scholarly journals The Novel Missense Mutation of GATA1 Caused Red Cell Adenosine Deaminase Overproduction Associated with Congenital Hemolytic Anemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 400-400
Author(s):  
Hiromi Ogura ◽  
Toshiyuki Yamamoto ◽  
Taiju Utsugisawa ◽  
Takako Aoki ◽  
Takuya Iwasaki ◽  
...  
Keyword(s):  
Adenosine Deaminase ◽  
Missense Mutation ◽  
Hemolytic Anemia ◽  
Conflicts Of Interest ◽  
Mean Value ◽  
Blood Type ◽  
Target Cells ◽  
Red Cell ◽  
Aberrant Expression ◽  
Congenital Hemolytic Anemia

Abstract Red cell adenosine deaminase (ADA) overproduction (OMIM 102730) is a rare form of congenital hemolytic anemia. To date, only four independent families have been reported. Recently, we examined the red cell enzyme activities of an 18-year-old male Japanese patient with congenital hemolytic anemia, and diagnosed a new case of ADA overproduction. His ADA activity was measured as 39.7 IU/gHb, representing an over 30-fold elevation of the normal mean value. The patient's mother also showed a high red cell ADA, 7.40 IU/gHb, and the father had normal ADA activity. To elucidate the molecular basis of the elevated ADA activity, we performed a target-captured sequencing focusing on the 67 congenital-anemia related genes. The results showed that there was no structural mutation of ADA gene, and that the proband had a novel missense mutation of GATA1, c.920G>A, p.R307H. The proband was hemizygous, and the mother was heterozygous for the mutation. Subsequently, we examined a previously reported case of ADA overproduction, and identified the identical missense mutation of GATA1. These two cases had clinical similarities, such as low birth weight with hypospadias, splenomegaly, and slightly decreased platelet counts, suggesting that these cases could be categorized as X-linked anemia with or without neutropenia and/or platelet abnormality (XLANP, OMIM#300835). The previous case showed a rare blood type, Lu(a-b-) and a low beta/alpha globin synthetic ratio, whereas the present case depicted abnormal red cell morphology, such as stomatocytosis and target cells. Taken together, the missense mutation of GATA1 might cause the aberrant expression of erythroid-genes, inducing a short life-span of red cells. Disclosures No relevant conflicts of interest to declare.

COL4A1 is a Novel Causative Gene Responsible for Congenital Hemolytic Anemia, Representing Characteristic Clinical Course in Infants

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 934-934
Author(s):  
Hiromi Ogura ◽  
Shouichi Ohga ◽  
Takako Aoki ◽  
Taiju Utsugisawa ◽  
Hidehiro Takahashi ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Small Vessel Disease ◽  
Gene Mutations ◽  
Basement Membranes ◽  
Red Cell ◽  
Missense Mutations ◽  
Causative Gene ◽  
Congenital Hemolytic Anemia

Abstract We have been working on the differential diagnosis of congenital hemolytic anemia, but even with extensive analysis of hemoglobin, red cell membrane and enzymes, approximately 40% of patients remained to be diagnosed. In this study, we analyzed 17 undiagnosed hemolytic anemia subjects under the age of 1 by whole-exome sequencing, and identified COL4A1 gene mutations in 5 cases (29.4%). All patients were de novo cases without family histories and exhibited moderate to severe neonatal hemolytic anemia: Hgb, 5.2-9.3 g/dl; MCV, 90.0-126.9; MCHC, 29.9-32.7; and reticulocyte count, 9.2-33.0%. Either schizocytes or poikilocytes were observed in peripheral blood smears of 3 cases, suggesting that the microangiopathy was attributable to hemolysis. Previous reports showed that mutation of COL4A1 accounts for brain small-vessel disease characterized by stroke and eye abnormalities and the most characteristic complications of the present cases were congenital anomaly in the central nervous system, such as porencephaly, schizencephaly, congenital hydrocephalus, cataracts or paraventricular calcification, as reported previously. Hemolytic anemia became less severe within 2 months after birth, and all cases no longer required red cell transfusion after Day 50. COL4A1 encodes subtype 1 of type IV collagen, which is most abundantly expressed in basement membranes, including the vasculature. The COL4A1 gene mutations identified in the cases were all novel missense mutations except one, located in exons 26, 27, 37, 38 and 51. Although the pathophysiological significance of the mutations remains unclear, COL4A1 is the first identified causative gene responsible for congenital hemolytic anemia without intrinsic defects of red blood cells, and mutation of COL4A1 is the most prevalent cause of neonatal hemolytic anemia. Disclosures No relevant conflicts of interest to declare.

