De novo missense variants in ZBTB47 are associated with developmental delays, hypotonia, seizures, gait abnormalities, and variable movement abnormalities.

The collection of known genetic etiologies of neurodevelopmental disorders continues to increase, including several syndromes associated with defects in zinc finger protein transcription factors (ZNFs) that vary in clinical severity from mild learning disabilities and developmental delay to refractory seizures and severe autism spectrum disorder. Here we describe a new neurodevelopmental disorder associated with variants in ZBTB47 (also known as ZNF651), which encodes zinc finger and BTB domain-containing protein 47. Exome sequencing (ES) was performed for five unrelated patients with neurodevelopmental disorders. All five patients are heterozygous for a de novo missense variant in ZBTB47, with p.(Glu680Gly) (c.2039A>G) detected in one patient and p.(Glu477Lys) (c.1429G>A) identified in the other four patients. Both variants impact conserved amino acid residues. Bioinformatic analysis of each variant is consistent with pathogenicity. We present five unrelated patients with de novo missense variants in ZBTB47 and a phenotype characterized by developmental delay with intellectual disability, seizures, hypotonia, gait abnormalities, and variable movement abnormalities. We propose that these variants in ZBTB47 are the basis of a new neurodevelopmental disorder.

Clinical outcome and cost effectiveness of acute ischemic stroke transfers for endovascular reperfusion therapy from geographically distant counties: Stroke transfer outcomes.

OBJECTIVES: Endovascular reperfusion therapy (EVT) for acute ischemic stroke (AIS) with large vessel occlusion (LVO) has resulted in increased patient transfers to comprehensive stroke centers (CSCs). Clinical outcomes including the financial impact of these transfers from geographically dispersed population are lacking. Hence, we studied outcomes and cost-effectiveness of stroke transfers from remote areas. MATERIALS AND METHODS: We used a 3-year cohort of AIS patients transferred from geographically dispersed counties (<100 mi., 101-200 mi., and >200 mi.). A 3-month modified Rankin scale (mRS) score of 0-2 defined a favorable clinical outcome. Cost-effectiveness is studied by calculating the incremental cost effectiveness ratio, using hospital costs reimbursed data and utility-weighted (UW)-mRS. RESULTS: Among 172 patients transferred for EVT, patients transferred from nearby counties were more likely to undergo intervention compared to other counties (56.9 % vs. 36.7 % vs. 49.2 % p = .11). Irrespective of proximity (in mi.) to CSC [21.5 (14-56.3)] vs. 185 (137-185) vs. 349 (325-355)], there was a similar delay (in min.) to arrival from all locations [321.5 (244-490), 366 (298-432), and 460 (385-554.5) respectively], but no statistically significant differences in favorable outcomes (18.0 %, 34.1 %, and 22.2 %, respectively, p = .41). Patients undergoing EVT had higher hospital costs reimbursed compared to non-EVT patients [$37,303 (25,745-40,658) vs. $14,008 (8,640-21,273) respectively, p < .001] and no statistically significant difference in UW-mRS [0.32 (0.06-0.56) vs. 0.06 (0-0.56), p = .30]. CONCLUSIONS: Our study identifies a need for targeted interventions to improve community awareness and optimize systems of care to improve outcomes and cost-effectiveness of EVT.

Biallelic variants in TUBGCP6 result in microcephaly and chorioretinopathy 1: Report of four cases and a literature review.

Autosomal recessive microcephaly and chorioretinopathy-1 (MCCRP1) is a rare Mendelian disorder resulting from biallelic loss of function variants in Tubulin-Gamma Complex Associated Protein 6 (TUBGCP6, MIM#610053). Clinical features of this disorder include microcephaly, cognitive impairment, dysmorphic features, and variable ophthalmological anomalies including chorioretinopathy. Microcephaly can be recognized prenatally and visual impairment becomes evident during the first year of life. The clinical presentation resembles the findings in some acquired conditions such as congenital toxoplasmosis and cytomegalovirus infections; thus, it is important to recognize and diagnose this syndrome in view of its impact on patient health management and familial reproductive plans. To date, only seven molecularly confirmed patients from five unrelated families have been reported. We report an additional four unrelated patients with TUBGCP6 variants including one prenatal diagnosis and review the clinical phenotypes and genotypes of all the known cases. This report expands the molecular and phenotypic spectrum of TUBGCP6 and includes additional prenatal findings associated with MCCRP1.

