PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment.

PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation.

Homozygous single base deletion in TUSC3 causes intellectual disability with developmental delay in an Omani family.

Intellectual disability (ID) is the term used to describe a diverse group of neurological conditions with congenital or juvenile onset, characterized by an IQ score of less than 70 and difficulties associated with limitations in cognitive function and adaptive behavior. The condition can be inherited or caused by environmental factors. The genetic forms are heterogeneous, with mutations in over 500 known genes shown to cause the disorder. We report a consanguineous Omani family in which multiple individuals have ID and developmental delay together with some variably present features including short stature, microcephaly, moderate facial dysmorphism, and congenital malformations of the toes or hands. Homozygosity mapping combined with whole exome next generation sequencing identified a novel homozygous single base pair deletion in TUSC3, c.222delA, p.R74 fs. The mutation segregates with the disease phenotype in a recessive manner and is absent in 60,706 unrelated individuals from various disease-specific and population genetic studies. TUSC3 mutations have been previously identified as causing either syndromic or non-syndromic ID in patients from France, Italy, Iran and Pakistan. This paper supports the previous clinical descriptions of the condition caused by TUSC3 mutations and describes the seventh family with mutations in this gene, thus contributing to the genetic spectrum of mutations. This is the first report of a family from the Arabian peninsula with this form of ID. © 2016 Wiley Periodicals, Inc.

Acute fulminant hepatic failure, encephalopathy and early CT changes.

BACKGROUND: Acute fulminant hepatic failure (AFHF) is common in tertiary care centres with transplant facilities. Cerebral edema frequently threatens the lives of such patients. We reviewed our cases of AFHF, noting the incidence of cerebral edema with serial CT scans and factors associated with mortality. METHODS: Patients were captured through HmRI classification of acute liver/hepatic failure. Chart review included tabulation of: demographics, INR; serum bilirubin, creatinine, albumin; in-hospital mortality. Computed tomogram (Ct) scans were re-read with blinding to clinical information and catalogued for changes in sulcal markings, ventricular size and grey-white differentiation (GWD). INCLUSION CRITERIA: age equal to or greater than 16 years, encephalopathy, hepatic failure within eight weeks of onset of liver disease, CT scans of head performed. RESULTS: Of our 25 cases with AFHF, acetaminophen toxicity was the most common etiology (nine cases). Twelve of the 25 patients (48%) had cerebral edema on CT, including eight of the nine (89%) with acetaminophen toxicity. Decrease in sulcal markings and ventricular size preceded conspicuous alterations in GWD. Fourteen died, including all 12 with cerebral edema, although death was due to herniation in only one patient. None of the hematological or biochemical variables correlated significantly with mortality. CONCLUSIONS: Acetaminophen toxicity is a common cause of AFHF; this combination has a strong association with cerebral edema. Cerebral edema can be detected in its early stages and followed by baseline and serial CT scans. This facilitates management to prevent fatal brain herniation.

Healthcare Workers' Assessment of a Visual Triage System (VTS).

Overcrowding and extended waiting times in the emergency department (ED) can pose a significant risk of COVID-19 transmission from patients to healthy individuals. In 2017, the Saudi Ministry of Health (MOH) introduced a visual triage system (VTS) with scoring to notify healthcare workers (HCWs) in EDs about the Middle East respiratory syndrome coronavirus (MERS-CoV) infection risk. During the COVID-19 pandemic, the MOH employed a VTS to classify patients according to their potential risk of COVID-19 infection upon their admission to the ED. Suspected patients were then directed along specific pathways to reduce their contact with healthy individuals. This study assessed HCWs' satisfaction with the VTS in the ED of two major government hospitals within the Riyadh region. Additionally, it assessed HCWs' perceptions of VTS effectiveness. This study used a cross-sectional, observational design and relied on surveys for data collection. A total of 127 participants completed the survey, of which 87 (68.5%) were based in the EDs of the two hospitals. Among the ED participants, 18.1% expressed satisfaction with the VTS, 46.4% were neutral, and 33.1% reported dissatisfaction. ED participants provided feedback on the system's effectiveness, with 24.1% finding it effective, 66.7% considering it somewhat effective, and 9.2% deeming it ineffective. Of the total (127) study participants (70.1%) reported that the HCWs required better training to effectively implement the VTS infection control plans for suspected cases. Fewer than half of the participants (35.4%) deemed the time spent by VTS personnel to identify COVID-19 cases to be reasonable, whereas 22% found it too short and 27.6% considered it too long. Of the total 127 participants, 63% reported that language differences between patients and HCWs constituted barriers to the effective application of the VTS. Our study findings indicated that most ED participants had a neutral outlook on their satisfaction with the VTS and a neutral perspective on the effectiveness of VTS, viewing it as only somewhat effective. Reported weaknesses and key obstacles to the successful implementation of the VTS included language barriers. and insufficient training for HCWs, and unclear VTS pathways. The reported strengths of the VTS included its effectiveness in reducing crowds and identification of COVID-19 patients.

PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies.

