Homozygous variants in WDR83OS lead to a neurodevelopmental disorder with hypercholanemia.

WD repeat domain 83 opposite strand (WDR83OS) encodes the 106-aa (amino acid) protein Asterix, which heterodimerizes with CCDC47 to form the PAT (protein associated with ER translocon) complex. This complex functions as a chaperone for large proteins containing transmembrane domains to ensure proper folding. Until recently, little was known about the role of WDR83OS or CCDC47 in human disease traits. However, biallelic variants in CCDC47 were identified in four unrelated families with trichohepatoneurodevelopmental syndrome, characterized by a neurodevelopmental disorder (NDD) with liver dysfunction. Three affected siblings in an additional family share a homozygous truncating WDR83OS variant and a phenotype of NDD, dysmorphic features, and liver dysfunction. Using family-based rare variant analyses of exome sequencing (ES) data and case matching through GeneMatcher, we describe the clinical phenotypes of 11 additional individuals in eight unrelated families (nine unrelated families, 14 individuals in total) with biallelic putative truncating variants in WDR83OS. Consistent clinical features include NDD (14/14), facial dysmorphism (13/14), intractable itching (9/14), and elevated bile acids (5/6). Whereas bile acids were significantly elevated in 5/6 of individuals tested, bilirubin was normal and liver enzymes were normal to mildly elevated in all 14 individuals. In three of six individuals for whom longitudinal data were available, we observed a progressive reduction in relative head circumference. A zebrafish model lacking Wdr83os function further supports its role in the nervous system, craniofacial development, and lipid absorption. Taken together, our data support a disease-gene association between biallelic loss-of-function of WDR83OS and a neurological disease trait with hypercholanemia.

Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum.

PURPOSE: FLVCR1 encodes a solute carrier (SLC) protein implicated in heme, choline, and ethanolamine transport. While Flvcr1-/- mice exhibit skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia (DBA), biallelic FLVCR1 variants in humans have previously only been linked to childhood or adult-onset ataxia, sensory neuropathy, and retinitis pigmentosa. METHODS: We identified individuals with undiagnosed neurodevelopmental disorders and biallelic FLVCR1 variants through international data sharing and characterized the functional consequences of their FLVCR1 variants. RESULTS: We ascertained 30 patients from 23 unrelated families with biallelic FLVCR1 variants and characterized a novel FLVCR1-related phenotype: severe developmental disorders with profound developmental delay, microcephaly (Z-score -2.5 to -10.5), brain malformations, epilepsy, spasticity, and premature death. Brain malformations ranged from mild brain volume reduction to hydranencephaly. Severely affected patients share traits including macrocytic anemia and skeletal malformations with Flvcr1-/- mice and DBA. FLVCR1 variants significantly reduce choline and ethanolamine transport and/or disrupt mRNA splicing. CONCLUSION: These data demonstrate a broad FLVCR1-related phenotypic spectrum ranging from severe multiorgan developmental disorders resembling DBA to adult-onset neurodegeneration. Our study expands our understanding of Mendelian choline and ethanolamine disorders and illustrates the importance of anticipating a wide phenotypic spectrum for known disease genes and incorporating model organism data into genome analysis to maximize genetic testing yield.

Tuberculosis of gastrointestinal tract revealed by acute abdomen due to ileocecal perforation in an HIV-infected patient: A case report.

INTRODUCTION: Gastrointestinal tuberculosis (TB) is a rare condition, but it poses significant diagnostic and management challenges, especially in immunocompromised individuals. This case report discusses the diagnostic complexities and therapeutic strategies for managing gastrointestinal TB in an HIV-positive patient, emphasizing the importance of considering TB in differential diagnoses. CASE PRESENTATION: A 33-year-old male with no significant medical history presented with a five-day history of severe abdominal pain, initially epigastric and later localized to the right lower quadrant (RLQ). Physical examination revealed RLQ tenderness, and elevated inflammatory markers were observed in laboratory tests. Imaging studies suggested splenomegaly and signs consistent with acute appendicitis. Laparotomy uncovered a perforated cecal mass and diffuse white lesions across the small intestine. Histopathological analysis confirmed necrotizing granulomatous colitis, and PCR identified Mycobacterium tuberculosis (MTB). During hospitalization, the patient was diagnosed with HIV. CLINICAL DISCUSSION: This case underscores the diagnostic challenge of abdominal TB, particularly in HIV-infected patients where clinical presentation can mimic other conditions like Crohn's disease or appendicitis. Effective management requires timely surgical intervention, followed by appropriate anti-tuberculous and antiretroviral therapies. The multidisciplinary approach ensures comprehensive care and better patient outcomes. CONCLUSION: Effective recognition and diagnosis of gastrointestinal TB in HIV-positive patients are critical for successful treatment. This report highlights the necessity for heightened clinical suspicion and a collaborative approach in managing such complex cases, ultimately improving patient prognosis and care.

Procalcitonin in inflammatory bowel disease: A diagnostic or prognostic marker.

