Alternative titles; symbols
SNOMEDCT: 236461000; ORPHA: 18, 93608;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q21.31 | Distal renal tubular acidosis 1 | 179800 | Autosomal dominant | 3 | SLC4A1 | 109270 |
A number sign (#) is used with this entry because of evidence that autosomal dominant distal renal tubular acidosis-1 (DRTA1) is caused by heterozygous mutation in the SLC4A1 gene (109270) on chromosome 17q21.
Distal renal tubular acidosis-4 with hemolytic anemia (DRTA4; 611590) is caused by biallelic mutation in the SLC4A1 gene.
Autosomal dominant distal renal tubular acidosis-1 (DRTA1) is characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, nephrolithiasis, and metabolic bone disease (summary by Bruce et al., 1997 and Karet et al., 1998).
Randall and Targgart (1961) observed renal tubular acidosis in members of several successive generations. All affected members showed both acidosis and nephrocalcinosis. Randall (1967) provided follow-up of this family. The pedigree included 4 instances of male-to-male transmission. The features were nephrocalcinosis, fixed urinary specific gravity, fixed urinary pH of about 5.0, high serum chloride, low serum bicarbonate, osteomalacia, and hypocalcemia. Alkalinization was effective therapy.
Seedat (1968) observed 18 affected persons in 3 generations. In the well-studied family reported by Gyory and Edwards (1968), 10 persons were affected by test, 3 others were (by genealogic connections) presumably affected and 2 others were reportedly affected. Male-to-male transmission occurred. Richards and Wrong (1972) described familial renal tubular acidosis in a mother and her 3 children.
Morris (1969) suggested that at least 3 types of renal tubular acidosis could be recognized: a classic type (RTA I), in which the bicarbonate threshold is normal and the defect is primarily in the distal tubule; a proximal type (RTA II, see 604278), in which the bicarbonate threshold is normal and the defect is primarily in the proximal tubule; and a 'dislocation,' or bicarbonate-wasting, type (RTA III, see 267200).
A phenocopy of the genetic disorder is produced by amphotericin B (McCurdy et al., 1968).
Buckalew et al. (1974) suggested that there are 2 autosomal dominant forms of RTA, one with hypercalciuria and one without. Hamed et al. (1979) presented studies of a large kindred that appeared to indicate that absorptive hypercalciuria is an autosomal dominant trait with complete penetrance and variable expressivity, that can lead to renal tubular acidosis and nephrocalcinosis. Buckalew et al. (1974) had also shown in 1 family that hypercalciuria preceded RTA.
Chaabani et al. (1994) reported a family in which 28 members had primary RTA I. In this large family, as well as in 2 other families with a small number of affected individuals, some of the affected members were asymptomatic. Clinical abnormalities commonly associated with RTA I, such as nephrocalcinosis and growth retardation, appeared only in 3 cases among offspring when both parents were affected. Linkage studies excluded close linkage to ABO, MNS, GM, and RH. Chaabani et al. (1994) suggested that theirs was the first reported large family with primary RTA I. Other families, such as those reported by Buckalew et al. (1974) and Hamed et al. (1979), had RTA I secondary to hereditary hypercalciuria.
In 2 unrelated males with primary renal tubular acidosis, Kondo et al. (1978) found an inactive form of carbonic anhydrase B (CA2; 611492) in red cells. Although antigenically and electrophoretically normal, it showed decreased zinc binding. The zinc contained in isolated enzyme was reduced and enzyme activity in hemolysates was restored by addition of zinc chloride. One mother had depressed CA-B, but no increase in specific activity was observed after addition of zinc. The authors estimated that 41 and 62% of CA-B was of mutant type in their 2 cases and apparently favored dominant inheritance. RTA of prominently distal type associated with osteopetrosis (259730) has been found to have a defect in CA2.
Bruce et al. (1997) studied 4 families with distal RTA. Most of the patients presented clinically with renal stones, and the majority had nephrocalcinosis. One patient had rickets when initially seen at age 10 years and developed osteomalacia at the age of 32 after she stopped taking alkali therapy, but no other patient had bone disease. Eight patients were not acidotic when first seen, and were diagnosed as 'incomplete' dominant RTA because they were unable to excrete a urine more acid than pH 5.3 after oral acute ammonium chloride challenge. Compared with acidotic cases, these patients tended to be younger, with lower plasma creatinines, better preservation of urinary concentrating ability, and less (or no) nephrocalcinosis; over a 10-year period, 2 of the patients spontaneously developed acidosis. Acidotic patients were treated with oral alkalis, usually 6 gm of sodium bicarbonate daily, and had normal acid-base status at the time of the study; nonacidotic patients were not treated.
The transmission pattern of distal renal tubular acidosis in the patients reported by Bruce et al. (1997) and Karet et al. (1998) was consistent with autosomal dominant inheritance.
Bruce et al. (1997) and Karet et al. (1998) identified heterozygous mutations in the SLC4A1 gene (see 109270.0012-109270.0015), which encodes the band 3 protein of the red cell membrane, in patients with distal renal tubular acidosis. Three of the mutations involved arginine-589.
Fry and Karet (2007) reviewed the clinical features and molecular genetics of the inherited renal acidoses.
Lewis (1992) proposed that Tiny Tim, the crippled son of Ebenezer Scrooge's clerk, Bob Cratchit, in 'A Christmas Carol' by Charles Dickens (1843), had distal renal tubular acidosis (type I). The description of his affliction suggests the growth failure, osteomalacia with pathologic fractures, hypokalemic muscle weakness, and periodic paralysis that are characteristic of that disorder.