The Flow Cytometric Osmotic Fragility Test Is an Effective Screening Method for Dehydrated Hereditary Stomatocytosis

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 929-929
Author(s):  
Taiju Utsugisawa ◽  
Takuya Iwasaki ◽  
Takako Aoki ◽  
Yoshio Okamoto ◽  
Takahiro Kawakami ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Conflicts Of Interest ◽  
Screening Method ◽  
Osmotic Fragility ◽  
Target Cells ◽  
Next Generation ◽  
Causative Gene ◽  
Rbc Membrane ◽  
Flow Cytometric ◽  
Congenital Hemolytic Anemia

Abstract Introduction: Dehydrated hereditary stomatocytosis (DHSt) or hereditary xerocytosis (HX) is a form of congenital hemolytic anemia characterized by red blood cell (RBC) dehydration. Heterozygous mutations in PIEZO1, a mechanically-activated ion channel, cause DHSt. Recently, KCNN4, which encodes the Gardos channel, has been found to be the second pathogenic gene for DHSt. DHSt is characterized by an alteration in the RBC morphology in target cells, stomatocytes, and/or echinocytes, and RBC deformability assessments by ektacytometry as well as RBC ion flux measurements are currently the standard laboratory tests for DHSt, but their use in laboratories is limited. The flow cytometric osmotic fragility (FCM-OF) test is a useful diagnostic test for hereditary spherocytosis (HS) and also for hereditary elliptocytosis (HE). In this study, we showed that the FCM-OF test could also successfully diagnose DHSt. Subjects: A total of 46 cases of RBC membrane disorders were examined, and tentative diagnoses were made based on the RBC morphology, acid glycerol lysis time, and eosin 5'-maleimide binding tests, resulting in HS (n=31), HE (n=6), and DHSt (n=9). Methods: The number of RBCs in isotonic and hypotonic buffers were measured by flow cytometry. The degree of osmotic fragility was expressed as the "percentage residual RBCs (%RRC)". We confirmed the DHSt diagnosis by the massively paralleled sequencing using our custom panels targeting 68 hemolytic anemia-related genes with the next-generation sequencer. Results: Both HS and HE patients showed a decrease in %RRC; HS (18.0±8.9%, p<0.001) and HE (41.8±15.7%, p<0.001) compared to normal control (66.7±1.5%). DHSt patients showed a significant increase (112.6±34.5%, p<0.001) in FCM-OF. Additionally, next-generation sequencing revealed consistent causative gene mutations for DHSt; PIEZO1 (p.R2488Q and p.E2496ELE) or KCNN4 (p.P204R, p.A279T and p.R352H). Discussion: We examined 77 patients with congenital hemolytic anemia recently, and 59 cases were confirmed by diagnostic tests (76.6%). The results were as follows: 48 cases of RBC membrane abnormality (62.3%), 6 cases of RBC enzymopathy (7.8%), and 5 cases of hemoglobinopathy (6.5%). Of the cases of RBC membrane disorders, 31 cases of HS, 9 cases of DHSt, and 8 cases of HE were identified. These observations suggest that DHSt is the second-most common RBC membranopathy in Japan, and that the FCM-OF test and targeted sequencing efficiently discriminate DHSt from other RBC membrane disorders. Disclosures No relevant conflicts of interest to declare.

scholarly journals Congenital Hemolytic Anemia with Abnormal Pigment Metabolism and Red Cell Inclusion Bodies: a New Clinical Syndrome

Blood ◽  
1958 ◽  
Vol 13 (10) ◽  
pp. 950-958 ◽  
Author(s):  
ROBERT D. LANGE ◽  
JOSEPH H. AKEROYD
Keyword(s):  
Case Report ◽  
Hemolytic Anemia ◽  
Inborn Error ◽  
Inclusion Bodies ◽  
Clinical Syndrome ◽  
Red Cell ◽  
Dark Urine ◽  
Special Studies ◽  
Congenital Hemolytic Anemia

Abstract 1. A case report and special studies of a 14-year-old girl with a congenital hemolytic anemia are reported. 2. Fourteen per cent of her erythrocytes contained unusual inclusion bodies. 3. In addition, the child has been known to pass dark urine since the age of 2½ years. The pigment probably belongs to the bilifuscin and mesobilifuscin group. 4. It is believed that the syndrome is probably caused by an inborn error in erythrocytic metabolism. 5. It has been proposed that the syndrome be named "congenital hemolytic anemia with abnormal pigment metabolism and red cell inclusion bodies."

