The congenital dyserythropoieitic anemias: genetics and pathophysiology

King, Richard A.; Gallagher, Patrick J.; Khoriaty, Rami

doi:10.1097/moh.0000000000000697

Cited by 13 publications

(8 citation statements)

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“…Erythroid-specific deletion of RhoA in mice was embryonic lethal because of severe anemia, and the primitive red blood cells were macrocytic, poikilocytes and frequently multinucleated ( Konstantinidis et al, 2015 ). Binucleated and multinucleated erythroid cells are the key features in certain types of CDAs ( King et al, 2022 ). Interestingly, we observed an erythroid lineage phenotype similar to congenital dyserythropoietic anemia type II (CDA II) in the two patients who had undergone bone marrow examinations (patients five and six) ( Figure 3 ).…”

Section: Discussionmentioning

confidence: 99%

Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease

Tallgren¹,

Kager²,

O’Grady³

et al. 2023

Front. Neurosci.

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PurposeFINCA disease (Fibrosis, Neurodegeneration and Cerebral Angiomatosis, OMIM 618278) is an infantile-onset neurodevelopmental and multiorgan disease. Since our initial report in 2018, additional patients have been described. FINCA is the first human disease caused by recessive variants in the highly conserved NHLRC2 gene. Our previous studies have shown that Nhlrc2-null mouse embryos die during gastrulation, indicating the essential role of the protein in embryonic development. Defect in NHLRC2 leads to cerebral neurodegeneration and severe pulmonary, hepatic and cardiac fibrosis. Despite having a structure suggestive of an enzymatic role and the clinical importance of NHLRC2 in multiple organs, the specific physiological role of the protein is unknown.MethodsThe clinical histories of five novel FINCA patients diagnosed with whole exome sequencing were reviewed. Segregation analysis of the biallelic, potentially pathogenic NHLRC2 variants was performed using Sanger sequencing. Studies on neuropathology and NHLRC2 expression in different brain regions were performed on autopsy samples of three previously described deceased FINCA patients.ResultsOne patient was homozygous for the pathogenic variant c.442G > T, while the other four were compound heterozygous for this variant and two other pathogenic NHLRC2 gene variants. All five patients presented with multiorgan dysfunction with neurodevelopmental delay, recurrent infections and macrocytic anemia as key features. Interstitial lung disease was pronounced in infancy but often stabilized. Autopsy samples revealed widespread, albeit at a lower intensity than the control, NHLRC2 expression in the brain.ConclusionThis report expands on the characteristic clinical features of FINCA disease. Presentation is typically in infancy, and although patients can live to late adulthood, the key clinical and histopathological features are fibrosis, infection susceptibility/immunodeficiency/intellectual disability, neurodevelopmental disorder/neurodegeneration and chronic anemia/cerebral angiomatosis (hence the acronym FINCA) that enable an early diagnosis confirmed by genetic investigations.

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Section: Discussionmentioning

confidence: 99%

Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease

Tallgren¹,

Kager²,

O’Grady³

et al. 2023

Front. Neurosci.

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“…The increased expression of SEC23A ameliorated the erythroid defects, suggesting a novel therapeutic target for the disease. Additional new genes have also been identified underlying the pathogenesis of CDA, such as RACGAP1 and VPS4A in CDA type III 13…”

Section: Discussionmentioning

confidence: 99%

SEC23Bmissense mutation-associated congenital dyserythropoietic anaemia type II in a child: a rare mimic of chronic haemolytic anaemia

Alam

Mandal

et al. 2022

BMJ Case Rep

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We report a case of congenital dyserythropoietic anaemia (CDA) type II in a female child, which is an extremely rare cause of hereditary anaemia. The patient, still in her early childhood, presented to us with transfusion-dependent anaemia, unexplained jaundice, passage of cola-coloured urine and hepatosplenomegaly. Further investigations revealed evidence of iron overload, ineffective erythropoiesis and inadequate bone marrow response. Bone marrow aspiration study demonstrated dyserythropoiesis and findings typical of CDA type II. Targeted exome genome sequencing was done and identified heterozygous missense mutation of the SEC23B gene. CDA, being clinically similar to other more prevalent causes of anaemia, should be kept in mind especially when the common causes have already been ruled out.

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“…CDAs are a group of heterozygous disorders characterized by ineffective erythropoiesis with inadequate reticulocyte values, ineffective erythropoiesis and hemolysis. 11 All of the patients suffer from moderate anemia, jaundice, and splenomegaly. Older patients with CDAs often present with complications of cholelithiasis and iron overload following frequent blood transfusions.…”

Section: Discussionmentioning

confidence: 99%

Ultrastructural characteristics of erythroid cells in congenital dyserythropoietic anemia type II, with a focus on peripheral cisternae and double membranes

Dong

Liu

et al. 2022

Blood Science

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Peripheral cisternae and double membranes (PCDMs) in erythroid cells are a landmark of type II congenital dyserythropoietic anemia (CDA). To gain further insights into the mechanism of dyserythropoiesis, erythroblasts and erythrocytes in bone marrow were studied in 22 Chinese patients with CDA Ⅱ by transmission electron microscopy. The study demonstrated an increase in all patients in erythroblasts with PCDMs with development from pro-erythroblast to red blood cells. PCDMs often connected with cisternae of endoplasmic reticulum (ER) and the perinuclear space, and were accompanied by karyopyknosis, karyolysis and disruption in polychromatic and orthochromatic erythroblasts. The results suggest that PCDMs are transformed from ER during erythropoiesis and participate in the dissolution and deletion of late erythroid cells in patients with CDA II.

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The congenital dyserythropoieitic anemias: genetics and pathophysiology

Cited by 13 publications

References 139 publications

Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease

Novel patients with NHLRC2 variants expand the phenotypic spectrum of FINCA disease

SEC23Bmissense mutation-associated congenital dyserythropoietic anaemia type II in a child: a rare mimic of chronic haemolytic anaemia

Ultrastructural characteristics of erythroid cells in congenital dyserythropoietic anemia type II, with a focus on peripheral cisternae and double membranes

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