I.Randi's Bartter syndrome

Generality

Bartter syndrome is a rare disease characterized by impaired sodium, chlorine and potassium reabsorption in the loop of Henle .

This disease owes its name to the American endocrinologist who discovered it: Frederic Crosby Bartter. The annual incidence was estimated at 1 / 830, 000.

There are several variants of Bartter's syndrome whose transmission, although still autosomal, can vary from recessive to dominant depending on the case.

If not timely diagnosed and treated, Bartter's syndrome can severely affect the patient's development, growth and quality of life. Furthermore, in particularly serious cases, life expectancy is considerably reduced.

Please note

Bartter syndrome should NOT be confused with Schwartz-Bartter syndrome, a disease characterized by an altered antiduiretic hormone secretion (ADH), also known as the syndrome of inappropriate ADH secretion (SIADH).

What is that

What is Bartter Syndrome?

Bartter's syndrome is a rare disease in which there is a reduced reabsorption of chlorine, sodium and potassium at the level of the ascending branch of the loop of Henle, ie in that area responsible for the reabsorption of solutes such as ions sodium, chlorine and potassium.

The disease can be either autosomal recessive or autosomal dominant, depending on the variant considered. In fact, at present, five genetic variants of Bartter's syndrome have been identified. More in detail, four of the variants are transmitted in an autosomal recessive manner, while one is transmitted in an autosomal dominant manner.

Depending on the variant transmitted, the patient may experience Bartter's syndrome at prenatal age, either immediately after birth or in early childhood.

Causes

What are the Causes of Bartter Syndrome?

The altered reabsorption of mineral salts that occurs at the level of the loop of Henle is due to an alteration of the synthesis of some channel receptors / transporters (particular proteins that carry ions of different nature) located in this area of ​​the kidney. This phenomenon is caused by a series of genetic mutations affecting the genes encoding the aforementioned particular proteins.

Depending on the affected gene, the different variants of Bartter's syndrome are distinguished. More detailed information on this can be found in the following chapter.

variants

What are the Variations of Bartter Syndrome?

As mentioned, several variants of Bartter's syndrome have been identified that differ in the type of mutated gene, consequently, for the type of channel / transporter involved in the altered reabsorption of mineral salts at the renal level.

The following table will then report the different variants of the syndrome, the mutated genes involved, the proteins (channel receptors / transporters) for which they encode and the clinical presentation of the variant in question.

As can be seen from the table, despite the presence of five genetic variants, it is not possible to distinguish as many clinical forms; in fact only four are distinguished: prenatal or infantile Bartter syndrome (type I and II), classic Bartter's syndrome (type III), prenatal or infantile Bartter's syndrome associated with sensorineural deafness (type IV A and IV B; some sources, however, they group these variants together with types I and II) and, finally, Bartter's syndrome with hypocalcemia (type V).

Did you know that ...

Given the existence of a variant IV (or IV A) and an IV B variant of Bartter's syndrome, some sources consider, on the whole, six variants of Bartter's syndrome. Other sources, on the other hand, consider the IV B variant as a subtype of the IV variant and, for this reason, contemplate the existence of only five genetic variants of Bartter's syndrome.

The type I, II, III, IV and IV B variants are diseases with autosomal recessive transmission, this means that to manifest the syndrome, the individual must possess both mutated alleles inheriting them from the parents who, therefore, will be healthy carriers. The V variant of the syndrome, on the other hand, is an autosomal dominant transmission disease, which means that to manifest the symptoms, it is sufficient that the patient possesses a single mutated allele which, therefore, can also be inherited by only one (also sick ) of the two parents.

Bartter's pseudo-syndrome

Bartter's pseudo-syndrome is a condition characterized by symptoms similar to those induced by Bartter's syndrome but whose cause is to be found in the abuse of diuretic drugs such as furosemide .

Gitelman syndrome

This syndrome is caused by a localized mutation on the SLC12A3 gene that codes for the sodium-chlorine transporter (NCC). Because of this mutation - transmitted in an autosomal recessive manner - the patient undergoes an impairment of sodium, chlorine and potassium reabsorption in the distal convoluted tubule, unlike Bartter's syndrome in which the resorption impairment is localized in the loop of Henle. However, Gitelman syndrome can give rise to symptoms similar to Bartter's syndrome, so in clinical practice it can sometimes be difficult to distinguish the two diseases.

Manifestations and Symptoms

Manifestations and Symptoms Induced by Bartter Syndrome

Symptoms of Bartter's syndrome can occur at prenatal, neonatal or early childhood, depending on the variant affecting the patient. In any case, the syndrome tends to manifest itself immediately and not later than the period of childhood.

When Bartter's syndrome occurs in the prenatal period, it is possible to undergo reduced development and premature birth . Children with Bartter syndrome may experience reduced growth after birth and an intellectual disability .

Due to the compromised renal salt reabsorption, Bartter syndrome causes hypokalaemia, hypochloraemia and metabolic alkalosis which can be associated with hyperreninemia (high blood renin) and hyperaldosteronism . Clearly, all these conditions can, in turn, give rise to a series of symptoms that can compromise the patient's quality of life (for example, nausea, vomiting, dizziness, weakness, headache, hypotension, etc.).

