulness might motivate the incorporation of BRCA1/2 genetic testing into primary care practices. These findings would help guide future educational efforts to promote provision of cancer genetic services by non‐genetic professionals.
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