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The New England Journal of Medicine Aug 2023Increasing evidence links genetic defects affecting actin-regulatory proteins to diseases with severe autoimmunity and autoinflammation, yet the underlying molecular...
BACKGROUND
Increasing evidence links genetic defects affecting actin-regulatory proteins to diseases with severe autoimmunity and autoinflammation, yet the underlying molecular mechanisms are poorly understood. Dedicator of cytokinesis 11 (DOCK11) activates the small Rho guanosine triphosphatase (GTPase) cell division cycle 42 (CDC42), a central regulator of actin cytoskeleton dynamics. The role of DOCK11 in human immune-cell function and disease remains unknown.
METHODS
We conducted genetic, immunologic, and molecular assays in four patients from four unrelated families who presented with infections, early-onset severe immune dysregulation, normocytic anemia of variable severity associated with anisopoikilocytosis, and developmental delay. Functional assays were performed in patient-derived cells, as well as in mouse and zebrafish models.
RESULTS
We identified rare, X-linked germline mutations in in the patients, leading to a loss of protein expression in two patients and impaired CDC42 activation in all four patients. Patient-derived T cells did not form filopodia and showed abnormal migration. In addition, the patient-derived T cells, as well as the T cells from -knockout mice, showed overt activation and production of proinflammatory cytokines that were associated with an increased degree of nuclear translocation of nuclear factor of activated T cell 1 (NFATc1). Anemia and aberrant erythrocyte morphologic features were recapitulated in a newly generated -knockout zebrafish model, and anemia was amenable to rescue on ectopic expression of constitutively active CDC42.
CONCLUSIONS
Germline hemizygous loss-of-function mutations affecting the actin regulator DOCK11 were shown to cause a previously unknown inborn error of hematopoiesis and immunity characterized by severe immune dysregulation and systemic inflammation, recurrent infections, and anemia. (Funded by the European Research Council and others.).
Topics: Animals; Humans; Mice; Actins; Anemia; Disease Models, Animal; Guanine Nucleotide Exchange Factors; Hematopoiesis; Inflammation; Zebrafish
PubMed: 37342957
DOI: 10.1056/NEJMoa2210054 -
Blood Jan 2018
Topics: Anemia, Megaloblastic; Anemia, Pernicious; Child; Elliptocytosis, Hereditary; Erythrocytes, Abnormal; Female; Hematologic Diseases; Humans; Malabsorption Syndromes; Prognosis; Proteinuria; Vitamin B 12 Deficiency
PubMed: 29301775
DOI: 10.1182/blood-2017-10-809178 -
British Journal of Haematology Sep 2020
Topics: Aged; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carbazoles; Erythrocytes; Female; Hemolysis; Humans; Lung Neoplasms; Male; Piperidines; Protein Kinase Inhibitors
PubMed: 32537738
DOI: 10.1111/bjh.16813 -
Brain : a Journal of Neurology Feb 2017Unexplained global developmental delay and epilepsy in childhood pose a major socioeconomic burden. Progress in defining the molecular bases does not often translate...
Unexplained global developmental delay and epilepsy in childhood pose a major socioeconomic burden. Progress in defining the molecular bases does not often translate into effective treatment. Notable exceptions include certain inborn errors of metabolism amenable to dietary intervention. CAD encodes a multifunctional enzyme involved in de novo pyrimidine biosynthesis. Alternatively, pyrimidines can be recycled from uridine. Exome sequencing in three families identified biallelic CAD mutations in four children with global developmental delay, epileptic encephalopathy, and anaemia with anisopoikilocytosis. Two died aged 4 and 5 years after a neurodegenerative disease course. Supplementation of the two surviving children with oral uridine led to immediate cessation of seizures in both. A 4-year-old female, previously in a minimally conscious state, began to communicate and walk with assistance after 9 weeks of treatment. A 3-year-old female likewise showed developmental progress. Blood smears normalized and anaemia resolved. We establish CAD as a gene confidently implicated in this neurometabolic disorder, characterized by co-occurrence of global developmental delay, dyserythropoietic anaemia and seizures. While the natural disease course can be lethal in early childhood, our findings support the efficacy of uridine supplementation, rendering CAD deficiency a treatable neurometabolic disorder and therefore a potential condition for future (genetic) newborn screening.