Serological biomarkers have been rapidly progressing as non-invasive tests for the early detection of inflammatory bowel disease (IBD). Procalcitonin (PCT) is a novel acute-phase reactant protein that is elevated in the inflammatory process, especially in bacterial infections. This study aimed to review the diagnostic value of PCT in IBD activity. However, there were controversies about the role of PCT in the detecting of IBD disease activity. Studies showed varied diagnostic cut-points (ranging from 0.13 to 1.0 ng/dl) and sensitivity up to 93 %. Although the clear role of PCT as a valuable diagnostic marker was not identified in determining disease activity, PCT measurement in addition to other inflammatory markers can improve the diagnostic value of these markers. Moreover, further studies are required to confirm PCT's value in distinguishing IBD disease activity.

An inappropriate decline in ribosome levels drives a diverse set of neurodevelopmental disorders.

Many neurodevelopmental defects are linked to perturbations in genes involved in housekeeping functions, such as those encoding ribosome biogenesis factors. However, how reductions in ribosome biogenesis can result in tissue and developmental specific defects remains a mystery. Here we describe new allelic variants in the ribosome biogenesis factor AIRIM primarily associated with neurodevelopmental disorders. Using human cerebral organoids in combination with proteomic analysis, single-cell transcriptome analysis across multiple developmental stages, and single organoid translatome analysis, we identify a previously unappreciated mechanism linking changes in ribosome levels and the timing of cell fate specification during early brain development. We find ribosome levels decrease during neuroepithelial differentiation, making differentiating cells particularly vulnerable to perturbations in ribosome biogenesis during this time. Reduced ribosome availability more profoundly impacts the translation of specific transcripts, disrupting both survival and cell fate commitment of transitioning neuroepithelia. Enhancing mTOR activity by both genetic and pharmacologic approaches ameliorates the growth and developmental defects associated with intellectual disability linked variants, identifying potential treatment options for specific brain ribosomopathies. This work reveals the cellular and molecular origins of protein synthesis defect-related disorders of human brain development. Highlights: AIRIM variants reduce ribosome levels specifically in neural progenitor cells. Inappropriately low ribosome levels cause a transient delay in radial glia fate commitment.Reduced ribosome levels impair translation of a selected subset of mRNAs.Genetic and pharmacologic activation of mTORC1 suppresses AIRIM-linked phenotypes.

Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders.

FLVCR1 encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed transmembrane protein with plasma membrane and mitochondrial isoforms implicated in heme, choline, and ethanolamine transport. While Flvcr1 knockout mice die in utero with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic FLVCR1 variants are linked to childhood or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. We ascertained from research and clinical exome sequencing 27 individuals from 20 unrelated families with biallelic ultra-rare missense and predicted loss-of-function (pLoF) FLVCR1 variant alleles. We characterize an expansive FLVCR1 phenotypic spectrum ranging from adult-onset retinitis pigmentosa to severe developmental disorders with microcephaly, reduced brain volume, epilepsy, spasticity, and premature death. The most severely affected individuals, including three individuals with homozygous pLoF variants, share traits with Flvcr1 knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. Pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1 with minimal impact on FLVCR1 stability or subcellular localization. Several variants disrupt splicing in a mini-gene assay which may contribute to genotype-phenotype correlations. Taken together, these data support an allele-specific gene dosage model in which phenotypic severity reflects residual FLVCR1 activity. This study expands our understanding of Mendelian disorders of choline and ethanolamine transport and demonstrates the importance of choline and ethanolamine in neurodevelopment and neuronal homeostasis.

From Radiological Manifestations to Pulmonary Pathogenesis of COVID-19: A Bench to Bedside Review.

In this review, we aim to assess previous radiologic studies in COVID-19 and suggest a pulmonary pathogenesis based on radiologic findings. Although radiologic features are not specific and there is heterogeneity in symptoms and radiologic and clinical manifestation, we suggest that the dominant pattern of computed tomography is consistent with limited pneumonia, followed by interstitial pneumonitis and organizing pneumonia.

Incidence and Main Determinants of Contrast-Induced Nephropathy following Coronary Angiography or Subsequent Balloon Angioplasty.

BACKGROUND/AIMS: Patient assessment by imaging studies using contrast media is currently replacing open procedures, especially in high-risk patients. However, the use of such contrast media might result in acute events and injuries after the procedure. In the present study, we first determined the incidence of contrast-induced nephropathy (CIN) in a sample of Iranian patients who candidated for coronary angiography and/or angioplasty, and then assessed major risk factors predicting the appearance of CIN following these procedures. METHODS: Two hundred and fifty consecutive, eligible patients scheduled for coronary angiography and/or angioplasty at the Afshar Hospital in Yazd between January 2009 and August 2010 were considered for enrollment. Renal function was measured at baseline and 48 h after the intervention, and CIN was defined by an increase in creatinine of >0.5 mg/dl or 25% of the initial value. The predictive role of potential risk factors was determined in a multivariate model adjusted for comorbidities, preexisting renal impairment, and angiographic data. RESULTS: CIN following coronary angiography or angioplasty appeared in 12.8% of the cases. A myocardial infarction before the procedure (OR = 2.121, p = 0.036) and a prior history of hypertension (OR = 2.789, p = 0.025) predicted the appearance of acute renal failure following angiography or subsequent angioplasty. A low estimated glomerular filtration rate at baseline slightly predicted CIN after these interventions. CONCLUSION: Transient acute renal dysfunction occurred in 12.8% of the patients within 48 h after angiography or subsequent angioplasty and could be predicted by a myocardial infarction before the procedure or by a prior history of systolic hypertension.