Hypomagnesemia with secondary hypocalcemia

Hypomagnesemia with secondary hypocalcemia
Specialty	Endocrinology

Hypomagnesemia with secondary hypocalcemia (HSH) is an autosomal recessive genetic disorder affecting intestinal magnesium absorption. Decreased intestinal magnesium reabsorption and the resulting decrease in serum magnesium levels is believed to cause lowered parathyroid hormone (PTH) output by the parathyroid gland. This results in decreased PTH and decreased serum calcium levels (hypocalcemia). This manifests in convulsions and spasms in early infancy which, if left untreated, can lead to mental retardation or death. HSH is caused by mutations in the TRPM6 gene.

Pathophysiology

HSH is caused by decreased intestinal magnesium reabsorption through TRPM6 channels. When expressed in cells, TRPM6 produces outwardly rectifying currents with the outward portion composed of Na⁺ ions and the inward portion of divalent cations (particularly magnesium and calcium). Inward flow of sodium ions is blocked by extracellular divalent cations. Increased intracellular magnesium concentrations also decrease current through TRPM6 channels. There are currently more than 30 known mutations in TRPM6 that are associated with HSH and these mutations are spreading throughout the gene (table 1). Of the eight HSH mutations that have been tested, none have shown to produce whole-cell current. The S141L mutation, one of the few missense mutations, has been of particular interest to researchers. They have found that it prevents coassembly with TRPM7 (and presumably other TRPM6 subunits) and lacks the ability to traffic to the membrane. Whether other mutants are able to traffic properly to the surface or coassemble has not yet been further studied.

While the hypomagnesemia in patients with HSH is a direct result of TRPM6 mutations, hypocalcemia is an indirect, secondary result. Parathyroid gland secretion of PTH can be altered by changes in serum magnesium levels. The decreased serum magnesium levels seen in HSH result in decreased PTH secretion. PTH, in turn, controls the availability of serum calcium. Decreasing PTH levels cause a decrease in calcium availability in serum and, thus, the neurological symptoms of HSH.

**Table 1.** TRPM6 mutations associated with hypomagnesemia with secondary hypocalcemia
Mutation		Location	Functional?	Reference
Nucleotide	Amino acid	Location	Functional?	Reference
c.C166T	R56X	N-terminus		[1]
c.C422T	S141L	N-terminus	No	[2]^,[3]^,[4]^,[5]
c.G469T	E157X	N-terminus		[4]
c.T521G	I174R	N-terminus		[6]
c.668delA	D223fsX263	N-terminus		[4]
c.1010+5G→C	Splicing	N-terminus		[1]
c.A1060C	T354P	N-terminus		[6]
c.1134+5G→A	Splicing	N-terminus		[6]
c.1208-1G→A	Splicing	N-terminus		[4]
c.1280delA	H427fsX429	N-terminus	No	[2]^,[4]
c.1308+1G→A	Splicing	N-terminus		[4]
c.C1437A	Y479X	N-terminus		[6]
c.C1450T	R484X	N-terminus		[1]
c.C1769G	S590X	N-terminus	No	[2]^,[4]^,[7]
c.del1796-1797	P599fsX609	N-terminus		[4]
c.2009+1G→A	Splicing	N-terminus		[1]^,[6]
c.G2120A	C707Y	N-terminus		[6]
c.2207delG	R736fsX737	N-terminus	No	[2]^,[4]^,[7]
c.2537-2A→T	Splicing	N-terminus		[4]
c.2667+1G→A	Splicing			[2]^,[4]
c.C2782T	R928X	M3	No	[4]
c.del Ex 21		M4		[4]
c.Del2831-2832insG	I944fsX959	M4-M5		[4]
c.3209-68A→G	Splicing			[1]
c.del Ex 22 + 23		M5-6		[4]
C.3537-1G→A	Splicing			[2]^,[4]
c.3779-91del	Q1260fsX1283	C-terminus		[2]^,[4]
c.del Ex 25 - 27		C-terminus		[4]
c.del Ex 26	Y1533X	C-terminus	No	[4]
c.5017-18delT	L1673fsX1675	C-terminus	No	[4]
c.del Ex 31 + 32		C-terminus	No	[4]
c.5057+2T→C	Splicing	C-terminus		[4]
c.A5775G	Splicing	C-terminus		[4]

Diagnosis

Diagnosis typically occurs during the first 6 months of life due to characteristic neurological symptoms. These symptoms include muscle spasms, tetany, and seizures. Laboratory testing indicates hypomagnesemia (decreased serum magnesium levels), hypocalcemia (decreased serum calcium levels), and little to no measurable parathyroid hormone levels. Diagnosis is confirmed with these symptoms and can be further solidified with genetic sequencing of the TRPM6 gene.

Treatment

Treatment of HSH involves administration of high doses of magnesium salts. These salts may be taken orally or otherwise (e.g. subcutaneously). This treatment works by increasing magnesium absorption through the non-TRPM6 mediated paracellular uptake pathways. This treatment must be continued throughout life.

History

HSH was originally believed to be an X-linked disorder due to the preponderance of affected males. With the finding that mutations in TRPM6 (on chromosome 9) are causative for the disorder this is no longer the case. Of recent interest, however, is the characterization of a patient with symptoms similar to HSH who has a translocation of the chromosomes 9 and X.[6]

References

Konrad M, Schlingmann K, Gudermann T (2004). "Insights into the molecular nature of magnesium homeostasis". Am J Physiol Renal Physiol. 286 (4): F599–605. doi:10.1152/ajprenal.00312.2003. PMID 15001450.