BACKGROUND: The discovery of coding variants in genes that confer risk of intellectual disability (ID) is an important step toward understanding the pathophysiology of this common developmental disability. METHODS: Homozygosity mapping, whole-exome sequencing, and cosegregation analyses were used to identify gene variants responsible for syndromic ID with autistic features in two independent consanguineous families from the Arabian Peninsula. For in vivo functional studies of the implicated gene's function in cognition, Drosophila melanogaster and mice with targeted interference of the orthologous gene were used. Behavioral, electrophysiological, and structural magnetic resonance imaging analyses were conducted for phenotypic testing. RESULTS: Homozygous premature termination codons in PDZD8, encoding an endoplasmic reticulum-anchored lipid transfer protein, showed cosegregation with syndromic ID in both families. Drosophila melanogaster with knockdown of the PDZD8 ortholog exhibited impaired long-term courtship-based memory. Mice homozygous for a premature termination codon in Pdzd8 exhibited brain structural, hippocampal spatial memory, and synaptic plasticity deficits. CONCLUSIONS: These data demonstrate the involvement of homozygous loss-of-function mutations in PDZD8 in a neurodevelopmental cognitive disorder. Model organisms with manipulation of the orthologous gene replicate aspects of the human phenotype and suggest plausible pathophysiological mechanisms centered on disrupted brain development and synaptic function. These findings are thus consistent with accruing evidence that synaptic defects are a common denominator of ID and other neurodevelopmental conditions.

A Recessively Inherited Risk Locus on Chromosome 13q22-31 Conferring Susceptibility to Schizophrenia.

We report a consanguineous family in which schizophrenia segregates in a manner consistent with recessive inheritance of a rare, partial-penetrance susceptibility allele. From 4 marriages between 2 sets of siblings who are half first cousins, 6 offspring have diagnoses of psychotic disorder. Homozygosity mapping revealed a 6.1-Mb homozygous region on chromosome 13q22.2-31.1 shared by all affected individuals, containing 13 protein-coding genes. Microsatellite analysis confirmed homozygosity for the affected haplotype in 12 further apparently unaffected members of the family. Psychiatric reports suggested an endophenotype of milder psychiatric illness in 4 of these individuals. Exome and genome sequencing revealed no potentially pathogenic coding or structural variants within the risk haplotype. Filtering for noncoding variants with a minor allele frequency of <0.05 identified 17 variants predicted to have significant effects, the 2 most significant being within or adjacent to the SCEL gene. RNA sequencing of blood from an affected homozygote showed the upregulation of transcription from NDFIP2 and SCEL. NDFIP2 is highly expressed in brain, unlike SCEL, and is involved in determining T helper (Th) cell type 1 and Th2 phenotypes, which have previously been implicated with schizophrenia.

Ultrastructural morphology of lymphocytes of the Arabian oryx (Oryx leucoryx).

An ultrastructural study on the lymphocytes from peripheral blood samples from 20 healthy adult Arabian oryx (Oryx leucocoryx) was undertaken. Small lymphocytes ranged in size from 2-3.5 µm and exhibited the typical repertoire of organelles found in small lymphocytes of other animals but showed no evidence of azurophilic granules. Medium-sized lymphocytes were 5-6.5 µm in diameter and occasionally demonstrated azurophilic granules. Microvilli were a common finding of lymphocytes. Of particular interest was the presence of multivesicular bodies, which have previously only been described in human lymphocytes. Both small- and medium-sized lymphocytes of the Arabian oryx were smaller than those reported for other animals. Small lymphocytes exhibited short, thick microvilli, whereas medium-sized lymphocytes had long thin microvilli, a single nucleolus and occasionally azurophilic granules and multivesicular bodies.

Ultrastructural observations on the platelets of the Arabian oryx (Oryx leucoryx).

An ultrastructural study on the platelets from peripheral blood samples from 20 healthy adult Arabian oryx (Oryx leucocoryx) was performed. Characteristic was the extreme polymorphism of both the platelets, as well as their alpha granules. They vary in size from 100 to 800 nm in diameter and their numbers typically are less than those reported for humans and other animal species. Also, the alpha granules in contrast to those of humans and animals, such as the Arabian tahr, do not have nucleoids. Typically, the oryx platelets exhibit only 1-2 electron-dense bodies per cell and they lack an open canalicular system. Of particular interest is the presence of Type I multivesicular bodies, which have previously only been described in human megakaryocytes and are hypothesized as being intermediate development stages of alpha and dense granules.

LHFPL5 mutation: A rare cause of non-syndromic autosomal recessive hearing loss.

Hearing loss is a debilitating disorder that impairs language acquisition, resulting in disability in children and potential isolation in adulthood. Its onset can have a genetic basis, though environmental factors, which are often preventable, can also cause the condition. The genetic forms are highly heterogeneous, and early detection is necessary to arrange appropriate patient support. Here we report the molecular basis of hereditary hearing loss in a consanguineous family with multiple affected members from Oman. Combining homozygosity mapping with whole exome sequencing identified a novel homozygous nucleotide substitution c.575T > C in the lipoma HMGIC fusion partner-like 5 gene (LHFPL5), that converted the 192nd amino acid residue in the protein from a leucine to a proline, p.(Leu192Pro). Sanger sequencing confirmed segregation with the disease phenotype as expected for a recessive condition and the variant was absent in 123,490 subjects from various disease-specific and population genetic studies as well as 150 unrelated individuals and 35 deaf patients of Omani ethnicity. This study, which describes a novel LHFPL5 mutation in a family of Omani origin with hereditary hearing loss, supports previous clinical descriptions of the condition and contributes to the genetic spectrum of mutations in this form of deafness.

Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition.

Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modeling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4B(Y358C) mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and ß-Arrestin in hippocampus and amygdala. In behavioral assays, PDE4B(Y358C) mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4B(Y358C) mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 h, was decreased at 7 days in PDE4B(Y358C) mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signaling by PDE4B in a very late phase of consolidation. No effect of the PDE4B(Y358C) mutation was observed in the prepulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory.