Panel testing recommended at Breda Genetics for this condition:
Bartter syndrome (BSND, CASR, CLCNKA, CLCNKB, KCNJ1, MAGED2, SLC12A1, SLC12A3)
Summary
Bartter syndrome (whose name derives from the endocrinologist who discovered it in 1962) includes a group of rare kidney diseases that belong to the class of primitive tubulopathies or salt-losing tubulopathies. These diseases are due to an impaired ability to reabsorb electrolytes such as sodium, potassium and chloride in the ascending tract of the loop of Henle. This causes the activation of the renin-angiotensin system which leads to the onset of hypokalemic and hypochloraemic metabolic alkalosis. There are 5 different clinical forms of Bartter syndrome, due to mutations in different genes, which have a heterogeneous clinical manifestation from the point of view of the age of onset, progression and severity. Inheritance is autosomal recessive or X-linked recessive. There is no definitive cure for this condition, but treatment consists of an attempt to rebalance electrolyte imbalances through drugs such as NSAIDs, potassium-sparing diuretics, and mineral supplements.
Detailed clinical description
Bartter syndrome (BS) is characterized by a high degree of phenotypic variability, due both to the presence of different clinical forms (depending on the underlying genetic defect) and to the variability between individuals with the same pathological subtype. In general, the hallmarks of Bartter syndrome include polyuria, hypokalemia, hypochloraemic metabolic alkalosis, normotensive hyperreninemic hyperaldosteronism. Due to electrolyte imbalance, patients may experience hypovolaemia and low blood pressure. Furthermore, the inability to retain sodium, potassium and chloride can cause the appearance of muscle symptoms such as spasms, contractures, cramps, weakness. Finally, polydipsia, vomiting, and poor growth may be present.
Initially, the various types of BS were divided on the basis of the age of onset and phenotypic severity; however, over the years it has been realized that each subtype can manifest itself with variable severity and unpredictable course. For this reason, classification on the basis of the genetic defect of origin is preferred.
Bartter syndrome type 1 This subtype is one of the most severe forms of the disease, usually has an onset in the prenatal period and manifests itself with poor intrauterine growth, polyhydramnios and premature birth. Symptoms at birth include poor growth, salt loss, increased prostaglandin E levels, and hypokalaemic metabolic alkalosis. A common sign is the presence of hypercalciuria which can cause nephrocalcinosis.
Bartter syndrome type 2 Also this subtype, very similar to BS type 1, usually has onset in the prenatal period, although several patients have been described with a later onset and a milder phenotype. In this case, hypokalaemia is milder than type I BS and transient hyperkalaemia can be observed in the first days of life.
Bartter syndrome type 3 This subtype is defined as “classic BS”, it is the most frequent subtype and usually with a milder phenotype, although it includes a very broad phenotypic spectrum ranging from antenatal onset to late onset (Gitelman-like). The main symptoms are hypokalaemia, polyuria, polydipsia, loss of salts in the urine and poor growth. Compared to the first two forms, polyhydramnios and nephrocalcinosis are rarer, while hypochloremia is much more severe. Additionally, some patients experience hypomagnesaemia.
Bartter syndrome type 4a and 4b These subtypes are usually quite severe with prenatal onset manifesting as polyhydramnios. Growth retardation, poor response to treatment and in some cases renal failure are also present. These patients also have sensorineural hearing loss.
Bartter syndrome, type 5, antenatal, transient (BS type 5) This is a prenatal onset form of BS with polyhydramnios, polyuria, and increased intrauterine growth, but resolves spontaneously at birth or in the first months of life.
A noteworthy exception is autosomal dominant hypocalcemia with Bartter syndrome. This condition, which does not fall directly into the subtypes of BS, causes hypocalcemia, hypercalciuria and salt loss. Hypokalaemia, metabolic alkalosis with hypereninemia and hyperaldosteronism are also often found, all of which are attributable to BS.
Diagnosis is mainly based on the identification of characteristic clinical signs and the exclusion of other pathogenic causes. In particular, it is recommended, from a biochemical point of view, to carry out laboratory tests to evaluate the levels of serum and urinary electrolytes (such as sodium, potassium and chloride) and of other substances such as renin, aldosterone and prostaglandin E. Genetic testing is always recommended to confirm the diagnosis.
Prevalence
BS is a rare condition, with an estimated prevalence of around 1/1,000,000.
Molecular genetics
BS is a recessively inherited disease (autosomal or X-linked) due to mutations in genes encoding salt membrane transporters.
Type 1 BS is due to bi-allelic mutations in the SLC12A1 gene, which encodes the sodium-potassium-chloride co-transporter NKCC2. Mutations are primarily loss-of-function and include missense, nonsense, splice mutations, and small deletions/duplications; large intragenic deletions have also rarely been reported.
Type 2 BS is an autosomal recessive condition due to mutations in the KCNJ1 gene, which encodes the ROMK potassium channel. Also in this case, the mutations are loss-of-function and mainly include missense and nonsense clustered in exon 2, which encodes an important protein domain.
Type 3 BS is due to mutations in the CLCNKB gene, which encodes for variant b of the basolateral chloride channel. In this case, the mutations are predominantly missense, although nonsense, frameshift and splice mutations have been reported. Furthermore, large rearrangements (such as multiexonic deletions) are particularly frequent in this gene. Although there is no clear genotype-phenotype correlation, it seems that patients with a large deletion have an earlier onset of the disease.
BS type 4 is due to recessive digenic mutations in the CLCNKA and CLCNKB genes (BS type 4b), which encode respectively for variants a and b of two voltage-dependent chloride channels, or to monogenic mutations in BSND, which encodes for a regulatory protein of these channels.
