Clinical Significance of Heterozygosity for Mutations of the SLC12A3 Gene Coding for the Thiazide Sensitive Na-Cl Cotransporter

Study Overview
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Brief Summary
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Gitelman syndrome is a salt wasting tubulopathy caused by mutations in the SLC12A3 gene coding for the thiazide sensitive sodium chloride cotransporter. This disease mimics the chronic treatment with thiazide diuretics and is characterized by renal hypokalemia, low to normal blood pressure, hypocalciuria and hypomagnesemia. The purpose of this study is to determine whether the heterozygous carriers present the metabolic risks and/or the benefits of this disease.

Detailed Description
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Gitelman syndrome (GS), is an autosomal recessive salt wasting tubulopathy caused mainly by loss of function mutations in the SLC12A3 gene coding for the thiazide sensitive sodium-chloride cotransporter (NCC). Thus, GS mimics a chronic treatment with high doses of thiazide diuretics. NCC is expressed in the distal convoluted tubule, which is responsible for 7% of NaCl reabsorption. GS is the more frequent hereditary tubulopathie with estimated prevalence of 1/40000, which implicates that 1% of general population are heterozygous carriers (600 000 in France). Previous publications suggest that the apparently asymptomatic heterozygous carriers could present some clinical traits of GS or chronic thiazide treatment. These including: beneficial aspects (low blood pressure, low urinary calcium excretions) or metabolic risks (hypokalemia, insulin resistance). Nevertheless, these studies do not evaluate all the aspects and blood pressure was evaluated once in hospital setting. This study aims to compare home monitoring blood pressure; salt balance; potassium, glucose lipid and mineral metabolism and vascular function in 80 heterozygous carriers, 80 GS patients and 80 controls persons (without mutations in SLC12A3 gene).

Official Title
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Clinical Significance of Heterozygosity for Mutations of the SLC12A3 Gene Coding for the Thiazide Sensitive Na-Cl Cotransporter

Conditions
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Heterozygous Carriers of Gitelman Syndrome

Intervention / Treatment
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* Procedure: Samplings of blood
* Procedure: Sampling of urine
* Procedure: Measure of the blood pressure
* Procedure: glycemia test


Participation Criteria
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Eligibility Criteria
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Gitelman syndrome patients, relatives carrying heterozygous mutations and relatives or healthy voluntarees without mutations.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: study's population<br> | Procedure: Samplings of blood<br> <br> Procedure: Sampling of urine<br> <br> Procedure: Measure of the blood pressure<br> <br> Procedure: glycemia test<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systolic blood pressure evaluated by self-measurement | self-measurement at home, 3 times a day during 3 consecutive days | 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Salt balance | Blood renin and aldosterone measurements, 24h urinary sodium and aldosterone excretion | 1 day | 
| Potassium metabolism | Dietary intake, blood potassium and 24 h urinary potassium excretion | 1 day | 
| Glucose and lipide metabolism | BMI, blood glucose, insulin, cholesterol, LDL, HDL and triglycerides. | 1 day | 
| Oral glucose tolerance test |  | 1 day | 
| Mineral metabolism | Blood and urinary calcium, magnesium and phosphate. bone remodeling markers | 1 day | 
| Renal fonction | Estimated GFR, proteinuria and albuminuria | 1 day | 
| Vascular fonction evaluation | Pulse wave analysis and central blood pressure. Blood and urinary vascular fonction markers | 1 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gitelman, Heterozygous SLC12A3 mutation, Blood pressure, Hypokalemia