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder.

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.

Strokes and Predictors of Outcomes.

Stroke is a leading cause of long-term disability and fifth leading cause of death. Acute ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage, the 3 subtypes of strokes, have varying treatment modalities. Common themes in management advocate for early interventions to reduce morbidity and mortality but not all perception is supported through randomized controlled trials. Each stroke subtype has varying premorbid-related and ictus-related outcome predictive models that have differing sensitivities and specificities.

Colonization of Honey Bee Digestive Tracts by Environmental Yeast Lachancea thermotolerans Is Naturally Occurring, Temperature Dependent, and Impacts the Microbiome of Newly Emerged Bees.

Honey bees are critical pollinators in both agricultural and ecological settings. Recent declines in honey bee colonies in the United States have put increased strain on agricultural pollination. Although there are many environmental stressors implicated in honey bee disease, there has been intensifying focus on the role of microbial attacks on honey bee health. Despite the long-standing appreciation for the association of fungi of various groups with honey bees and their broader environment, the effects of these interactions on honey bee health are incompletely understood. Here, we report the discovery of colonization of the honey bee digestive tract by the environmental yeast Lachancea thermotolerans. Experimental colonization of honey bee digestive tracts by L. thermotolerans revealed that this yeast species maintains high levels in the honey bee midgut only at temperatures below the typical colony temperature. In newly eclosed bees, L. thermotolerans colonization alters the microbiome, suggesting that environmental yeasts can impact its composition. Future studies should be undertaken to better understand the role of L. thermotolerans and other environmental yeasts in honey bee health. IMPORTANCE Although many fungal species are found in association with honey bees and their broader environment, the effects of these interactions on honey bee health are largely unknown. Here, we report the discovery that a yeast commonly found in the environment can be found at high levels in honey bee digestive tracts. Experimentally feeding this yeast to honey bees showed that the yeast's ability to maintain high levels in the digestive tract is influenced by temperature and can lead to alterations of the microbiome in young bees. These studies provide a foundation for future studies to better understand the role of environmental yeasts in honey bee health.

CE: Acute Ischemic Stroke.

ABSTRACT: Stroke, the most common form of cerebrovascular disease, is a leading cause of death and disability throughout the world. There have been no significant advances in the development of effective therapeutics for hemorrhagic stroke, and for ischemic stroke highly effective, evidence-based therapies such as alteplase and mechanical thrombectomy are widely underutilized. Improving outcomes for patients experiencing ischemic stroke requires faster recognition and appropriate intervention within the treatment window (the first 24 hours after symptom onset). This article discusses the pathophysiology underlying the various types of ischemic stroke; the risk factors for ischemic stroke; stroke presentation; and the evidence-based treatments, nursing assessments, and monitoring protocols that are critical to patient recovery.

Refractory Heparin-Induced Thrombocytopenia in a Patient With Subarachnoid Hemorrhage-A Clinical Conundrum.

Heparin induced thrombocytopenia (HIT) often resolves with discontinuation of heparin/ heparinoid products. Severe HIT with platelet counts <20,000/µL and disseminated intravascular coagulation is frequently associated with consumptive coagulopathy and systemic thrombosis. Management of severe HIT in patients who fail to improve on discontinuing heparinoid products and argatroban infusion is not well established. We describe a patient admitted with aneurysmal subarachnoid hemorrhage (SAH) who developed severe autoimmune HIT, failed conventional anticoagulation therapy with argatroban and progressed to develop extensive deep venous thrombosis and limb ischemia. She was successfully treated using bivalirudin, immunomodulation with 2 cycles of intravenous immunoglobulin and immunosuppression with methylprednisolone. Refractory severe HIT among SAH patients is rare and pose several therapeutic challenges. We report successful treatment using alternate anticoagulant and immune suppression and modulation.

Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms.

The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B-related disorders.