Understanding the genetic basis and inheritance patterns of Bartter Syndrome is crucial for proper diagnosis, treatment and genetic counselling. With a good grasp on the genes involved and their functions, along with the autosomal recessive inheritance pattern, I can offer a detailed explanation of how Bartter Syndrome is inherited and managed.
Keywords:
- The loop of Henle - a U-shaped section of the tubule that has a critical role in conducting urine within each nephron of the kidney
- Hypokalemia - potassium deficiency
- Alkalosis - excessive blood alkalinity
- Polyhydramnios - an increase in the amniotic fluid in pregnancy
- Hypochloremic alkalosis - an extreme lack of chloride
- Nephrocalcinosis - increased calcium levels in the kidneys
- Hyposthenuria - osmolality of the urine is increased
- Transient hyperkalemia - electrolyte abnormality
- Hypocalcemia - calcium levels in the blood are too low
- Hypercalcemia - calcium levels in the blood are too high
- Interstitum - contiguous fluid-filled space existing between a structural barrier
Introduction
Bartter syndrome is an inherited renal tubular disorder characterised by defective salt reabsorption in the thick ascending limb of the loop of Henle, leading to salt wasting, hypokalemia, and metabolic alkalosis.1 This condition is caused by mutations in the genes that are responsible for transporters and channels involved in salt reabsorption.1 While phenotypic identification remains crucial for suspecting Bartter syndrome, its rarity and limited genetic characterisation pose challenges for treatment. When it comes to other genetic disorders, such as dystrophinopathies, it was found that the importance of genetic understanding in medical diagnosis is accurate diagnosis, personalised treatment plans, prognosis, disease management, and genetic counselling.2
Overview of bartter syndrome
Before understanding the genetic basis and inheritance patterns of Bartter Syndrome, we first need to know the different types and what varies between them. There are five main subtypes of Bartter Syndrome.3
| Type | Gene | Function of genes | Affected Protein | Function of proteins | Clinical features and symptoms |
| Type 1 | SLC12A11 | Encodes for sodium-coupled electrolyte transporters1 | NKCC21 | A cotransporter that reabsorbs sodium, potassium, and chloride in the thick ascending limb of the loop of Henle | - Prematurity - Polyhydramnios - Hypochloremic alkalosis - Nephrocalcinosis - Hyposthenuria |
| Type 2 | KCNJ11 | Encodes for the ROMK channel (potassium channel)1 | ROMK1 | Recycles potassium ions back into the tubular lumen | - Prematurity - Polyhydramnios - Hypochloremic alkalosis - Nephrocalcinosis - Hyposthenuria - Transient - hyperkalemia |
| Type 3 | CLCNKB1 | Encodes for the CIC-Kb chloride channel1 | ClC-Kb1 | Facilitates chloride ions to exit from the cell into the interstitium | - Hypokalemia - Hypochloremic alkalosis |
| Type 4 | BSND1 and CLCNKA1 | BSND - encodes for the barttin protein1CLCNKA - encodes for CIC-Ka chloride channel1 | ClC-Ka1, ClC-Kb1 and Barttin protein | Barttin protein - vital for the chloride channels to function properly | - Prematurity - Polyhydramnios - Hypochloremic alkalosis - Serial deafness - Hypokalemia |
| Type 5 | CASR3 | Encodes for calcium-sensing receptors1 | CaSR3 | Regulates NKCC2 activity | - Hypocalcemia - Hypercalciuria |
Table 1: A table showing the different types of Bartter Syndrome, the genetic basis and the clinical features of each type
As well as this, the different types of Bartter Syndrome can manifest at various stages of life, such as Antenatal4 and Neonatal5 periods.
