Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

DRUG METABOLISM DISPOSITION AND PROTEIN BINDING OF VALPROIC ACID IN THE DEVELOPING RAT

ABSTRACT: The dlsposftlon of valprolc acid (VPA) In serum and braIn tissue was #{149}xamlnedIn developing rats (5, 10, 20, and 60 days postpartum) following both single and multlpi. Materials and Methods Chemicals. CCA and 2-propylpentanoic acid (VPA) were purchased from Sigma Chemical Company (St. Louis MO) and were used without further purification. VPA dosing solutions and analytical standards were prepared by dissolving the free acid in excess 2 N NaOH, and titrating to pH 7.5 with 2 N HO. All other reagents were obtained from cornmercial sources and were ofthe highest purity available. Animsis. Male and female progeny of Sprague-Dawley rats, outbred from Hilltop Laboratory Animals (Scotidale, PA) stock, were used in this study. Rat pups were housed with their dams in polypropylene cages and maintained on a 12-hr light/dark cycle. Adult rats (60-day-old) were weaned at 21 days postpartum and then were housed as gender-matched pairs in wire-mesh cages. Free access to food and water was allowed at all times. received multiple YPA doses (4 mg/kg for 5-, 10-, and 20-dayold rats; 6 mg/kg for 60-day-old rats) at timed intervals (every 30 mm for 5-, 20-, and 60-day-old rats; every 60 mm for 10-day-old rats, for a total of 1 1, 9, 7, and 5 doses in 5-, 10-, 20-, and 60-day-old rats, respectively. These dosing regimens were calculated to produce similar average steady-state concemtration

Further delineation of Basel-Vanagaite-Smirin-Yosef syndrome: Report of three patients.

Basel-Vanagaite-Smirin-Yosef syndrome is a recently described autosomal recessive intellectual disability syndrome caused by variants in the MED25 gene. While it was originally identified in Brazil, it was further described in Israel by authors who are now the namesake of the condition. A 2018 publication further contributed to its delineation, but the patient\u27s phenotype was complicated by a dual diagnosis. More recently, an article describing a set of affected siblings was published. We describe three, previously unreported, patients showing clinical variability for this newly defined syndrome. The major features determined by reverse phenotyping include significant to profound developmental delays/intellectual disability with absent or delayed speech, epilepsy, ocular abnormalities, cleft lip and/or palate, congenital heart disease, urogenital anomalies, skeletal abnormalities, brain malformations and/or microcephaly, failure to thrive, and dysmorphic features. The authors suggest the delineation of an acronym using the gene name and common features seen across the majority of patients reported so far. This new nomination, MED-DOCS, may help clinicians to recognize, suspect, and remember this novel syndrome

Completion of Advance Directives Among U.S. Consumers

BACKGROUND: Current, ongoing national surveys do not include questions about end-of-life (EOL) issues. In particular, population-based data are lacking regarding the factors associated with advance directive completion. PURPOSE: To characterize U.S. adults who did and did not have an advance directive and examine factors associated with their completion, such as the presence of a chronic condition and regular source of health care. METHODS: Data were analyzed in 2013 from adults aged 18 years and older who participated in the 2009 or 2010 HealthStyles Survey, a mail panel survey designed to be representative of the U.S. population. Likelihood ratio tests were used to examine the associations between advance directive completion and demographic and socioeconomic variables (education, income, employment status); presence of a chronic condition; regular source of health care; and self-reported EOL concerns or discussions. Multiple logistic regression analyses identified independent predictors related to advance directive completion. RESULTS: Of the 7946 respondents, 26.3% had an advance directive. The most frequently reported reason for not having one was lack of awareness. Advance directive completion was associated with older age, more education, and higher income and was less frequent among non-white respondents. Respondents with advance directives also were more likely to report having a chronic disease and a regular source of care. Advance directives were less frequent among those who reported not knowing if they had an EOL concern. CONCLUSIONS: These data indicate racial and educational disparities in advance directive completion and highlight the need for education about their role in facilitating EOL decisions

Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome:WNT signaling perturbation and phenotypic variability

Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated (DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A). RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics. To further explore the genetic heterogeneity, paralog contribution, and phenotypic variability of RS, we investigated a cohort of 22 individuals clinically diagnosed with RS from 18 unrelated families. Pathogenic or likely pathogenic variants in genes associated with RS or RS phenocopies were identified in all 22 individuals, including the first variant to be reported in DVL2. We retrospectively collected medical records of 16 individuals from this cohort and extracted clinical descriptions from 52 previously published cases. We performed Human Phenotype Ontology (HPO) based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Individuals with FZD2 variants clustered into two groups with demonstrable phenotypic differences between those with missense and truncating alleles. Probands with biallelic NXN variants clustered together with the majority of probands carrying DVL1, DVL2, and DVL3 variants, demonstrating no phenotypic distinction between the NXN-autosomal recessive and dominant forms of RS. While phenotypically similar diseases on the RS differential matched through HPO analysis, clustering using phenotype similarity score placed RS-associated phenotypes in a unique cluster containing WNT5A, FZD2, and ROR2 apart from non-RS-associated paralogs. Through human phenotype analyses of this RS cohort and OMIM clinical synopses of Mendelian disease, this study begins to tease apart specific biologic roles for non-canonical WNT-pathway proteins