Type 5 BS is an X-linked recessive disease due to loss-of-function mutations in the MAGED2 gene. MAGED2 encodes the melanoma-associated D2 antigen, a protein that interacts with NKCC2 and increases its expression on the cell surface and its activity.
Autosomal dominant hypocalcemia with Bartter syndrome is an autosomal dominant inherited disease, due to gain-of-function mutations in CASR, which encodes a calcium receptor.
According to the recommendations issued by the European Rare Kidney Disease Reference Network Working Group for tubulopathies, in case there is a suspicion of BS, it is important to include in the genetic test in addition to the SLC12A1, KCNJ1, CLCNKB, CLCNKA, BSND, MAGED2 and CASR , also the genes for differential diagnosis SLC12A3, KCNJ10, SLC26A3, SCNN1A, SCNN1B, SCNN1G, CLDN10, NR3C2, HSD11B2, CYP11B1, CLCN2, KCNJ5 and CACNA1H.
Differential diagnosis
Gitelman syndrome Gitelman syndrome (GS) is a salt-losing primary tubulopathy, whose phenotype is very similar and often indistinguishable from type 3 BS. It is in fact characterized by hypokalaemia, metabolic alkalosis, hypocalciuria and hypomegnesemia. It is an autosomal recessive condition due to mutations in the SLC12A3 gene. One of the main differences between GS and BS is the age of onset, as GS generally has a later onset (after 6 years, up to adulthood). Another difference between the two syndromes consists in the fact that in GS the values ​​of urinary calcium measurement in 24 hours or the urinary Ca/creatinine ratio are low, while in BS they are high or normal. The definitive distinction is made through genetic testing.
Congenital secretory chloride diarrhea Autosomal recessive disease characterized by congenital watery diarrhea with high levels of chloride, which causes dehydration, hypokalaemia and metabolic alkalosis, but in which calcium levels are not altered. It is due to biallelic mutations in the SLC26A3 gene.
Cystic Fibrosis Some patients with cystic fibrosis may have a BS-like manifestation characterized by hypokalemic hypochloraemic alkalosis, due to the loss of salts through sweat. The gene associated with cystic fibrosis is CFTR.
EAST syndrome This is a rare autosomal recessive disease due to mutations in the KCNJ10 gene characterized by early onset epilepsy, congenital sensorineural hearing loss, ataxia and salt-losing tubulopathy.
Infantile hypertrophic pyloric stenosis A condition characterized by vomiting, loss of gastric acids which in turn causes hypochloremia and secondary aldosteronism which results in hypokalaemia. The resulting phenotype is that of a pseudo-BS syndrome.
Pseudo-Bartter Syndrome This is not a real disease, but includes a group of conditions that cause a BS-like phenotype in the absence of a primary hereditary tubulopathy. The causes can be eating disorders, cyclic vomiting, use and/or abuse of certain drugs such as diuretics.
Hereditary defects of the proximal tubule, pathologies that due to the failure of the reabsorption at the level of the proximal tubule can cause electrolyte imbalances and symptoms similar to BS. However, these diseases can have a systemic presentation and affect also other organs. These include cystinosis (CTNS gene) and Dent disease, an X-linked recessive disorder that primarily affects the kidneys, due to mutations in the CLCN5 and OCRL genes.
Genetic testing strategy
The first level of diagnosis, in the case of suspicion of Bartter syndrome, consists of carrying out biochemical tests to evaluate the electrolyte profile, in particular sodium, potassium, chloride, calcium and magnesium. For confirmation of the diagnosis from a molecular point of view, the analysis of a multigene next generation sequencing panel is the most suitable choice. Panel analysis can be performed successfully on the basis of exome or genome sequencing. Solutions based on whole genome sequencing also allow for the screening of copy number variations (CNVs), i.e. large deletions and large duplications on the entire genome. In the event of a negative result, it is advisable to carry out the testing for large deletions/duplications through techniques such as MLPA and qPCR.
Panel testing recommended at Breda Genetics for this condition:
Bartter syndrome (BSND, CASR, CLCNKA, CLCNKB, KCNJ1, MAGED2, SLC12A1, SLC12A3)
References
Konrad M, Nijenhuis T, Ariceta G, Bertholet-Thomas A, Calo LA, Capasso G, Emma F, Schlingmann KP, Singh M, Trepiccione F, Walsh SB, Whitton K, Vargas-Poussou R, Bockenhauer D. Diagnosis and management of Bartter syndrome: executive summary of the consensus and recommendations from the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders. Kidney Int. 2021 Feb;99(2):324-335. doi: 10.1016/j.kint.2020.10.035. PMID: 33509356.
Cunha TDS, Heilberg IP. Bartter syndrome: causes, diagnosis, and treatment. Int J Nephrol Renovasc Dis. 2018 Nov 9;11:291-301. doi: 10.2147/IJNRD.S155397. PMID: 30519073.
Bamgbola OF, Ahmed Y. Differential diagnosis of perinatal Bartter, Bartter and Gitelman syndromes. Clin Kidney J. 2020 Oct 25;14(1):36-48. doi: 10.1093/ckj/sfaa172. Erratum in: Clin Kidney J. 2021 Jan 09;14(4):1296. PMID: 33564404
Mrad FCC, Soares SBM, de Menezes Silva LAW, Dos Anjos Menezes PV, Simões-E-Silva AC. Bartter’s syndrome: clinical findings, genetic causes and therapeutic approach. World J Pediatr. 2021 Feb;17(1):31-39. doi: 10.1007/s12519-020-00370-4. Epub 2020 Jun 1. PMID: 32488762.
