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Dominant Hypomagnesemia

Features

Defect in renal tubular reabsorption of magnesium.

Clinical Manifestations

Patients may experience muscle weakness, recurrent cramps, clinical tetany (positive Chvostek’s and Trousseau’s signs) and paresthesias. Other times it may be asymptomatic. In addition, chondrocalcinosis can develop in adulthood. Myokymia and cerebellar atrophy resulting in ataxia have been also described in patients with KCNA1 mutations. Renal cysts, hyperuricemia and diabetes mellitus have been described in patients with HNF1b mutations. Primary hypomagnesemia is a heterogeneous group of disorders characterized by renal or intestinal magnesium (Mg2+) wasting, resulting in tetany, cardiac arrhythmias, and seizures.

Diagnosis

Reduced levels of magnesemia and of urinary calcium excretion. Hypocalcemia can be detected in patients with HNF1B mutations. Calciuria is not reduced in patients with KCNA1 mutations.

Genetics

The inheritance pattern of this disease is autosomal dominant. Patients may have mutations in genes FXYD2, which encodes the basolateral gamma subunit of Na + / K + - ATPase (Hypomagnesemia 2, RENAL, HOMG2) HNF1B, encoding nuclear factor hepatocyte 1B (HNF1B) or KCNA1, which encoding the potassium channel Kv1.1 voltage regulated. These three proteins are involved in tubular reabsorption of magnesium in the distal convoluted tubule. For the genetic study it will be necessary samples of the index case and the parents.

Treatment

Being a rare disease, the therapeutic experience is very limited and basically consists of oral administration of magnesium salts.

Prognosis

It is not certain due to the small number of families studied.

Complications

In patients with mutations in HNF-1b has been described chronic kidney disease.

Bibliography

  • Meij IC, Koenderink JB, van Bokhoven H, Assink KF, Groenestege WT, de Pont JJ, Bindels RJ, Monnens LA, van den Heuvel LP, Knoers NV. Dominant isolated renal magnesium loss is caused by misrouting of the Na(+),K(+)-ATPase gamma-subunit. Nat Genet. 2000; 26: 265-6.
  • Sha Q, Pearson W, Burcea LC, Wigfall DA, Schlesinger PH, Nichols CG, Mercer RW. Human FXYD2 G41R mutation responsible for renal hypomagnesemia behaves as an inward-rectifying cation channel. Am J Physiol Renal Physiol. 2008; 295: F91-9.
  • Glaudemans B, van der Wijst J, Scola RH, Lorenzoni PJ, Heister A, van der Kemp AW, Knoers NV, Hoenderop JG, Bindels RJ. A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia. J Clin Invest. 2009; 119: 936-42.
  • Adalat S, Woolf AS, Johnstone KA, Wirsing A, Harries LW, Long DA, Hennekam RC, Ledermann SE, Rees L, van't Hoff W, Marks SD, Trompeter RS, Tullus K, Winyard PJ, Cansick J, Mushtaq I, Dhillon HK, Bingham C, Edghill EL, Shroff R, Stanescu H, Ryffel GU, Ellard S, Bockenhauer D. HNF1B mutations associate with hypomagnesemia and renal magnesium wasting. J Am Soc Nephrol. 2009;20: 1123-31.
  • van der Wijst J, Glaudemans B, Venselaar H, Nair AV, Forst AL, Hoenderop JG, Bindels RJ. Functional analysis of the Kv1.1 N255D mutation associated with autosomal dominant hypomagnesemia. J Biol Chem. 2010; 285: 171-8.