scholarly journals HEMOLYTIC ANEMIA AND LOW RED CELL ATP/dATP RATIO IN GENETIC ADENOSINE DEAMINASE DEFICIENCY: 86

1985 ◽  
Vol 19 (7) ◽  
pp. 758-758
Author(s):  
Michael S Hershfield ◽  
Joanne Kurtzberg ◽  
Richard Schlff
Keyword(s):  
Adenosine Deaminase ◽  
Hemolytic Anemia ◽  
Red Cell ◽  
Adenosine Deaminase Deficiency

scholarly journals A family with red cell pyrimidine 5'-nucleotidase deficiency

Blood ◽  
1976 ◽  
Vol 47 (6) ◽  
pp. 919-922
Author(s):  
I Ben-Bassat ◽  
F Brok-Simoni ◽  
G Kende ◽  
F Holtzmann ◽  
B Ramot
Keyword(s):  
Hemolytic Anemia ◽  
Peripheral Blood ◽  
Blood Smear ◽  
Peripheral Blood Smear ◽  
Early Infancy ◽  
Red Cell ◽  
Chronic Hemolytic Anemia ◽  
Congenital Hemolytic Anemia

Congenital hemolytic anemia associated with pyrimidine 5′-nucleotidase deficiency is reported in two siblings. Both have had moderate chronic hemolytic anemia, splenomegaly, and jaundice since early infancy. The peripheral blood smear is characterized by striking red cell basophilic stippling. As this feature has been found in all previously reported cases, it should be the clue to the diagnosis.

scholarly journals IVIG-Induced Abrupt Hemolysis in Neurological Conditions

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4991-4991 ◽  
Author(s):  
Juskaran Chadha ◽  
Randy L. Levine ◽  
Omer Ilyas
Keyword(s):  
Folic Acid ◽  
Vitamin B12 ◽  
Hemolytic Anemia ◽  
Conflicts Of Interest ◽  
Type A ◽  
Blood Type ◽  
Lower Extremity Weakness ◽  
Autoimmune Conditions ◽  
History Of ◽  
Work Up

Background Immunoglobulin (IVIG) is used to treat autoimmune conditions, but there are reports of brisk hemolysis within 48 hours (hrs) of treatment due to anti-A isohemogglutinins(1). Despite these reports, hemolysis remains an unrecognized side effect of IVIG. Methods We presented a series of 3 cases of IVIG-induced hemolysis in patients with autoimmune neurological disorders. In the investigative phase, we traced the cases to a common IVIG lot number. The sample was tested to determine the anti-A titer levels. Case Studies (See Table 1) Case 1 75-year-old man presented with SOB and dysarthria from myasthenia gravis (MG). He received IVIG for 4 days. He developed a hemolytic anemia with 3 g drop in hemoglobin (Hb) 48 hours later. He needed a pRBC transfusion and folic acid. Case 2 59-year-old female with history of MG treated with IVIG at another hospital until 3 months earlier in crisis, with SOB and dysphagia. She received IVIG for 5 days and rituximab. She improved and was discharged, but returned to the ER 7 days later with SOB. Her Hb fell to 8.0 g/dL from 13 g/dL on last admission. She required a pRBC transfusion, folic acid, and vitamin B12 with improvement of SOB. Case 3 20-year-old female admitted for lower extremity weakness, diagnosed with presumed syndrome (GBS). She received IVIG for 4 days. On the 5th day, her Hb fell from 15 g/dL to 9 g/dL. She began prednisone, folic acid, and vitamin B12 with improvement in her Hb. Conclusions Although acute hemolysis is well described in the literature, it is under recognized, as exemplified by the first two cases. Their initial SOB was due to MG, so when SOB recurred, they were misdiagnosed with recurrent MG. A hemolytic anemia was later suspected, and a work up revealed a positive DAT. The initial eluate was negative against type O panel cells, suggesting a drug related hemolysis. It was only when the eluate was tested against type A cells that the etiology became clear. The third patient's hemolytic reaction was then rapidly identified. These cases remind us to consider IVIG induced anti-A hemolysis in patients who are blood type A and AB, and to evaluate the eluate against the appropriate reagent cells. These patients should receive specific IVIG that is low in anti-A isohemagglutinins. Since the second patient did not hemolyze from earlier exposure to IVIG, she likely received a low titer product. Disclosures No relevant conflicts of interest to declare.

scholarly journals Red cell calcium leak in congenital hemolytic anemia with extreme microcytosis

Blood ◽  
1976 ◽  
Vol 47 (2) ◽  
pp. 197-210 ◽  
Author(s):  
JS Wiley ◽  
FM Gill
Keyword(s):  
Hemolytic Anemia ◽  
Cell Morphology ◽  
Osmotic Fragility ◽  
Red Cells ◽  
Red Cell ◽  
Fresh Blood ◽  
Ouabain Binding ◽  
Red Cell Membrane ◽  
Membrane Area ◽  
Congenital Hemolytic Anemia

