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  • 总部: 泰国曼谷市巴吞汪区仑披尼分区 普勒吉路齐隆巷5号.
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Alternative titles; symbolsRTADRThe maintenance of body fluid pH within a narrow range is critical for a wide variety of essential biochemical and metabolic func...

Alternative titles; symbols


The maintenance of body fluid pH within a narrow range is critical for a wide variety of essential biochemical and metabolic functions. The kidney plays a key role in this homeostasis under normal circumstances, owing to its ability to vary bicarbonate reclamation and net acid excretion over a wide range. In the renal tubular acidoses (RTAs), however, acid-base balance becomes deranged either because of inability to secrete acid in the distal nephron or because of proximal bicarbonate loss (267200). Primary distal RTA is characterized by the failure of the kidney to produce an appropriately acid urine in the presence of systemic metabolic acidosis or after acid loading, due to failure of hydrogen ion secretion or bicarbonate reabsorption in the distal nephron. This results in hyperchloremic metabolic acidosis of varying severity. The condition is usually accompanied by nephrocalcinosis or nephrolithiasis. Other findings include hypokalemia and normal serum calcium and phosphate levels, although osteomalacia or rickets may supervene in untreated cases. Alkali replacement serves to reverse most of the biochemical abnormalities. Both autosomal dominant (see 179800) and autosomal recessive patterns have been observed in kindreds with primary distal RTA, and the spectrum of clinical severity is wide. Some patients with autosomal dominant distal RTA remain asymptomatic until adolescence or adulthood, whereas others, and those with recessive disease, may be severely affected in infancy, with impaired growth and early nephrocalcinosis causing eventual renal insufficiency.

Seedat (1964) reported a family with 8 affected members in 4 generations. The proband was born of first-cousin parents. In another first-cousin marriage, 4 of his half sibs were affected. Kuhlencordt et al. (1967) observed affected monozygotic twins whose parents were first cousins.

Karet et al. (1998) assembled information on 26 kindreds with primary distal RTA. Autosomal recessive inheritance was found in at least 17 kindreds; affected individuals were offspring of consanguineous unions in 14 of these families and there were 2 or more affected sibs of unaffected parents in the other 3. Among the recessive kindreds, 19 of the 25 patients were diagnosed at 1 year of age or less, and the remainder presented at 6 years or younger. All index cases presented either acutely with vomiting and dehydration, or with failure to thrive, or delayed growth. Younger affected sibs were often diagnosed prospectively. All patients with recessive disease were found to have nephrocalcinosis, nephrolithiasis, or both, and several had rickets. Nine of these patients from 6 families also had bilateral sensorineural deafness confirmed by audiometry.

Vargas-Poussou et al. (2006) found that 9 of 23 patients with DRTA3 had sensorineural hearing loss. Age at onset was unknown in 2 patients; in the other 7 patients, hearing loss was detected between the ages of 2 months and 10 years. Only 1 of 2 affected sibs in family 10 had hearing loss, indicating that intrafamilial variability of hearing loss can occur. Additionally, 12 of the patients were younger than 10 years and could yet develop hearing loss.

▼ Mapping
Karet et al. (1999) performed genomewide linkage analysis in 13 kindreds with recessive dRTA and found evidence for linkage with locus heterogeneity to a segment of 7q33-q34; a maximum multipoint lod score of 8.84 with this region was obtained with 68% of kindreds linked. That 4 of these 13 kindreds did not support linkage to 7q33-q34 or to chromosome 2 (see dRTA with progressive nerve deafness, 267300) implied the existence of at least 1 additional distal RTA locus.

▼ Molecular Genetics
In 8 of 9 renal tubular acidosis kindreds with normal audiometry linked to the ATP6N1B locus, Smith et al. (2000) identified homozygous mutations in the ATP6N1B gene (605239.0001-605239.0008). These included nonsense, deletion, and splice site changes, all of which were predicted to truncate the protein. The findings identified a new kidney-specific proton pump 116-kD accessory subunit that is highly expressed in proton-secreting cells in the distal nephron, and illustrated its essential role in normal vectorial acid transport into the urine by the kidney.

In 12 new kindreds with autosomal recessive dRTA and 11 sporadic cases, Stover et al. (2002) identified 19 ATP6V0A4 mutations in 23 patients. Several of these patients, including 1 with a previously identified splice site mutation (605239.0003) and 2 with missense mutations (605239.0009-605239.0010), were found to have developed later onset of hearing loss than occurs in dRTA families with progressive sensorineural hearing loss and mutation in the ATP6V1B1 gene (192132). Review of a previously studied ATP6V0A4 cohort revealed 1 patient who had developed mild sensorineural hearing loss at the age of 22 years. Stover et al. (2002) also found ATP6V0A4 expression within the cochlea of both fetal and adult tissue specimens. Another 4 dRTA families (2 with normal audiometry, 1 with sensorineural hearing loss, and 1 of unknown hearing status) were not linked to ATP6V0A4 or ATP6V1B1, providing further evidence for additional genetic heterogeneity in dRTA. The discovery of late-onset sensorineural hearing loss in some cases of autosomal recessive dRTA, as well as the demonstration that ATP6V0A4 is expressed within the cochlea, suggested that RTA with or without sensorineural hearing loss is the same disorder.

Vargas-Poussou et al. (2006) screened 39 new kindreds with recessive dRTA for mutations in the ATP6V0A4 and ATP6V1B1 genes. Fourteen new and 5 recurrent mutations in the ATP6V0A4 gene were identified in 21 families. Two new and 2 recurrent mutations were detected in the ATP6V1B1 gene in 10 families. No mutation was detected in 8 families. Loss-of-function mutations were found in a total of 31 families, with a global detection rate of 79.5%. Mutations in the ATP6V0A4 gene were twice as frequent as mutations in the ATP6V1B1 gene. The authors noted that this finding conflicts with previous studies, in which mutations in the ATP6V1B1 gene were more frequent than mutations in the ATP6V0A4 gene. Vargas-Poussou et al. (2006) found early-onset hearing loss in 70% of patients with ATP6V1B1 mutations and 39% of patients with ATP6V0A4 mutations (see, e.g., 605239.0011). The authors concluded that a genetic screening strategy based on early-onset hearing loss would be misleading and is not recommended.

Exclusion Studies

Karet et al. (1998) analyzed the SLC4A2 gene (109280) in 17 families with autosomal recessive distal RTA but found no mutations.

Tags: 7q34