Online Mendelian Inheritance in Humans (OMIM) (2023)


A number sign (#) is used in this entry because there is evidence that hemolytic anemia due to elevated adenosine deaminase (HAEADA) is caused by a hemizygous or heterozygous mutation in the GATA1 gene (305371) on chromosome Xp11.


Hemolytic anemia due to elevated adenosine deaminase (HAEADA) is an X-linked hematological disorder characterized by the onset of mild to moderate erythrocyte anemia soon after birth or in childhood. The anemia is associated with a significantly increased activity of ADA (608958), particularly in erythrocyte progenitors. ATP levels can be secondarily decreased. Additional features may include low birth weight, thrombocytopenia, hypospadias, and splenomegaly. Males are preferentially affected, although female carriers may have elevated erythrocyte ADA or mild features (Ludwig et al., 2022).

Clinical Features

Early reports without genetic confirmation

Valentine et al. (1977) reported a kindred in which 12 individuals over 3 generations had hemolytic anemia associated with increased red blood cell ADA activity and decreased red blood cell ATP levels. Both males and females were affected. The anemia was mild and compensated in most cases. ADA activities were 45- to 70-fold higher than controls. The authors concluded that the hemolytic disorder may result from the red blood cells' inability to rescue adenine nucleotides on which anucleated erythrocytes, incapable of de novo synthesis, are so dependent. Chottiner et al. (1987) investigated the originally proposed by Valentine et al. described family. (1977). They confirmed that the ADA-specific activity of the red blood cells was 70 to 100 times the normal values. Western blots showed a corresponding increase in ADA-specific red blood cell immunoreactive protein. Analysis of the genomic DNA showed no evidence of amplification or major structural changes in the ADA gene. ADA-specific mRNA from volunteer reticulocytes was comparable in size and quantity to mRNA from control reticulocytes. This finding ruled out increased transcription of the gene or increased stability of red blood cell ADA mRNA.

Miwa et al. (1978) reported on a 38-year-old Japanese man with compensated hemolytic anemia. His erythrocytes showed moderate stomatocytosis and his erythrocyte ADA activity was 40 times normal. The mother showed a 4-fold increase in red blood cell ADA; the father's enzyme levels were normal. ADA levels in the lymphocytes were close to normal. The serum uric acid level was slightly elevated. The authors suggested that the genetic defect likely affects a regulatory gene at a location separate from the structural location for ADA on chromosome 20.

Perignon et al. (1982) reported a 10-year-old boy with severe hemolytic anemia associated with ADA activity approximately 85 times the normal range. Excessive ADA activity in red blood cells has been shown to be due to an abnormal amount of a catalytically and immunologically normal enzyme.

Patients with confirmed GATA1 mutations

Kanno et al. (1988) reported on a 10-year-old Japanese boy who presented at birth with pallor, hypospadias, and cryptorchidism. He had persistent hemolytic anemia with reticulocytosis and elevated bilirubin. Bone marrow examination showed hypercellularity and erythroid hyperplasia, and blood smear showed stomatocytosis. The half-life of the erythrocytes was reduced, but the osmotic fragility was normal. The enzymatic activity of erythrocyte ADA was significantly increased at 88.6 IU/gHb; Lymphocyte ADA activity was normal. ATP levels were slightly decreased compared to controls. The patient underwent splenectomy at age 11, resulting in elevated hemoglobin levels. The patients' erythrocytes showed an increased rate of ADA synthesis and abnormal accumulation of ADA protein at normal mRNA levels. No ADA overproduction was observed in other tissues. Maternal erythrocyte ADA was slightly elevated at 1.74 IU/gHb; ADA in father was normal. Kanno et al. (1988) concluded that the regulation of protein synthesis was altered in a tissue specific pattern, namely in erythroid progenitors. The patient had 3 siblings, all of whom died in the perinatal period from congenital heart disease of unknown cause or erythroblastosis fetalis; No DNA was available from these individuals.

Ogura et al. (2016) reported on an 18-year-old Japanese man with congenital hemolytic anemia. Other features included low birth weight, hypospadias, splenomegaly, and slightly decreased platelet counts. The anemia was associated with an elevated erythrocyte ADA (39.7 IU/gHb), representing an over 30-fold increase from normal. The mother's red blood cell ADA was slightly elevated at 7.4, while it was normal in the father. Ludwig et al. (2022) reported that hemolytic anemia was evident at birth and required blood transfusion, with eventual improvement during childhood. At age 17, he had an episode of intravascular hemolysis with severe anemia and abnormal blood smear morphology, including anisocytosis, target cells, and ovalostomatocytes.

