Renal Tubular Acidosis, Distal, With Hemolytic Anemia

A number sign (#) is used with this entry because autosomal recessive distal renal tubular acidosis (dRTA) with hemolytic anemia is caused by mutation in the SLC4A1 gene (109270).

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive distal RTA, see 267300.

Clinical Features

Tanphaichitr et al. (1998) described a Thai brother and sister with autosomal recessive distal RTA and hemolytic anemia. The male proband presented at age 3.5 years with a history of lethargy, anorexia, and slow growth. Physical examination showed height and weight less than the third percentile, pallor, and hepatosplenomegaly. Hypokalemia, hyperchloremic metabolic acidosis, and normal creatinine were accompanied by isosthenuria and alkaline urinary pH, bilateral nephrocalcinosis, and rachitic bone changes. Mild anemia (hematocrit 11 g/dl) with microcytosis, reticulocytosis, and a peripheral smear consistent with a xerocytic type of hemolytic anemia were accompanied by homozygosity for hemoglobin E, a clinically benign hemoglobin frequently encountered in Southeast Asia. The sister showed similar findings.

Molecular Genetics

Tanphaichitr et al. (1998) described novel SLC4A1 mutations in a Thai family with a recessive syndrome of distal renal tubular acidosis and hemolytic anemia in which red cell anion transport was normal. A brother and sister were triply homozygous for 2 benign mutations, M31T and K56E (109270.0001), and for a loss-of-function mutation, G701D (109270.0016). The genetic and functional data suggested that the homozygous SLC4A1 G701D mutation caused recessively transmitted dRTA in this kindred with apparently normal erythroid anion transport.

Bruce et al. (2000) studied 3 Malaysian and 6 Papua New Guinean families with dRTA and Southeast Asian ovalocytosis (SAO; 166900). The SAO deletion mutation (109270.0002) in the SLC4A1 gene occurred in many of the families but did not itself result in dRTA. Compound heterozygotes of each of 3 dRTA mutations (G701D; A858D, 109270.0020; and delV850, 109270.0021) with SAO all had dRTA, evidence of hemolytic anemia, and abnormal red cell properties. The A858D mutation showed dominant inheritance and the recessive delV850 and G701D mutations showed a pseudodominant phenotype when the transport-inactive SAO allele was also present.

Sritippayawan et al. (2004) reported 2 Thai families with recessive dRTA due to different compound heterozygous mutations of the SLC4A1 gene. In the first family, the proband was a 5-year-old boy with dRTA, rickets, failure to thrive, nephrocalcinosis, and hypokalemic/hyperchloremic metabolic acidosis with a urine pH of 7.00. He had a normal hemoglobin level and normal red cell morphology. The proband was found to have compound heterozygous G701D (109270.0016)/S773P (109270.0026) mutations, inherited from his clinically normal mother and father, respectively. In the second family, a 19-year-old man and his 15-year-old sister had dRTA and Southeast Asian ovalocytosis, and were compound heterozygotes for the SAO deletion mutation (109270.0002) and an R602H mutation (109270.0027). Their mother had SAO and an unaffected brother was heterozygous for the R602P mutation. Sritippayawan et al. (2004) noted that the second patient had a severe form of dRTA whereas his sister had only mild metabolic acidosis, indicating that other modifying factors or genes might play a role in governing the severity of the disease.

Population Genetics

Yenchitsomanus et al. (2002) found that all Thai patients with autosomal recessive dRTA caused by homozygosity for the G701D mutation originated from northeastern Thailand. Yenchitsomanus et al. (2003) confirmed the higher allele frequency of the G701D mutation in this population. This suggested that the G701D allele might have arisen in northeastern Thailand. The presence of patients with dRTA who were compound heterozygotes for the Southeast Asian ovalocytosis deletion mutation and G701D in southern Thailand and Malaysia and their apparent absence in northeastern Thailand indicated that the G701D allele may have migrated to the southern peninsula region where SAO is common, resulting in pathogenic allelic interaction.