Inheritance patterns of bartter syndrome
In order to manage the condition, genetic counselling is needed. One purpose of genetic counselling is to understand the inheritance pattern of Bartter Syndrome. Bartter Syndrome follows the inheritance pattern, autosomal recessive inheritance. Autosomal recessive inheritance is a mode of inheritance in which two copies of a mutated gene from both parents are required for an individual to express the resulting trait.6 This is why it is common for siblings to have Bartter Syndrome, while it skips generations.7 Antenatal (before birth) Bartter Syndrome is an autosomal recessive renal tubular disorder.4 The resulting defective chloride transport in the loop of Henle can lead to premature delivery.4 Another purpose is to have a risk assessment and discuss family planning. It is important for individuals diagnosed to have conversations about their carrier status and the chances of passing down Bartter Syndrome.
Diagnosis and genetic testing
Once a clinical diagnosis is made, genetic testing is used to identify the type of Bartter Syndrome the patient has. Due to seven genes (namely, SCL12A1, KCNJ1, CLCNKA, CLCNKB, BSND, MAGED2, SLC12A3) being recognised as responsible for BS,8 genetic testing is typically performed using methods such as targeted gene panels, next-generation sequencing (NGS),8 or whole exome sequencing (WES). These techniques help identify mutations in the specific genes, enabling accurate diagnosis and classification of the different types of Bartter syndrome. Through genetic testing, personalised treatment for the patient can begin.
Summary
Bartter Syndrome is an inherited renal tubular condition that follows the inheritance pattern, autosomal recessive inheritance. The condition is caused by mutations in the genes SLC12A1, KCNJ1, CLCNKB, BSND, CLCNKA and CASR, which are crucial for salt reabsorption in the thick ascending limb of the loop of Henle. The symptoms of Bartter Syndrome include salt wasting, hypokalemia, metabolic alkalosis, and prematurity. Genetic testing plays a vital role in accurately diagnosing Bartter Syndrome and in determining how best to treat a patient.
References
- Cunha T da S, Heilberg IP. Bartter syndrome: causes, diagnosis, and treatment. Int J Nephrol Renovasc Dis [Internet]. 2018 Nov 9 [cited 2024 Jul 15];11:291–301. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233707/
- Ferlini A, Neri M, Gualandi F. The medical genetics of dystrophinopathies: Molecular genetic diagnosis and its impact on clinical practice. Neuromuscular Disorders [Internet]. 2013 Jan 1 [cited 2024 Jul 16];23(1):4–14. Available from: https://www.sciencedirect.com/science/article/pii/S0960896612006001
- Yousefichijan P, Dorreh F, Zamenjany MR. Bartter’s syndrome type 5; a case report. J Renal Inj Prev [Internet]. 2017 Jan 16 [cited 2024 Jul 16];6(4):244–6. Available from: https://journalrip.com/Article/JRIP_20170624154827
- Bhat YR, Vinayaka G, Sreelakshmi K. Antenatal bartter syndrome: a review. Int J Pediatr. 2012;2012:857136.
- Reinalter S, Devlieger H, Proesmans W. Neonatal Bartter syndrome: spontaneous resolution of all signs and symptoms. Pediatr Nephrol [Internet]. 1998 Apr 1 [cited 2024 Jul 16];12(3):186–8. Available from: https://doi.org/10.1007/s004670050433
- Goldstein DY, Prystowsky M. Autosomal recessive inheritance. Acad Pathol [Internet]. 2017 Jul 24 [cited 2024 Jul 16];4:2374289517691769. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528909/
- He M, Tang B ‐S., Li N, Mao X, Li J, Zhang J ‐G., et al. Using a combination of whole‐exome sequencing and homozygosity mapping to identify a novel mutation of SCARB2. Clinical Genetics [Internet]. 2014 Dec [cited 2024 Jul 16];86(6):598–600. Available from: https://onlinelibrary.wiley.com/doi/10.1111/cge.12338
- Palazzo V, Raglianti V, Landini S, Cirillo L, Errichiello C, Buti E, et al. Clinical and genetic characterisation of patients with bartter and gitelman syndrome. Int J Mol Sci [Internet]. 2022 May 18 [cited 2024 Jul 18];23(10):5641. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9144947/
