The portal for rare diseases and orphan drugs

Prevalence is unknown. Hereditary forms are more prevalent in areas of high consanguinity (Arabic peninsula and North Africa) whereas acquired dRTA has been reported more frequently in Western countries.

Disease onset can occur at any age, depending on cause. Hereditary forms include autosomal dominant (AD) and autosomal recessive (AR) dRTA. AR, less frequently AD, subtypes associated with hemolytic anemia and ovalocytosis, stomatocytosis or spherocytosis have also been described in Southeast Asia. AR forms are frequently diagnosed in infants and young children, AD dRTA mostly in adolescents and young adults. Patients with primary dRTA can be asymptomatic or present with polyuria, polydipsia, weakness, and fatigue (symptoms associated with hypokalemia). Failure to thrive, rickets, stunting of growth (in children) and osteomalacia or osteopenia (in adults) are a result of urinary calcium wastage and loss of calcium salts from the bones. Hypercalciuria, nephrolithiasis and nephrocalcinosis usually occur. Low plasma potassium levels in the classic form can also cause cardiac arrhythmias, paralysis and even death. In AR forms, bilateral sensorineural hearing loss (SNHL) may be present at diagnosis or appear later, following a progressive and irreversible course of highly variable severity.

AD dRTA, the most common dRTA, is usually due to mutations in the SLC4A1 gene (17q21.31). ATP6V1B1 (2p13) or ATP6V0A4 (7q34) mutations cause AR dRTA with or without SNHL. AR dRTA without or with late onset SNHL has been mainly described in patients with ATP6V0A4 mutations. These 3 genes explain 60-80% of primary dRTA. Other rare genetic causes are FOXI1 mutations causing dRTA associated with early hearing loss, and variants in WDR72, which have been described in milder dRTA. Acquired forms of dRTA are thought to be caused by autoimmune diseases or secondary to other conditions like sickle cell anemia, chronic obstructive uropathy, or post-renal transplantation.

The disease is characterized by hyperchloremic metabolic acidosis. The inability to lower urine pH below 5.5 and a positive urine anion gap during spontaneous metabolic acidosis are indicative of dRTA. Provocative tests for further diagnosis include the NH4Cl acidifying test and the furosemide test. Patients also show renal potassium wasting except in the hyperkalemic type. Extra-renal manifestations may facilitate the diagnosis, which can be confirmed by molecular genetic testing, preferably using a next-generation-sequencing-based panel for all potential causative genes.

Main differential diagnosis is proximal RTA along with other causes of chronic metabolic acidosis. A transient proximal tubular dysfunction associated with severe acidosis resembling incomplete Fanconi syndrome is commonly observed in infants with dRTA at diagnosis. Incomplete dRTA refers to an impaired ability to acidify the urine below 5.5 in the absence of overt metabolic acidosis and is diagnosed predominantly in adults with nephrocalcinosis, recurrent nephrolithiasis, osteopenia or hypocitraturia.

Prenatal diagnosis is possible where the pathogenic variants have previously been identified in a family member.

In families with AR dRTA, genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation), informing them that there is a 25% risk of having an affected child at each pregnancy. In AD dRTA, genetic counseling should be offered to affected individuals, informing them that there is a 50% risk of having an affected child at each pregnancy..

Alkali therapy, usually with sodium bicarbonate or sodium citrate, is the standard treatment (to achieve normal serum bicarbonate levels). Children require very high doses (4-8 meq/kg/day) as compared to adults (1-2 meq/kg/day). Potassium replacement, usually with potassium citrate, is necessary in hypokalemic patients. Hyperkalemic types require low dietary potassium intake and other therapies.

All forms of dRTA are chronic and may have significant effects on growth and development. With treatment, life expectancy is normal and renal failure uncommon but progressive chronic kidney disease is more often observed than expected in the long term, associated with non-adherence, recurrent kidney stones, and when nephrocalcinosis is very severe.