In addition to what has been said so far, each variant can give rise to specific manifestations and symptoms closely related to the mutated gene and to the consequent involvement of the canal or the transporter for which this gene encodes. Therefore, the typical symptoms and manifestations associated with each of the five different forms of Bartter syndrome will be briefly described below.

Bartter syndrome type I

In type I Bartter syndrome, mutations affect the gene encoding the sodium-potassium-chlorine transporter on the loop of Henle. Due to the compromised resorption, hypovolemia occurs due to loss of salts . At the same time, since calcium reabsorption is also linked to the activity of the aforementioned transporter, hypercalciuria appears. All this can lead to the onset of nephrocalcinosis . It is also possible to experience hypermagnesia . In the prenatal period polydramnios may develop secondary to fetal polyuria .

Bartter syndrome type II

Type II Bartter syndrome is caused by a mutation in the gene that codes for the adrenal medullary potassium channel. Manifestations and symptoms are similar to those of variant I and even in this case polydramnios can be found secondary to fetal polyuria . However, at an early stage, the newborn may exhibit a transient hyperkalemic metabolic acidosis . This condition then evolves towards the characteristic clinical picture of Bartter's syndrome.

Type III Bartter syndrome

Also known as classical Bartter's syndrome, the III variant of the disease is caused by mutations in the gene encoding the Kb-type chlorine channel. Since in this form the Ka-type chlorine channels are preserved, the symptomatology tends to to be lighter, though still present. Generally, there is no nephrocalcinosis.

Bartter syndrome type IV and IV B

In both types of variant IV there is the involvement of genes implicated in the correct synthesis of the Ka and Kb chlorine channels. Since both channels are compromised, the symptomatology tends to be more severe than in the case of variant III of the syndrome . Newborns may initially show a clinical picture that mimics hypoaldosteronism but then evolves towards hypokalemic metabolic alkalosis when the body tries to compensate for the lack of activity of the aforementioned calcium channels. Characteristic of the IV and IV B variants of Bartter's syndrome is the appearance of sensorineural deafness .

Type V Bartter syndrome

The V variant of Bartter syndrome is caused by a mutation that affects the gene encoding the receptor sensitive to calcium, implicated in the inhibition of water reabsorption and of different ions, such as calcium, potassium and sodium. The altered functioning of this receptor leads to the appearance of hypocalcemia and consequent hypercalciuria associated with the characteristic symptoms of Bartter's syndrome.

Did you know that ...

The variants I, II, IV and IV B of Bartter's syndrome - as well as the name of prenatal Bartter's syndrome - are sometimes also referred to as the hypeprostaglandin E2 syndrome, as they are characterized by an increase in plasma levels of this prostaglandin.

Diagnosis

How is Bartter Syndrome Diagnosed?

The diagnosis of Bartter's syndrome is made on the basis of the patient's clinical picture and on the execution of specific tests - of blood and urine - aimed at identifying the presence and concentration of electrolytes (sodium, potassium, chloride, magnesium, bicarbonate, calcium) and specific substances (renin and aldosterone) at plasmatic and / or urinary level.

However, definitive diagnosis is only possible with specific genetic tests .

The differential diagnosis, on the other hand, must be placed against Bartter's pseudo-syndrome, Gitelman's syndrome, cystic fibrosis and celiac disease.

In cases where there is a certain risk (for example, healthy and / or sick carrier parents) that the newborn can manifest the disease, prenatal diagnosis is also possible.

Care and Treatment

Are There Cures and Treatments Against Bartter Syndrome?

Unfortunately, since it is a disease whose causes lie in a genetic mutation, at the moment there are no definitive cures able to definitively resolve Bartter's syndrome. The therapies put into practice, therefore, are generally symptomatological and aim to restore, as far as possible, the normal conditions and physiological levels of salts that are not efficiently reabsorbed by the kidney.

More in detail, currently, the pharmacological treatment involves the administration of:

• Supplements of mineral salts (in particular but not exclusively, of potassium) in order to compensate for their failure to reabsorb;
• Non-steroidal anti-inflammatory drugs (NSAIDs) such as, for example, indomethacin. These drugs are administered in order to reduce excessively high levels of prostaglandin E2;
• Potassium-sparing diuretics (administered for the purpose of reducing the excretion of potassium with urine).

In the most serious cases and / or in stressful conditions (onset of other diseases, surgical interventions, etc.), the reintegration of potassium and other mineral salts can be carried out intravenously, of course, a similar operation must be carried out by health personnel specialized.

Prognosis

What is the Prognosis for Patients with Bartter Syndrome?

The prognosis of Bartter's syndrome depends on several factors, such as the variant that affected the patient, the earliness of the diagnosis and the consequent timeliness in the beginning of therapy.

In patients with classic Bartter syndrome (variant III), following early diagnosis and appropriate treatment in infants and young children, it appears that significant improvements can be achieved in terms of growth and development.

In very serious cases, however, the life expectancy of patients suffering from Bartter's syndrome, unfortunately, is rather low.