Bartter and Gitelman syndromes

Definition

Bartter syndrome and Gitelman syndrome are rare, mostly autosomal recessive salt-wasting tubulopathies. Both share renal loss of sodium, chloride, potassium and hydrogen ions, hypokalemia, metabolic alkalosis and elevated renin and aldosterone with normal or low blood pressure.

Occurrence & epidemiology

Reliable frequency data are scarce. For Bartter syndrome, an annual incidence of 1.2 per million was found in Sweden; the prevalence of Gitelman syndrome in the United States is estimated at about 1 in 40,000.

Aetiopathogenesis

Pathophysiology and genetics

The cause is impaired sodium chloride reabsorption: in Bartter syndrome in the thick ascending limb of the loop of Henle, in Gitelman syndrome in the distal tubule. Salt loss causes mild volume depletion, which activates renin and aldosterone, leading to loss of potassium and hydrogen ions. In Bartter syndrome, renal prostaglandin E2 production is also increased and urine concentration is impaired; in Gitelman syndrome, hypomagnesemia and low calcium excretion are typical.

• Type I: SLC12A1 (NKCC2), antenatal/neonatal
• Type II: KCNJ1 (ROMK), antenatal/neonatal
• Type III: CLCNKB (ClC-Kb), childhood onset, sometimes Gitelman-like
• Types IVa/IVb: BSND (barttin) or CLCNKA and CLCNKB, antenatal, with sensorineural hearing loss
• Type V: activating CASR mutation with hypocalcemia and hypercalciuria
• An X-linked MAGED2 mutation causes severe but transient antenatal Bartter syndrome that resolves by 1 to 2 years of age.

Clinical features

• Bartter syndrome: onset before birth to early childhood; polyhydramnios and intrauterine growth restriction, prematurity, polyuria, failure to thrive and developmental delay, sometimes intellectual disability; depending on the type, nephrocalcinosis, hypocalcemia or hearing loss
• Gitelman syndrome: onset late childhood to adulthood, often an incidental finding; muscle weakness, cramps, spasms, tetany and fatigue due to potassium and magnesium loss
• Both: polydipsia, polyuria, salt craving, vomiting; low to low-normal blood pressure, possibly signs of volume depletion

Bartter and Gitelman compared

• Shared: hypokalemic metabolic alkalosis with salt wasting, elevated renin and aldosterone, without hypertension
• Urinary calcium excretion: Bartter normal or increased, often with nephrocalcinosis; Gitelman decreased
• Serum magnesium: Bartter normal or decreased; Gitelman decreased, sometimes markedly
• Renal prostaglandin E2 production: Bartter increased, Gitelman normal
• Age at presentation: Bartter before birth to early childhood; Gitelman late childhood to adulthood
• Neuromuscular symptoms (e.g. muscle spasms, weakness): Bartter uncommon or mild, Gitelman common

Diagnosis

• Blood: hypokalemia, metabolic alkalosis, often marked hypomagnesemia in Gitelman syndrome; elevated renin and aldosterone
• Urine: sodium, potassium and chloride excretion inappropriately high for the volume status
• Calcium excretion (24-hour urine or calcium-to-creatinine ratio): normal to increased in Bartter syndrome, decreased in Gitelman syndrome
• Exclusion of similar disorders: primary aldosteronism (hypertension, low renin); surreptitious vomiting or laxative abuse (urine chloride usually < 20 mmol/L); covert use of drugs that increase urine output (urine chloride, urine screening for these substances)
• Molecular genetics: confirms the diagnosis and subtype; siblings have a 25% risk with recessive inheritance.

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Further reading (open access)

1. MSD Manual Professional: Bartter Syndrome and Gitelman Syndrome

Cross-references