Bruce, L. J., Cope, D. L., Jones, G. K., Schofield, A. E., Burley, M., Povey, S., Unwin, R. J., Wrong, O., Tanner, M. J. A. Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (band 3, AE1) gene. J. Clin. Invest. 100: 1693-1707, 1997. [PubMed: 9312167] [Full Text: https://doi.org/10.1172/JCI119694]
Buckalew, V. M., Jr. Familial renal tubular acidosis. Ann. Intern. Med. 68: 1367-1368, 1968. [PubMed: 5653635] [Full Text: https://doi.org/10.7326/0003-4819-68-6-1367]
Buckalew, V. M., Purvis, M. L., Shulman, M. G., Herndon, C. N., Rudman, D. Hereditary renal tubular acidosis: report of a 64 member kindred with variable clinical expression including idiopathic hypercalcinuria. Medicine 53: 229-254, 1974. [PubMed: 4834851] [Full Text: https://doi.org/10.1097/00005792-197407000-00001]
Chaabani, H., Hadj-Khlil, A., Ben-Dhia, N., Braham, H. The primary hereditary form of distal renal tubular acidosis: clinical and genetic studies in 60-member kindred. Clin. Genet. 45: 194-199, 1994. [PubMed: 8062438] [Full Text: https://doi.org/10.1111/j.1399-0004.1994.tb04022.x]
Coe, F. L., Parks, J. H. Stone disease in hereditary distal renal tubular acidosis. Ann. Intern. Med. 93: 60-61, 1980. [PubMed: 7396320] [Full Text: https://doi.org/10.7326/0003-4819-93-1-60]
Fry, A. C., Karet, F. E. Inherited renal acidoses. Physiology 22: 202-211, 2007. [PubMed: 17557941] [Full Text: https://doi.org/10.1152/physiol.00044.2006]
Gyory, A. Z., Edwards, K. D. G. Renal tubular acidosis: a family with an autosomal dominant genetic defect in renal hydrogen ion transport with proximal tubular and collecting duct dysfunction and increased metabolism of citrate and ammonia. Am. J. Med. 45: 43-62, 1968. [PubMed: 5658868] [Full Text: https://doi.org/10.1016/0002-9343(68)90006-5]
Hamed, I. A., Czerwinski, A. W., Coats, B., Kaufman, C., Altmiller, D. H. Familial absorptive hypercalcinuria and renal tubular acidosis. Am. J. Med. 67: 385-391, 1979. [PubMed: 224701] [Full Text: https://doi.org/10.1016/0002-9343(79)90783-6]
Karet, F. E., Gainza, F. J., Gyory, A. Z., Unwin, R. J., Wrong, O., Tanner, M. J. A., Nayir, A., Alpay, H., Santos, F., Hulton, S. A., Bakkaloglu, A., Ozen, S., Cunningham, M. J., di Pietro, A., Walker, W. G., Lifton, R. P. Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis. Proc. Nat. Acad. Sci. 95: 6337-6342, 1998. [PubMed: 9600966] [Full Text: https://doi.org/10.1073/pnas.95.11.6337]
Kondo, T., Taniguchi, N., Taniguchi, K., Matsuda, I., Murao, M. Inactive form of erythrocyte carbonic anhydrase B in patients with primary renal tubular acidosis. J. Clin. Invest. 62: 610-617, 1978. [PubMed: 99456] [Full Text: https://doi.org/10.1172/JCI109167]
Lewis, D. W. What was wrong with Tiny Tim? Am. J. Dis. Child. 146: 1403-1407, 1992. [PubMed: 1340779] [Full Text: https://doi.org/10.1001/archpedi.1992.02160240013002]
McCurdy, D. K., Frederic, M., Elkinton, J. R. Renal tubular acidosis due to amphotericin B. New Eng. J. Med. 278: 124-131, 1968. [PubMed: 5634966] [Full Text: https://doi.org/10.1056/NEJM196801182780302]
Morris, R. C., Jr. Renal tubular acidosis: mechanisms, classification and implications. New Eng. J. Med. 281: 1405-1413, 1969. [PubMed: 4901460] [Full Text: https://doi.org/10.1056/NEJM196912182812508]
Musgrave, J. E., Bennett, W. M., Campbell, R. A., Eisenberg, C. S. Renal tubular acidosis. (Letter) Lancet 300: 1364 only, 1972. Note: Originally Volume II. [PubMed: 4118225]
Randall, R. E., Jr., Targgart, W. H. Familial renal tubular acidosis. Ann. Intern. Med. 54: 1108-1116, 1961. [PubMed: 13739450] [Full Text: https://doi.org/10.7326/0003-4819-54-6-1108]
Randall, R. E., Jr. Familial renal tubular acidosis revisited. (Letter) Ann. Intern. Med. 66: 1024-1025, 1967. [PubMed: 6025225] [Full Text: https://doi.org/10.7326/0003-4819-66-5-1024_2]
Richards, P., Wrong, O. M. Dominant inheritance in a family with familial renal tubular acidosis. Lancet 300: 998-999, 1972. Note: Originally Volume 2. [PubMed: 4116984] [Full Text: https://doi.org/10.1016/s0140-6736(72)92406-3]
Seedat, Y. K. Familial renal tubular acidosis. (Letter) Ann. Intern. Med. 69: 1329 only, 1968. [PubMed: 5725743]
Seldin, D. W., Wilson, J. D. Renal tubular acidosis.In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S. (eds.) : The Metabolic Basis of Inherited Disease. (3rd ed.) New York: McGraw-Hill (pub.) 1972. Pp. 1548-1566.