Gitelman syndrome

Gitelman syndrome is a rare condition in which too much salt loss in the urine occurs due to an abnormality in the renal tubules. The disease is usually caused by a defect (mutation) in the genetic material (DNA). Due to such a defect, specific cells in the kidney tubules that normally retain certain salts no longer work properly. Such a problem may be caused by a mutation in the gene SLC12A3 or the gene CLCNKB.
SLC12A3 is responsible for the production of the sodium-chloride co-transporter (NCC) in the distal tubule, a specific part of the kidney tubule. NCC is responsible for the re-uptake of sodium and chloride from the pro-urine. CLCNKB is responsible for the production of chloride channels in the distal tubule. Reduced or absent function of this chloride channel can also lead to reduced re-uptake of sodium and chloride in the renal tubules.

Signs and symptoms
Due to a mutation in either SLC12A3 or CLCNKB,  a defect in the re-absorption of sodium and chloride develops whereby too many salts (sodium and chloride) are excreted into the urine. This results in  other disorders, such as low concentrations of potassium and magnesium in the blood by too much potassium and magnesium loss in the urine. In addition, patients often have a metabolic alkalosis (a high pH of the blood because there will be too little excretion of acids in the urine), and too little calcium is excreted into the urine. Through these salt and mineral disorders, patients may experience various symptoms  which can vary greatly from person to person. Possible symptoms are muscle cramps or weakness, tingling, chronic fatigue, difficulty concentrating, depression, thirst, frequent urination, diarrhea or even constipation symptoms, arrhythmias, muscle and joint pains, and sometimes calcium deposits in or around the joints. In childhood can occur slowdown. Patients with Gitelman syndrome tend to have a slightly lower blood pressure with dizziness complaints which may occur particularly when standing up.

Inheritance
Gitelman syndrome is an inherited disease which is inherited autosomal recessive. This means that a person will get the disease when he or she has a mutation in the genetic material from both father as mother in SLC12A3 or CLCNKB. Because two mutations are needed, and the mutations are quite rare (1%), the likelihood that children of patients with the disease have Gitelman syndrome is not large (0.5%). Siblings of patients on the other hand do have a higher risk (25%) to also have Gitelman syndrome.

Diagnosis
The diagnosis can be confirmed by genetic testing.  It is also possible to perform a so-called thiazide  test, which tests the activity of NCC. In patients with Gitelman’s syndrome, NCC activity is reduced.

Treatment
There is no causal treatment available to treat the underlying disorder. In other words: the dysfunctional transport protein in the renal tubule cannot be repaired. The treatment, therefore, consists of the treatment of the mineral and salt  disorders, and is directed to the prevention or treatment of complaints. This (lifetime) treatment often consists of potassium-sparing diuretics, potassium supplements and, if necessary, magnesium supplementation. Unfortunately this does not always lead to a reduction or elimination of symptoms, and sometimes the treatment is complicated by side effects.

Prognosis
Gitelman syndrome is a chronic condition. This means that it persists lifelong. The overall prognosis of patients with Gitelman syndrome is good. It is, however, not always possible to resolve all symptoms with current treatment options. In some patients a reduction in kidney function occurs. Gitelman syndrome usually does not lead to such renal deterioration that renal replacement therapy (dialysis, kidney transplantation) is necessary.