ATP6V1B1-related Distal Renal Tubular Acidosis and Sensorineural Hearing Loss

Introduction

ATP6V1B

ATP6V1B1-related Distal Renal Tubular Acidosis (dRTA) with Sensorineural Hearing Loss (SNHL) is a rare inherited condition that disrupts the body’s ability to maintain its acid-base balance and to preserve normal hearing. Symptoms usually begin early in life, often in infancy or early childhood, and can significantly affect growth, bone development, and kidney health. The underlying problem arises because the kidneys are unable to efficiently excrete acid, which leads to a persistent state of metabolic acidosis. Over time, this acid buildup interferes with growth and bone strength, while the same genetic defect also impairs the maintenance of normal pH levels in the inner ear, resulting in hearing loss that typically worsens with age.

This overview explains the genetics behind the disorder, its clinical presentation, diagnostic approaches, management strategies, and long-term outlook. The goal is to present information that is both accessible and scientifically reliable for patients, families, and healthcare professionals seeking a clear understanding of the condition.

Genetics and Molecular Basis

The ATP6V1B1 Gene and Its Function

The ATP6V1B1 gene is located on the short arm of chromosome 2, in the region known as 2p13.3. It encodes the B1 subunit of the vacuolar-type H⁺-ATPase (V-ATPase), a specialized proton pump that transports hydrogen ions across cell membranes. This pump is critical for maintaining proper pH balance both inside cells and in the fluids surrounding them.

In the kidneys, this pump operates in type A intercalated cells located in the collecting ducts, where it removes hydrogen ions from the blood and secretes them into the urine. This process acidifies the urine and prevents harmful acid accumulation in the bloodstream. In the inner ear, the same proton pump regulates the pH of cochlear fluids, which is necessary for the delicate sensory structures involved in hearing to function correctly. When the ATP6V1B1 gene is mutated, the proton pump’s activity is reduced or completely lost, leading to a dual effect: acid retention in the body and disrupted pH balance in the inner ear.

Inheritance Pattern

This disorder follows an autosomal recessive inheritance pattern. For a child to develop symptoms, both parents must pass down a copy of the mutated gene. Parents who each carry a single mutation typically show no symptoms themselves but have a 25 percent chance of having an affected child with each pregnancy.

Clinical Overview

Mechanism of Disease

The pathophysiology of this condition is well understood. When the proton pump in the kidneys does not function, acid accumulates in the bloodstream, leading to chronic metabolic acidosis. This acidic environment interferes with bone mineralization and growth in children, which explains why stunted growth and skeletal abnormalities are often among the first signs noticed. Similarly, in the inner ear, disrupted pH regulation damages the sensory hair cells and other structures within the cochlea, causing progressive sensorineural hearing loss that typically affects both ears.

Onset and Course

Symptoms generally appear during infancy or early childhood. If the condition is not recognized and treated promptly, complications such as growth failure, rickets in children, osteomalacia in adults, kidney stones, and progressive kidney dysfunction can occur. Hearing impairment usually becomes apparent in early childhood and progresses over time, underscoring the importance of early detection and auditory support.

Epidemiology

ATP6V1B1-related dRTA with SNHL is considered a very rare condition. Global data estimate its prevalence at approximately one in 600,000 individuals. The carrier frequency—individuals carrying one mutated copy of the gene without symptoms—is about one in 15,000. In regions where marriages between close relatives are more common, the prevalence is higher, as the likelihood of inheriting two mutated copies of the gene increases. Case reports and epidemiological data consistently show that most patients present in early childhood, reflecting the strong genetic basis and early onset of the disease.

Etiology

The root cause of this condition is the presence of mutations in both copies of the ATP6V1B1 gene. These mutations impair the assembly or function of the V-ATPase pump. When this pump is defective in the kidneys, the body cannot excrete acid effectively, leading to metabolic acidosis. In the cochlea, the same disruption interferes with the delicate acid-base balance required for normal auditory function. This explains why patients present with a combination of renal and auditory symptoms.

Symptoms

The clinical presentation is shaped by the effects of chronic metabolic acidosis and impaired inner ear function. Many infants and children fail to grow at a normal rate and may exhibit poor weight gain. Persistent vomiting, dehydration, and excessive urination often accompany the acid-base imbalance. Low potassium levels in the blood, or hypokalemia, are common and can lead to muscle weakness; in severe cases, transient paralysis has been reported.

Bone health is another major area of concern. In children, metabolic acidosis impairs bone mineralization, leading to rickets, a condition characterized by soft bones and bowed legs. Adults who are diagnosed later or inadequately treated may develop osteomalacia, which manifests as bone pain and an increased risk of fractures.

Kidney complications are frequent. Patients often develop nephrocalcinosis, the deposition of calcium in kidney tissues, or kidney stones, both of which can worsen kidney function over time.

Hearing loss is a consistent feature of this condition. The hearing impairment is sensorineural in nature, progressive, and usually bilateral. Imaging studies often reveal an enlarged vestibular aqueduct, a structural change in the inner ear observed in many affected individuals.