Ludwig et al. (2022) reported on a 3-year-old boy born to unrelated parents of Irish/English descent who presented shortly after birth with macrocytic anemia and thrombocytopenia requiring blood and platelet transfusions. He had a complicated neonatal course with a small ventricular septal defect (VSD), rash, micropenis, hepatosplenomegaly, clubfoot and required a prolonged stay in the NICU. Brain imaging showed extensive neuronal migration abnormalities with pachygyria, a schizencephalic cleft, and periventricular white matter calcifications. Perinatal infections were excluded. Over time, his only hematological abnormality was a mild macrocytic hemolytic anemia. Erythrocyte ADA was increased to 14.4 IU/gHb. He was verbal and could stand but was not able to walk. Maternal red blood cell ADA levels were not reported.


The transmission pattern HAEADA in the Ludwig et al. (2022) was consistent with X-linked recessive inheritance.

Molecular genetics

In 3 unrelated male patients with HAEADA, including those reported by Kanno et al. (1988) and Ogura et al. (2016), Ludwig et al. (2022) identified hemizygous mutations affecting the same residue in the GATA1 gene (R307C, 305371.0012 and R307H, 305371.0013). The mutations affected a conserved residue in an intrinsically disordered region (IDR) in the C-terminal domain. The mutations found by whole exome sequencing were not present in the gnomAD database. Patient-derived erythroid cells showed impaired differentiation, reduced proliferation, and altered morphology compared to controls, which could be partially rescued by expression of wild-type GATA1. Cells transduced with the mutations showed increased levels of erythrocyte ADA and increased levels of ADA mRNA compared to controls. RNA-seq analysis revealed differential expression of genes involved in hematopoiesis and terminal erythroid maturation. Mouse-derived Gata1-null cells transduced with Gata1 showed induction of Ter119, a marker for erythroid differentiation; Cells transduced with the R307C/H mutants had reduced Ter119 expression. The R307C/H mutations partially disrupted a predicted nuclear localization signal, and the mutant proteins showed a 40% reduction in the nucleus and increased retention in the cytoplasm compared to wild-type. The results of the RNA-seq analysis were consistent with an altered transcriptional activity of the mutants towards canonical GATA1 target genes. Further studies on mutant cells revealed altered chromatin accessibility and DNA binding associated with the mutations, consistent with the observed changes in gene expression that indicated impaired transcriptional regulation. Taken together, the findings suggested a primary erythroid defect in terminal differentiation due to specific mutations in the GATA1 master transcription factor.


Glader et al. (1983) suggested that increased ADA activity is a feature of Blackfan-Diamond anemia (105650).

Novelli et al. (1986) found a 4-fold increase in ADA in red blood cells in a 16-month-old Libyan infant without hemolytic anemia but with mild anisopoikilocytosis. The parents, who were related as first cousins, and one healthy brother had normal levels of ADA in their red blood cells.

In severe combined immunodeficiency with ADA (102700) deficiency, structural changes such as point mutations in the ADA gene (608958) on chromosome 20 have been identified and the deficiency is found in all tissues. In the perturbation of ADA excess, only the erythroid elements show the abnormality and the ADA molecule is structurally normal by all the usual criteria, including electrophoretic migration, kinetics for various substrates and inhibitors, heat stability, specific activity, pH optimum, immunological reactivity, Amino acid composition and peptide pattern. The mutation is believed to be in a separate gene from the structural gene for ADA. Examination of these families with DNA markers located in the region of the ADA gene at 20q could conclusively prove that the determinant moved at a distance away from the ADA gene location. Such experiments were reported by Chen et al. (1993) who, to determine whether increased ADA mRNA is due to a cis-acting or a trans-acting mutation, exploited a highly polymorphic TAAA repeat located at the tail end of an Alu repeat approximately 1,1 kb gene located upstream of ADA. Using PCR to amplify this region, they identified 5 different alleles in 19 members of an affected family (Valentine et al., 1977). All 11 affected individuals had an ADA allele with 12 TAAA repeats, while none of the 8 healthy individuals did. They concluded that this disorder is due to a cis-acting mutation near the ADA gene. Chen and Mitchell (1994) examined reporter gene activity using constructs containing 10.6 kb of the 5-prime flanking sequence and 12.3 kb of the first intron of the ADA gene of normal and mutant alleles. No differences in chloramphenicol acetyltransferase (CAT) activity were found in transient transfection experiments using erythroleukemia cell lines. In addition, transgenic mice harboring the ADA constructs displayed CAT activities in erythrocytes and bone marrow that did not differ between the normal and mutant alleles. The results were interpreted to mean that it is unlikely that the mutation responsible for ADA overexpression resides in the 5 prime and promoter regions or in the regulatory regions of the first intron of the ADA gene.

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