What is Gitelman syndrome?

What is Gitelman Syndrome

Gitelman syndrome is an autosomal recessive, salt-losing tubulopathy caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC), characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. 1, 2, 3

Genetic Basis and Inheritance

• The disease results from biallelic inactivating mutations in the SLC12A3 gene, which impairs the thiazide-sensitive sodium-chloride cotransporter in the distal convoluted tubule. 2, 3
• Gitelman syndrome is inherited in an autosomal recessive pattern, meaning both parents must carry a mutation for offspring to be affected. 2
• Missense mutations account for approximately 70% of all mutations, with a predisposition to large genomic rearrangements caused by repeated sequences within the SLC12A3 gene. 4
• Genetic confirmation requires identification of pathogenic mutations in the SLC12A3 gene through comprehensive genetic testing. 5

Epidemiology and Prevalence

• Gitelman syndrome is one of the most common inherited renal tubulopathies, with an estimated prevalence of approximately 1 to 10 per 40,000 people. 2
• The prevalence is notably higher in Asian populations compared to other geographic regions. 2

Pathophysiology

• The primary molecular defect leads to impaired salt reabsorption in the distal convoluted tubule, resulting in renal salt wasting. 3
• This triggers activation of the renin-angiotensin-aldosterone system in an attempt to restore intravascular volume and maintain glomerular perfusion. 6
• The resulting hormonal cascade produces the characteristic biochemical abnormalities: hypokalemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria. 1, 3

Clinical Presentation and Age of Onset

• Gitelman syndrome typically presents during adolescence or adulthood, usually after age 6 years, which distinguishes it from Bartter syndrome that presents prenatally or in early infancy. 1
• The disease is often detected either fortuitously during routine laboratory testing or when patients present with mild, nonspecific symptoms. 3
• The phenotype is highly variable, ranging from asymptomatic to severe manifestations affecting quality of life. 2, 3

Clinical Manifestations

Electrolyte-Related Symptoms:

• Muscle weakness, cramps, and aches are the most common musculoskeletal complaints related to hypokalemia and hypomagnesemia. 2, 7
• Tetany can occur due to severe hypomagnesemia impairing calcium homeostasis. 2, 8
• Salt craving is frequently reported as patients attempt to compensate for renal salt wasting. 7

Constitutional Symptoms:

• Fatigue and generalized weakness are prominent complaints that significantly impact daily functioning. 7
• Dizziness, nocturia, and polydipsia are common. 7
• Palpitations may occur, and sudden cardiac deaths have been reported in severe cases. 8

Severe Manifestations:

• Paralysis and rhabdomyolysis can occur in severe, untreated cases. 7
• Cardiac arrhythmias are a potential life-threatening complication. 8

Diagnostic Criteria

The diagnostic triad consists of:

• Hypokalemia (low serum potassium)
• Hypomagnesemia (low serum magnesium)
• Hypocalciuria (low urinary calcium excretion, with calcium-to-creatinine ratio ≤ 0.20) 1

Additional biochemical features include:

• Metabolic alkalosis
• Normal or low blood pressure
• Increased activity of the renin-angiotensin-aldosterone system
• Fractional excretion of chloride >0.5%, indicating renal salt wasting 1, 2

Key Distinguishing Feature from Bartter Syndrome

• Hypocalciuria is the critical distinguishing feature from Bartter syndrome, which presents with hypercalciuria (calcium-to-creatinine ratio > 0.20). 1
• Age of onset also helps differentiate: Gitelman syndrome manifests after age 6 years (typically adolescence/adulthood), while Bartter syndrome type 3 presents prenatally or in early infancy. 1
• Gitelman syndrome generally has a milder clinical course and better long-term prognosis compared to Bartter syndrome. 1

Differential Diagnosis

The differential diagnosis includes:

• Bartter syndrome (especially type III) - the most important genetic disorder to consider due to similar manifestations 2
• Renal tubular acidosis
• Primary hyperaldosteronism
• Liddle syndrome
• Diuretic abuse (must be excluded)
• Other causes of hypokalemia 2

Impact on Quality of Life

• Gitelman syndrome is not an asymptomatic disease and significantly adversely affects quality of life. 7
• Forty-five percent of patients consider their symptoms a moderate to big problem. 7
• Health-related quality of life measures are significantly lower in Gitelman syndrome patients compared to controls, particularly regarding role limitations caused by physical health, emotional issues, energy levels, and general health perception. 7
• The disease is characterized by significant phenotypic variability and a notable reduction in quality of life. 3

Diagnostic Pitfalls to Avoid

• Diuretic function tests (thiazide or loop diuretic challenges) are obsolete for diagnosing Gitelman syndrome and pose a risk of severe volume depletion; therefore, they should be avoided in the diagnostic work-up. 1
• Approximately 18-40% of suspected Gitelman syndrome patients carry only one SLC12A3 mutant allele, so large genomic rearrangements must be considered when genetic testing reveals only one mutation. 4
• A single genetic variant is insufficient for diagnosis without clinical correlation and comprehensive genetic analysis. 5