Testing and Diagnosis

Accurate diagnosis requires a combination of laboratory tests, functional assessments, imaging, and genetic analysis.

Blood and urine tests typically show metabolic acidosis with low blood pH, low serum potassium levels, elevated urine pH, and increased urinary calcium with reduced citrate levels. These findings point to an impaired ability of the kidneys to acidify urine. Functional testing, such as the furosemide and fludrocortisone challenge, can provide direct evidence of defective acid secretion, while the older ammonium chloride loading test is now less commonly used.

Imaging studies play an important role. Ultrasound or CT scans of the kidneys can identify nephrocalcinosis or kidney stones, while CT or MRI scans of the temporal bones often confirm the presence of an enlarged vestibular aqueduct.

Hearing is assessed through audiological tests. A standard audiogram evaluates hearing thresholds, while auditory brainstem response testing can assess the integrity of the auditory pathways, especially in younger children who may not cooperate with standard testing.

Genetic testing is the definitive method of confirming the diagnosis. Sequencing the ATP6V1B1 gene, along with related genes such as ATP6V0A4 and SLC4A1, identifies mutations responsible for the condition. Confirming a pathogenic variant not only supports diagnosis but also enables genetic counseling for families, allowing for informed decisions about future pregnancies and screening of relatives.

Treatment & Management

Management focuses on correcting acid-base imbalances, supporting growth and bone health, preserving kidney function, and addressing hearing loss.

Potassium citrate is the mainstay of treatment, particularly for correcting hypokalemia and reducing acid retention. Sodium bicarbonate is often added to optimize acid-base balance, with dosing carefully tailored to age and weight. Infants and children typically require 1.9 to 3.0 mEq/kg/day, while adults need slightly lower doses, around 1 to 2 mEq/kg/day.

Supportive care is equally important. Ensuring adequate hydration reduces the risk of kidney stone formation. For hearing loss, timely use of hearing aids or cochlear implants, combined with speech therapy, supports language development and quality of life. Ongoing monitoring through regular laboratory testing, imaging, and audiological follow-ups helps track disease progression and adjust therapy as needed.

Prognosis

With early diagnosis and consistent treatment, children can achieve normal growth and better bone health, and the risk of severe kidney complications can be reduced. However, delayed or inadequate treatment significantly increases the likelihood of progressing to chronic kidney disease, with studies indicating that 25 to 40 percent of patients reach stages III or IV of chronic kidney disease over time. Hearing loss, while manageable with supportive interventions, is irreversible and progressive, which is why early intervention and auditory rehabilitation are critical for optimal outcomes.

Helpful Terms

A gene is a segment of DNA that provides the instructions for producing proteins essential to bodily function. When a gene undergoes mutation, its instructions are altered, and the resulting protein may not function as intended, leading to disease. The ATP6V1B1 gene specifically encodes a protein vital for maintaining acid-base balance in the kidneys and inner ear. Autosomal recessive inheritance describes a pattern where an individual needs two copies of the mutated gene, one from each parent, to exhibit the condition. Distal Renal Tubular Acidosis (dRTA) refers to the failure of the kidneys to acidify urine effectively, while sensorineural hearing loss refers to hearing impairment resulting from damage to the inner ear or the auditory nerve. Genetic testing analyzes an individual’s DNA to identify mutations, providing a definitive diagnosis and guiding management.

References

• Giglio, S., Montini, G., Trepiccione, F. et al. Distal renal tubular acidosis: a systematic approach from diagnosis to treatment. J Nephrol 34, 2073–2083 (2021). https://doi.org/10.1007/s40620-021-01032-y
• Mohebbi, N., Wagner, C.A. Pathophysiology, diagnosis and treatment of inherited distal renal tubular acidosis. J Nephrol 31, 511–522 (2018). https://doi.org/10.1007/s40620-017-0447-1
• Watanabe, T. (2018). Improving outcomes for patients with distal renal tubular acidosis: recent advances and challenges ahead. Pediatric Health, Medicine and Therapeutics, 9, 181–190. https://doi.org/10.2147/PHMT.S174459
• Almomani, Ensaf, et al. ‘Intercalated Cells: More than pH Regulation’. Diseases, vol. 2, no. 2, Apr. 2014, pp. 71–92. DOI.org (Crossref), https://doi.org/10.3390/diseases2020071.
• Pyeritz, Reed E. ‘Renal Tubular Disorders’. Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics, Elsevier, 2023, pp. 115–24. DOI.org (Crossref), https://doi.org/10.1016/B978-0-12-812534-2.00011-4.
• Perez G, Barber GP, Benet-Pages A, Casper J, Clawson H, Diekhans M, Fischer C, Gonzalez JN, Hinrichs AS, Lee CM, Nassar LR, Raney BJ, Speir ML, van Baren MJ, Vaske CJ, Haussler D, Kent WJ, Haeussler M. The UCSC Genome Browser database: 2025 update. Nucleic Acids Res. 2025 Jan 6;53(D1):D1243-D1249. doi: 10.1093/nar/gkae974. PMID: 39460617; PMCID: PMC11701590.