Renal tubular acidosis with deafness

Other Names: Renal tubular acidosis, distal, with progressive nerve deafness; Autosomal recessive distal renal tubular acidosis with deafness; AR dRTA with hearing loss; AR dRTA wth deafness; Autosomal recessive distal renal tubular acidosis with hearing loss; Renal tubular acidosis type 1b; Renal tubular acidosis progressive nerve deafness; RTA with progressive nerve deafness; Renal tubular acidosis with progressive nerve deafness; Renal tubular acidosis, autosomal recessive, with progressive nerve deafness

Renal tubular acidosis with deafness is characterized by kidney (renal) problems and sensorineural hearing loss. The kidneys normally filter fluid and waste products from the body and remove them in urine; however, in people with this disorder, the kidneys do not remove enough acidic compounds from the body. Instead, the acids are absorbed back into the bloodstream, and the blood becomes too acidic. This chemical imbalance, called metabolic acidosis, can result in a range of signs and symptoms that vary in severity.

Epidemiology

Renal tubular acidosis with deafness is a rare disorder; its prevalence is unknown.

Cause

Renal tubular acidosis with deafness is caused by mutations in the ATP6V1B1 or ATP6V0A4 gene. These genes provide instructions for making proteins that are parts (subunits) of a large protein complex known as vacuolar H+-ATPase (V-ATPase). V-ATPases are a group of similar complexes that act as pumps to move positively charged hydrogen atoms (protons) across membranes. Because acids are substances that can "donate" protons to other molecules, this movement of protons helps regulate the relative acidity (pH) of cells and their surrounding environment. Tight control of pH is necessary for most biological reactions to proceed properly.

The V-ATPase that includes subunits produced from the ATP6V1B1 and ATP6V0A4 genes is found in the inner ear and in nephrons, which are the functional structures within the kidneys. Each nephron consists of two parts: a renal corpuscle (also known as a glomerulus) that filters the blood, and a renal tubule that reabsorbs substances that are needed and eliminates unneeded substances in urine. The V-ATPase is involved in regulating the amount of acid that is removed from the blood into the urine, and also in maintaining the proper pH of the fluid in the inner ear (endolymph).

Mutations in the ATP6V1B1 or ATP6V0A4 gene impair the function of the V-ATPase complex and reduce the body's capability to control the pH of the blood and the fluid in the inner ear, resulting in the signs and symptoms of renal tubular acidosis with deafness.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Metabolic acidosis often causes nausea, vomiting, and dehydration; affected infants tend to have problems feeding and gaining weight (failure to thrive). Most children and adults with renal tubular acidosis with deafness have short stature, and many develop kidney stones.

The metabolic acidosis that occurs in renal tubular acidosis with deafness may also lead to softening and weakening of the bones, called rickets in children and osteomalacia in adults. This bone disorder is characterized by bone pain, bowed legs, and difficulty walking. Rarely, people with renal tubular acidosis with deafness have episodes of hypokalemic paralysis, a condition that causes extreme muscle weakness associated with low levels of potassium in the blood (hypokalemia).

In people with renal tubular acidosis with deafness, hearing loss caused by changes in the inner ear (sensorineural hearing loss) usually begins between childhood and young adulthood, and gradually gets worse. An inner ear abnormality affecting both ears occurs in most people with this disorder. This feature, which is called enlarged vestibular aqueduct, can be seen with medical imaging. The vestibular aqueduct is a bony canal that runs from the inner ear into the temporal bone of the skull and toward the brain. The relationship between enlarged vestibular aqueduct and hearing loss is unclear. In renal tubular acidosis with deafness, enlarged vestibular aqueduct typically occurs in individuals whose hearing loss begins in childhood.

Diagnosis

Hereditary dRTA should be suspected in individuals with the following clinical, laboratory, and radiographic features.

Clinical features

• Failure to thrive in childhood
• Sensorineural hearing loss
• Symptoms of hypokalemia, including muscle weakness and muscle cramps
• Bone manifestations (10%-23%): osteomalacia in adults, rickets in children, fractures, bone pain
• Exclusion of secondary causes of dRTA (e.g., autoimmune, drug induced)

\ Laboratory features

• Hyperchloremic non-anion gap metabolic acidosis in the absence of GI losses
• Hypokalemia (blood potassium level <3.5 mEq/L)
• Hypobicarbonatemia (blood bicarbonate levels below 20 mEq/L in infants and 22 mEq/L in older children), but with normal fractional excretion of bicarbonate
• Inappropriately elevated urine pH (>5.3) in the absence of gastrointestinal bicarbonate losses
• Absence of a negative urine anion gap (UAG) in an individual with metabolic acidosis. Calculation of the UAG (UAG=[Na+]U+[K+]U- [Cl-]U) can help to distinguish between primary forms of proximal and dRTA.
• Elevated urine calcium
• Decreased urine citrate
• Failure to acidify the urine (urine pH always >5.3):
• After an ammonium chloride challenge (100 mg/kg) [Wrong & Davies 1959]; OR
• When increased distal delivery of sodium is induced, via the co-administration of a mineralocorticoid (e.g., fludrocortisone 0.02 mg/kg) and furosemide (0.5 mg/kg) ; OR
• In an individual who presents with spontaneous acidosis

Imaging features Renal ultrasound. Nephrocalcinosis is almost universal; nephrolithiasis is less common, but does occur. Medullary cysts may be detected, typically in later childhood or in adults.

Plain radiographs of the bones may show rachitic changes.

Bone densitometry examination may show decreased bone density in children and adults [Besouw et al 2017]. CT examination of the inner ear may demonstrate dilation of the vestibular aqueduct in individuals with hereditary dRTA associated with hearing loss. Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Treatment

The goal of treatment is to correct the metabolic acidosis and hypokalemia. Maintaining bicarbonate and potassium in the normal range decreases the likelihood of acute symptoms and decreases the severity of long-term complications (e.g., poor growth, nephrocalcinosis, osteomalacia, decreased GFR).

Standard of care in dRTA is oral alkaline therapy, usually in the form of a bicarbonate and/or citrate salt . As these salts have a short half-life, they should be taken repeatedly throughout the day and night to maintain normal blood pH. The alkali salt is usually potassium given that hypokalemia is commonly associated, although some individuals may receive some sodium alkali preparations.

Other individuals require potassium chloride as an additional source of potassium. The alkali requirement is highest in infants (>8 mEq/kg/day of alkali in some individuals) but decreases to approximately 1 mEq/kg/day in adults. Dosing is ideally every six hours, although practical considerations may lead clinicians and affected individuals to adapt dosing to accommodate sleep, work, and school schedules. Sodium salts should be avoided due to their contribution to worsening hypercalciuria.

Note: (1) Compensated metabolic acidosis (normal pH but low bicarbonate) is not sufficient to facilitate growth. (2) Alkali and citrate supplementation prevent the progression of nephrocalcinosis, but do not reverse it. (3) Treatment decreases the risk of developing urolithiasis.

Growth retardation is corrected with appropriate alkali treatment. In most cohort studies, growth with treatment is within normal range, but still below average.

Skeletal manifestations. Alkali treatment has been shown to improve bone mineral density in individuals of Thai descent .

Sensorineural hearing loss. Correction of metabolic acidosis does not correct hypoacusia, which should be treated according to standard procedures.

NIH genetic and rare disease info

• NIH info on Renal tubular acidosis with deafness

Renal tubular acidosis with deafness is a rare disease.

Renal tubular acidosis with deafness Resources
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