Topics: Anemia; Aspartate Carbamoyltransferase; Brain; Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); Child; Child, Preschool; DNA Mutational Analysis; Developmental Disabilities; Dihydroorotase; Female; Humans; Infant; Magnetic Resonance Imaging; Male; Mutation; Spasms, Infantile; Uridine
PubMed: 28007989
DOI: 10.1093/brain/aww300 -
Journal of Thrombosis and Haemostasis :... Apr 2024The transcription factor GATA1 is an essential regulator of erythroid cell gene expression and maturation and is also relevant for platelet biogenesis. GATA1-related...
BACKGROUND
The transcription factor GATA1 is an essential regulator of erythroid cell gene expression and maturation and is also relevant for platelet biogenesis. GATA1-related thrombocytopenia (GATA1-RT) is a rare X-linked inherited platelet disorder (IPD) characterized by macrothrombocytopenia and dyserythropoiesis. Enlarged platelet size, reduced platelet granularity, and noticeable red blood cell anisopoikilocytosis are characteristic but unspecific morphological findings in GATA1-RT.
OBJECTIVES
To expand the investigation of platelet phenotype of patients with GATA1-RT by light- and immunofluorescence microscopy on a blood smear.
METHODS
We assessed blood smears by light- and immunofluorescence microscopy after May-Grünwald Giemsa staining using a set of 13 primary antibodies against markers belonging to different platelet structures. Antibody binding was visualized by fluorescently labeled secondary antibodies.
RESULTS
We investigated 12 individuals with genetically confirmed GATA1-RT from 8 unrelated families. While confirming the already known characteristic of platelet morphology (platelet macrocytosis and reduced expression of markers for α-granules), we also found aggregates of nonmuscular myosin heavy chain II A (NMMIIA) in the erythrocytes in all individuals (1-3 aggregates/cell, 1-3 μm diameter). By systematically reanalyzing blood smears from a cohort of patients with 19 different forms of IPD, we found similar NMMIIA aggregates in the red blood cells only in subjects with GFI1B-related thrombocytopenia (GFI1B-RT), the other major IPD featured by dyserythropoiesis.
CONCLUSION
Aggregates of NMMIIA in the erythrocytes associate with GATA1-RT and GFI1B-RT and can facilitate their diagnosis on blood smears. This previously unreported finding might represent a novel marker of dyserythropoiesis assessable in peripheral blood.
Topics: Humans; Anemia; Blood Platelets; Erythrocytes; GATA1 Transcription Factor; Nonmuscle Myosin Type IIA; Proto-Oncogene Proteins; Repressor Proteins; Thrombocytopenia
PubMed: 38103735
DOI: 10.1016/j.jtha.2023.12.007 -
Cureus Aug 2023While macrocytic anemia is common in vitamin B12 deficiency, rarely, pancytopenia and hemolytic anemia can occur. Homocysteine levels are elevated in severe B12...
While macrocytic anemia is common in vitamin B12 deficiency, rarely, pancytopenia and hemolytic anemia can occur. Homocysteine levels are elevated in severe B12 deficiency, and this is linked to thrombus formation with potentially life-threatening complications. We present a patient with severe vitamin B12 deficiency complicated by hyperhomocysteinemia and obstructive shock from pulmonary embolism. A 56-year-old male with no medical history presented to the hospital with altered mentation. The patient's family stated he was experiencing bilateral paresthesias of his lower extremities, progressive depression, anxiety, and insomnia. Initial vitals were blood pressure of 76/36, heart rate of 70 beats per minute, respiratory rate of 14, and temperature of 36.3 degrees Celsius. He was intubated due to severe encephalopathy. Relevant labs indicated severe macrocytic anemia, thrombocytopenia, decreased B12 levels, elevated methylmalonic acid, and elevated homocysteine. Imaging demonstrated a right common femoral vein thrombosis and subsegmental pulmonary emboli. Peripheral blood smear revealed schistocytes, anisopoikilocytosis, and decreased platelet count. The patient required fluid resuscitation, antibiotics, and multiple blood products. Vitamin B12 was administered intramuscularly, which improved the anemia. Esophagogastroduodenoscopy (EGD) demonstrated gastritis. Gastric and duodenal biopsies were negative for and celiac disease. He was negative for intrinsic factor (IF) antibodies but had elevated gastrin levels. An intravenous unfractionated heparin infusion was started when the platelet count was above 50000. The patient was extubated after seven days. Heparin was transitioned to apixaban and an inferior vena cava (IVC) filter was placed. Hyperhomocysteinemia is a known pro-thrombotic factor that can lead to the development of venous thromboembolism. B12 malabsorption can stem from inflammatory bowel disease, celiac disease, gastritis, pancreatic insufficiency, gastrectomy, gastric bypass surgery, or antibodies to IF. While this case showed gastritis and negative IF antibodies, gastrin levels were elevated, indicating a mixed picture. This highlights the challenge of definitively diagnosing pernicious anemia as the cause of vitamin B12 deficiency. Vitamin B12 deficiency may lead to critical illness in which thromboembolism develops secondary to hyperhomocysteinemia.
