Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination.

BACKGROUND: The combination of ataxia and hypogonadism was first described more than a century ago, but its genetic basis has remained elusive. METHODS: We performed whole-exome sequencing in a patient with ataxia and hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes in similarly affected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. The effects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model. RESULTS: Digenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase and a deubiquitinase, respectively, were found in three affected siblings in a consanguineous family. Additional screening identified compound heterozygous truncating mutations in RNF216 in an unrelated patient and single heterozygous deleterious mutations in four other patients. Knockdown of rnf216 or otud4 in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, human RNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss was observed in cerebellar pathways and the hippocampus; surviving hippocampal neurons contained ubiquitin-immunoreactive intranuclear inclusions. Defects were detected at the hypothalamic and pituitary levels of the reproductive endocrine axis. CONCLUSIONS: The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4. These findings link disordered ubiquitination to neurodegeneration and reproductive dysfunction and highlight the power of whole-exome sequencing in combination with functional studies to unveil genetic interactions that cause disease. (Funded by the National Institutes of Health and others.).

Parents' Sources of Adolescent Sexual Health Information and Their Interest in Resources From Primary Care.

OBJECTIVE: To examine sources of information used by parents to facilitate parent-adolescent communication about sexual and reproductive health (SRH), parents' preferences for receiving SRH information through primary care, and factors associated with parents' interest in primary-care-based SRH information (ie, resources recommended or offered in the primary care setting). METHODS: In this cross-sectional study, a nationally representative sample of 11-17-year-old adolescents and their parents (n = 1005 dyads) were surveyed online; 993 were retained for these analyses. Parents were asked about their use of 11 resources to help them talk with their adolescents about SRH and rated the likelihood of using specific primary-care-based resources. We used multivariable logistic regression to examine characteristics associated with parent interest in primary-care-based SRH resources. RESULTS: Only 25.8% of parents reported receiving at least a moderate amount of SRH information from primary care; half (53.3%) reported receiving no SRH information from their adolescent's provider. Parents received the most information from personal connections (eg, spouse/partner, friends). Most parents (59.1%) reported being likely to utilize a primary-care-based resource for SRH information. Parents who previously received SRH information from primary care sources had greater odds of reporting they would be likely to utilize a primary-care-based resources (AOR = 4.06, 95% CI: 2.55-6.46). CONCLUSIONS: This study provides insights into parents' sources of information for communicating with their adolescents about SRH and ways primary care practices might increase support for parents in having SRH conversations with their adolescents. Future studies are needed to establish clinical best practices for promoting parent-adolescent communication about SRH.

Suicide Among Transgender and Gender-Nonconforming People.

Suicide rates are higher in those who identify as transgender or gender nonconforming (TGNC) compared to the overall population. Suicide risk factors include discrimination, family rejection, internalized transphobia, and being denied appropriate bathroom or housing access. It is important to assess the risk of suicide among transgender and gender-nonconforming patients and discuss past experiences of prejudice or maltreatment to prevent further victimization. This narrative review includes the most pertinent literature from the past 17 years on issues related to suicide among individuals who identify as TGNC. ​.

Transgender and Gender Nonconforming Patient Experiences at a Family Medicine Clinic.

PURPOSE: Transgender and gender nonconforming (TGNC) patients have a wide array of often negative experiences when accessing health care, and may encounter insensitive or subcompetent care; thus, the authors conducted a qualitative study with patients at one family medicine residency clinic to assess how primary care clinics can improve care for TGNC patients. METHOD: In 2015, the authors held three separate focus groups at Smiley's Family Medicine Clinic in Minneapolis, Minnesota. They invited diverse TGNC participants who have accessed TGNC-related and/or primary care at Smiley's. The authors analyzed and coded data using a grounded theory approach with NVivo10 (QSR). The authors also administered short demographic questionnaires and analyzed the results with REDCap. RESULTS: Twenty-three patients participated in the focus groups, and 22 completed the survey. Gender identities among the participants were diverse. Four main themes emerged: (1) shared negative experiences with health care, (2) the need for sensitive and inclusive primary care, (3) defining TGNC-sensitive care, and (4) the challenges of mainstreaming TGNC-competent care into primary care settings. CONCLUSIONS: Providing sensitive and competent primary care to TGNC patients involves allowing patients to self-identify, respecting the gender identities of every patient, and focusing on the whole person-not the trans status of the patient. Education and training on TGNC care at a clinic-wide level is needed.