Footnotes

Walder R, Landau D, Meyer P, Shalev H, Tsolia M, Borochowitz Z, Boettger M, Beck G, Englehardt R, Carmi R, Sheffield V (2002). "Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia". Nat Genet. 31 (2): 171–4. doi:10.1038/ng901. PMID 12032570.
Schlingmann K, Weber S, Peters M, Niemann Nejsum L, Vitzthum H, Klingel K, Kratz M, Haddad E, Ristoff E, Dinour D, Syrrou M, Nielsen S, Sassen M, Waldegger S, Seyberth H, Konrad M (2002). "Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family". Nat Genet. 31 (2): 166–70. doi:10.1038/ng889. PMID 12032568.
Chubanov V, Waldegger S, Mederos y Schnitzler M, Vitzthum H, Sassen M, Seyberth H, Konrad M, Gudermann T (2004). "Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia". Proc Natl Acad Sci USA. 101 (9): 2894–9. Bibcode:2004PNAS..101.2894C. doi:10.1073/pnas.0305252101. PMC 365716. PMID 14976260.
Schlingmann K, Sassen M, Weber S, Pechmann U, Kusch K, Pelken L, Lotan D, Syrrou M, Prebble J, Cole D, Metzger D, Rahman S, Tajima T, Shu S, Waldegger S, Seyberth H, Konrad M (2005). "Novel TRPM6 mutations in 21 families with primary hypomagnesemia and secondary hypocalcemia". J Am Soc Nephrol. 16 (10): 3061–9. doi:10.1681/ASN.2004110989. PMID 16107578.
Li M, Jiang J, Yue L (2006). "Functional Characterization of Homo- and Heteromeric Channel Kinases TRPM6 and TRPM7". J Gen Physiol. 127 (5): 525–37. doi:10.1085/jgp.200609502. PMC 2151519. PMID 16636202.
Jalkanen R, Pronicka E, Tyynismaa H, Hanauer A, Walder R, Alitalo T (2006). "Genetic background of HSH in three Polish families and a patient with an X;9 translocation". Eur J Hum Genet. 14 (1): 55–62. doi:10.1038/sj.ejhg.5201515. PMID 16267500.
Voets T, Nilius B, Hoefs S, van der Kemp A, Droogmans G, Bindels R, Hoenderop J (2004). "TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption". J Biol Chem. 279 (1): 19–25. doi:10.1074/jbc.M311201200. PMID 14576148.

External links

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[Walder_2002-1] Walder R, Landau D, Meyer P, Shalev H, Tsolia M, Borochowitz Z, Boettger M, Beck G, Englehardt R, Carmi R, Sheffield V (2002). "Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia". Nat Genet. 31 (2): 171–4. doi:10.1038/ng901. PMID 12032570.

[Schlingmann_2002-2] Schlingmann K, Weber S, Peters M, Niemann Nejsum L, Vitzthum H, Klingel K, Kratz M, Haddad E, Ristoff E, Dinour D, Syrrou M, Nielsen S, Sassen M, Waldegger S, Seyberth H, Konrad M (2002). "Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family". Nat Genet. 31 (2): 166–70. doi:10.1038/ng889. PMID 12032568.

[Chubanov_2004-3] Chubanov V, Waldegger S, Mederos y Schnitzler M, Vitzthum H, Sassen M, Seyberth H, Konrad M, Gudermann T (2004). "Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia". Proc Natl Acad Sci USA. 101 (9): 2894–9. Bibcode:2004PNAS..101.2894C. doi:10.1073/pnas.0305252101. PMC 365716. PMID 14976260.

[Schlingmann_2005-4] Schlingmann K, Sassen M, Weber S, Pechmann U, Kusch K, Pelken L, Lotan D, Syrrou M, Prebble J, Cole D, Metzger D, Rahman S, Tajima T, Shu S, Waldegger S, Seyberth H, Konrad M (2005). "Novel TRPM6 mutations in 21 families with primary hypomagnesemia and secondary hypocalcemia". J Am Soc Nephrol. 16 (10): 3061–9. doi:10.1681/ASN.2004110989. PMID 16107578.

[Li_2006-5] Li M, Jiang J, Yue L (2006). "Functional Characterization of Homo- and Heteromeric Channel Kinases TRPM6 and TRPM7". J Gen Physiol. 127 (5): 525–37. doi:10.1085/jgp.200609502. PMC 2151519. PMID 16636202.

[Jalkanen_2006-6] Jalkanen R, Pronicka E, Tyynismaa H, Hanauer A, Walder R, Alitalo T (2006). "Genetic background of HSH in three Polish families and a patient with an X;9 translocation". Eur J Hum Genet. 14 (1): 55–62. doi:10.1038/sj.ejhg.5201515. PMID 16267500.

[Voets_2004-7] Voets T, Nilius B, Hoefs S, van der Kemp A, Droogmans G, Bindels R, Hoenderop J (2004). "TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption". J Biol Chem. 279 (1): 19–25. doi:10.1074/jbc.M311201200. PMID 14576148.