PubMed: 37664295
DOI: 10.7759/cureus.42908 -
Cancer Apr 1979Fifteen patients developed acute nonlymphocytic leukemia (ANLL) 31 to 182 months following chemotherapy and/or radiotherapy for various malignancies and one... (Comparative Study)
Comparative Study
Fifteen patients developed acute nonlymphocytic leukemia (ANLL) 31 to 182 months following chemotherapy and/or radiotherapy for various malignancies and one non-neoplastic disorder. The ANLL was commonly heralded by a brief preleukemic phase consisting of cytopenias and a variety of morphologic abnormalities. At diagnosis of ANLL, all of the patients had a panmyelosis with variation in the predominant abnormal cell line. Neutrophilic and erythroid abnormalities were most striking in 12 of the patients, megakaryocytic abnormalities predominated in 2 and monocytic abnormalities in 1. Pancytopenia, marked anisopoikilocytosis, normoblastemia, large hypogranular platelets, hypogranular neutrophils, pseudo-Pelger-Huet nuclei, low myeloblast counts and basophilia were the most common abnormalities in the blood. Bone marrows were hypercellular with increased myeloblasts and basophils, abnormal neutrophil precursors, occasional monocytoid blasts, dyserythropoiesis with PAS positive erythroblasts, ring sideroblasts and micromegakaryocytes. All of the 7 patients who had bone marrow chromosome studies exhibited major chromosomal abnormalities. Response to anti-leukemic therapy was poor. The morphologic and clinical findings of these 15 patients appear to define a clinical-pathologic entity.
Topics: Adult; Aged; Antineoplastic Agents; Biopsy; Blood Cell Count; Blood Cells; Bone Marrow; Chromosome Aberrations; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukemia; Male; Middle Aged; Neoplasms; Preleukemia
PubMed: 445330
DOI: 10.1002/1097-0142(197904)43:4<1285::aid-cncr2820430416>3.0.co;2-j -
British Journal of Haematology Mar 1999The purpose of this work was to develop a definition of myelofibrosis with myeloid metaplasia (MMM) using diagnostic criteria that would remain valid within the set of... (Review)
Review
The purpose of this work was to develop a definition of myelofibrosis with myeloid metaplasia (MMM) using diagnostic criteria that would remain valid within the set of patients with chronic myeloproliferative disorders or myelodysplastic syndromes. A list of 12 names for the disease and 37 diagnostic criteria were proposed to a Consensus Panel of 12 Italian experts who ranked them in order so as to identify a core set of criteria. The Panel was then asked to score the diagnosis of 46 patient profiles as appropriate or not appropriate for MMM. Using the experts' consensus as the gold standard, the performance of 90 possible definitions of the disease obtained through the core set was evaluated. 'Myelofibrosis with myeloid metaplasia' ranked as the preferred name of the disease. Necessary criteria consisted of 'diffuse bone marrow fibrosis' and 'absence of Philadelphia chromosome or BCR-ABL rearrangement in peripheral blood cells'. The six optional criteria in the core set consisted of: splenomegaly of any grade; anisopoikilocytosis with tear-drop erythrocytes; the presence of circulating immature myeloid cells; the presence of circulating erythroblasts: the presence of clusters of megakaryoblasts and anomalous megakaryocytes in bone marrow sections; myeloid metaplasia. The definition of the disease with the highest final score was as follows: necessary criteria plus any other two criteria when splenomegaly is present or any four when splenomegaly is absent. The use of this definition will help to standardize the conduct and reporting of clinical studies and should help practitioners in clinical practice.
Topics: Humans; Primary Myelofibrosis; Terminology as Topic
PubMed: 10192432
DOI: 10.1046/j.1365-2141.1999.01262.x