Abstract A child with congenital hemolytic anemia, extreme microcytosis and bizarre red cell morphology has been studied. Splenectomy at the age of 21 mo greatly improved the hemolytic anemia, although red cell morphology was unchanged. Aniso- and poikilocytosis were marked on a stained smear, and there were many small hyperchromatic cells of irregular shape. The MCV of 25 cu mu was very low and the MCHC was normal. Osmotic fragility of fresh blood was increased, and postsplenectomy blood showed a fraction of extremely fragile cells. Concentration and fluxes of Na+ and K+ were normal, except K+ efflux, which was stimulated by external Ca2+. Inward Ca2+ movement into the patient's red cells was elevated three- to fourfold above red cells of the same mean age. Red cell Ca2+ concentration was raised 2.5 times normal and most of the Ca2+ was localized in the stroma. Red cell lipid, sialic acid, and ouabain-binding sites, all per milliliter of cells, were increased by 16%-23%, and, since these substances estimate the amount of membrane, it was likely that Ca2+ content per unit of membrane area was at least twice normal. Deformability of the cells, as judged by their filterability was markedly impaired. It was concluded that the red cell membrane was defective, and an increased membrane Ca2+ content was associated with reduced deformability, hemolysis, and distorted red cell morphology in this syndrome.

Molecular Characterization of Hemoglobinopathies and Red Cell Enzymopathies in the Czech and Slovak Populations: An Update

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5307-5307
Author(s):  
Martina Divoka ◽  
Renata Mojzikova ◽  
Lucie Piterkova ◽  
Pavla Pospisilova ◽  
Martina Partschova ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Clinical Symptoms ◽  
Conflicts Of Interest ◽  
Slovak Republic ◽  
Globin Gene ◽  
Hereditary Hemochromatosis ◽  
Sequencing Analysis ◽  
Red Cell ◽  
Thalassemia Minor ◽  
Hemoglobin Variants

Abstract Abstract 5307 Background: Thalassemias are rare disorders in Middle Europe. However, as a result of historical and recent migration, thalassemias became common cause of congenital anemia in the Czech and Slovak populations. Abnormal hemoglobin variants and red-cell enzymopathies are rare cause of congenital anemia in this region. The aim of this work was to update the original reports of this research published almost two decades ago (Indrak et al., Hum Genet 1992; 88:399–404, Xu et al., Blood 1995; 85:257–63, Lenzner et al., Blood 1997; 89:1793–9). We assessed the frequency and spectrum of β-globin gene mutations in the patients with clinical symptoms of β-thalassemia or δ,β-thalassemia, the α-globin gene status in the patients with clinical symptoms of α-thalassemia, and we characterized red cell enzymopathies on molecular level in the Czech and Slovak populations. Patients and methods: Nearly 390 cases with clinical symptoms of thalassemia or hereditary nonspherocytic hemolytic anemia from several centers of Czech and Slovak Republic were analyzed. Hematological parameters, hemoglobin electrophoresis and enzyme activities were measured by standard procedures. Genomic DNA was used for PCR-sequencing analysis. Results: We identified 22 β-thalassemia mutations in more than 260 heterozygotes; most of the mutations were of Mediterranean origin. The newly discovered insertion of transposable element L1 into the HBB gene represents a novel etiology of β-thalassemia due to a silencing effect of repressive chromatin associated with retrotransposon insertion. The list of abnormal hemoglobins now contains 14 β-globin variants, involving Heinz body hemolytic anemia variant Hb Hana (β63(E7) His-Asn), phenotype of which was worsened by concomitant partial glutathione reductase deficiency (Mojzikova et al., Blood Cells Mol Dis 2010; 45:219–22). Several G6PD and PK variants were described in the Czech and Slovak populations; the G6PD variants include G6PD Olomouc, G6PD Varnsdorf and G6PD Praha. Recently, we identified a new frameshift mutation c. 1553delG (p. Arg518fs) at the homozygous state in exon 11 of the PKLR gene of the pediatric patient who suffered from transfusion dependent hemolytic anemia with Hb=9.4 g/dL, Ret=4.5%. His red cells PK activity was 4.52 IU/gHb (normal range 13–17 IU/gHb). The mutation occurs in C domain of PK-R subunit containing the binding site for fructose-1,6-bisphosphate. The patient's extremely elevated level of growth differentiation factor 15 (GDF15, 3577 pg/mL, healthy controls 231–345 pg/mL) could explain hereditary hemochromatosis and signs of iron overload in this patient. Conclusions: In the Czech and Slovak populations, hemoglobinopathies and red-cell enzymopathies appear to be an uncommon disorder, which, however, must be considered as the prevailing cause of congenital anemia. Most of the thalassemia patients were heterozygous, manifesting thalassemia minor. Most of the hemoglobin variants were described in single families, some of them originated locally. Among hemolytic anemias due to red-cell enzymopathies is the most frequent PK deficiency. This work was supported by grants NT11208, NS10281 (Ministry of Health Czech Republic), MSM6198959205 (Ministry of Education, Youth and Sports) and student projects LF_2011_006 and LF_2011_011 of the Palacky University. Disclosures: No relevant conflicts of interest to declare.

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