Hypomagnesemia with secondary hypocalcemia

Hypomagnesemia with secondary hypocalcemia
Hypomagnesemia with secondary hypocalcemia
Other names	Familial primary hypomagnesemia with hypocalcuria
Specialty	Endocrinology

Last updated July 03, 2023

Hypomagnesemia with secondary hypocalcemia (HSH) is an autosomal recessive genetic disorder that affects the absorption of magnesium in the intestines. It is characterized by reduced reabsorption of magnesium from our diet in the intestines, leading to decreased levels of magnesium in the bloodstream. This, in turn, causes a decrease in the production of parathyroid hormone (PTH) by the parathyroid gland. Consequently, there is a decrease in both PTH and serum calcium levels, resulting in secondary hypocalcemia.

One of the main symptoms of HSH is the occurrence of convulsions and spasms in early infancy. If left untreated, these symptoms can potentially lead to intellectual disability or even death. HSH is primarily caused by mutations in the TRPM6 gene, which plays a crucial role in maintaining the balance of magnesium in the body.

Pathophysiology

HSH is primarily caused by a reduction in intestinal magnesium reabsorption. Intestinal magnesium reabsorption primarily occurs by membrane transport through the TRPM6 ion channels and is crucial for magnesium homeostasis. TRPM6 is expressed on the part of the cell membrane facing the intestinal lumen on intestinal cells, known as enterocytes. It acts as an ion channel to allow the ions (charged atoms) of magnesium (Mg²⁺) and calcium (Ca²⁺) to flow into the cell. It generates “outwardly-rectifying" currents, and as a result a positive charge will then pass more easily in the outward direction, out the cell, than in the inward direction, into the cell. The outward portion of these currents consist of sodium (Na⁺), while the inward portion is composed of the divalent cations: magnesium and calcium. The entry of sodium ions is blocked by extracellular divalent cations. Additionally, increased levels of intracellular magnesium lead to a decrease in current through TRPM6 channels.^[1]

More than 30 mutations in the TRPM6 gene have been identified as being associated with HSH. These mutations are scattered throughout the gene (refer to Table 1). Out of the eight HSH mutations that have been tested, none have been shown to produce whole-cell current. One notable missense mutation, S141L, inhibits coassembly with TRPM7, as well as other TRPM6 subunits, and fails to allow traffic of the channel to the cell membrane. The trafficking ability and coassembly of other mutant forms of TRPM6 have yet to be extensively studied and require further investigation.^{[ citation needed ]}

While hypomagnesemia in patients with HSH directly results from TRPM6 mutations, hypocalcemia is an indirect and secondary consequence. Decreased serum magnesium levels result to reduced the secretion of parathyroid hormone (PTH) by the parathyroid gland. PTH plays a vital role in regulating serum calcium levels. Decreased levels of PTH result in a decrease in the availability of calcium in the bloodstream, which contributes to the neurological symptoms observed in HSH.^{[ citation needed ]}

**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		^[2]
c.C422T	S141L	N-terminus	No	^[3]^,^[4]^,^[5]^,^[6]
c.G469T	E157X	N-terminus		^[5]
c.T521G	I174R	N-terminus		^[7]
c.668delA	D223fsX263	N-terminus		^[5]
c.1010+5G→C	Splicing	N-terminus		^[2]
c.A1060C	T354P	N-terminus		^[7]
c.1134+5G→A	Splicing	N-terminus		^[7]
c.1208-1G→A	Splicing	N-terminus		^[5]
c.1280delA	H427fsX429	N-terminus	No	^[3]^,^[5]
c.1308+1G→A	Splicing	N-terminus		^[5]
c.C1437A	Y479X	N-terminus		^[7]
c.C1450T	R484X	N-terminus		^[2]
c.C1769G	S590X	N-terminus	No	^[3]^,^[5]^,^[8]
c.del1796-1797	P599fsX609	N-terminus		^[5]
c.2009+1G→A	Splicing	N-terminus		^[2]^,^[7]
c.G2120A	C707Y	N-terminus		^[7]
c.2207delG	R736fsX737	N-terminus	No	^[3]^,^[5]^,^[8]
c.2537-2A→T	Splicing	N-terminus		^[5]
c.2667+1G→A	Splicing			^[3]^,^[5]
c.C2782T	R928X	M3	No	^[5]
c.del Ex 21		M4		^[5]
c.Del2831-2832insG	I944fsX959	M4-M5		^[5]
c.3209-68A→G	Splicing			^[2]
c.del Ex 22 + 23		M5-6		^[5]
C.3537-1G→A	Splicing			^[3]^,^[5]
c.3779-91del	Q1260fsX1283	C-terminus		^[3]^,^[5]
c.del Ex 25 - 27		C-terminus		^[5]
c.del Ex 26	Y1533X	C-terminus	No	^[5]
c.5017-18delT	L1673fsX1675	C-terminus	No	^[5]
c.del Ex 31 + 32		C-terminus	No	^[5]
c.5057+2T→C	Splicing	C-terminus		^[5]
c.A5775G	Splicing	C-terminus		^[5]

Diagnosis

Diagnosis typically occurs during the first six months of life due to the characteristic neurological symptoms. These symptoms include muscle spasms, tetany, and seizures. Laboratory testing reveals hypomagnesemia (decreased serum magnesium levels), hypocalcemia (decreased serum calcium levels), and little to no measurable PTH levels. Diagnosis is confirmed with these symptoms and can be further solidified with genetic sequencing of the TRPM6 gene.^{[ citation needed ]}

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 transport pathways. This treatment must be continued throughout life.^{[ citation needed ]}

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.^[7]

Related Research Articles

<span class="mw-page-title-main">Parathyroid gland</span> Endocrine gland

Parathyroid glands are small endocrine glands in the neck of humans and other tetrapods. Humans usually have four parathyroid glands, located on the back of the thyroid gland in variable locations. The parathyroid gland produces and secretes parathyroid hormone in response to a low blood calcium, which plays a key role in regulating the amount of calcium in the blood and within the bones.

Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine.

Calcium metabolism is the movement and regulation of calcium ions (Ca²⁺) in (via the gut) and out (via the gut and kidneys) of the body, and between body compartments: the blood plasma, the extracellular and intracellular fluids, and bone. Bone acts as a calcium storage center for deposits and withdrawals as needed by the blood via continual bone remodeling.

Hypocalcemia is a medical condition characterized by low calcium levels in the blood serum. The normal range of blood calcium is typically between 2.1–2.6 mmol/L while levels less than 2.1 mmol/L are defined as hypocalcemic. Mildly low levels that develop slowly often have no symptoms. Otherwise symptoms may include numbness, muscle spasms, seizures, confusion, or cardiac arrest.

Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca²⁺) level in the blood serum. The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcemia. Those with a mild increase that has developed slowly typically have no symptoms. In those with greater levels or rapid onset, symptoms may include abdominal pain, bone pain, confusion, depression, weakness, kidney stones or an abnormal heart rhythm including cardiac arrest.

Disorders of calcium metabolism occur when the body has too little or too much calcium. The serum level of calcium is closely regulated within a fairly limited range in the human body. In a healthy physiology, extracellular calcium levels are maintained within a tight range through the actions of parathyroid hormone, vitamin D and the calcium sensing receptor. Disorders in calcium metabolism can lead to hypocalcemia, decreased plasma levels of calcium or hypercalcemia, elevated plasma calcium levels.

Hypoparathyroidism is decreased function of the parathyroid glands with underproduction of parathyroid hormone (PTH). This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany, and several other symptoms. It is a very rare disease. The condition can be inherited, but it is also encountered after thyroid or parathyroid gland surgery, and it can be caused by immune system-related damage as well as a number of rarer causes. The diagnosis is made with blood tests, and other investigations such as genetic testing depending on the results. The primary treatment of hypoparathyroidism is calcium and vitamin D supplementation. Calcium replacement or vitamin D can ameliorate the symptoms but can increase the risk of kidney stones and chronic kidney disease. Additionally, medications such as recombinant human parathyroid hormone or teriparatide may be given by injection to replace the missing hormone.

<span class="mw-page-title-main">Hyperparathyroidism</span> Increase in parathyroid hormone levels in the blood

Hyperparathyroidism is an increase in parathyroid hormone (PTH) levels in the blood. This occurs from a disorder either within the parathyroid glands or as response to external stimuli. Symptoms of hyperparathyroidism are caused by inappropriately normal or elevated blood calcium leaving the bones and flowing into the blood stream in response to increased production of parathyroid hormone. In healthy people, when blood calcium levels are high, parathyroid hormone levels should be low. With long-standing hyperparathyroidism, the most common symptom is kidney stones. Other symptoms may include bone pain, weakness, depression, confusion, and increased urination. Both primary and secondary may result in osteoporosis.

Electrolyte imbalance, or water-electrolyte imbalance, is an abnormality in the concentration of electrolytes in the body. Electrolytes play a vital role in maintaining homeostasis in the body. They help to regulate heart and neurological function, fluid balance, oxygen delivery, acid–base balance and much more. Electrolyte imbalances can develop by consuming too little or too much electrolyte as well as excreting too little or too much electrolyte.

Parathyroidectomy is the surgical removal of one or more of the (usually) four parathyroid glands. This procedure is used to remove an adenoma or hyperplasia of these glands when they are producing excessive parathyroid hormone (PTH): hyperparathyroidism. The glands are usually four in number and located adjacent to the posterior surface of the thyroid gland, but their exact location is variable. When an elevated PTH level is found, a sestamibi scan or an ultrasound may be performed in order to confirm the presence and location of abnormal parathyroid tissue.

The Chvostek sign is a clinical sign that someone may have a low blood calcium level. The Chvostek sign is the abnormal twitching of muscles that are activated (innervated) by the facial nerve. When the facial nerve is tapped in front of the ear, the facial muscles on the same side of the face will contract sporadically. The muscles that control the nose, lips and eyebrows are often the ones that will spasm.

Cinacalcet, sold under the brand name Sensipar among others, is a medication used to treat tertiary hyperparathyroidism, parathyroid carcinoma, and primary hyperparathyroidism.

Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. It is the most frequent hereditary salt-losing tubulopathy. Gitelman syndrome is caused by disease-causing variants on both alleles of the SLC12A3 gene. The SLC12A3 gene encodes the thiazide-sensitive sodium-chloride cotransporter, which can be found in the distal convoluted tubule of the kidney.

Magnesium deficiency is an electrolyte disturbance in which there is a low level of magnesium in the body. It can result in multiple symptoms. Symptoms include tremor, poor coordination, muscle spasms, loss of appetite, personality changes, and nystagmus. Complications may include seizures or cardiac arrest such as from torsade de pointes. Those with low magnesium often have low potassium.

<span class="mw-page-title-main">Secondary hyperparathyroidism</span> Medical condition

Secondary hyperparathyroidism is the medical condition of excessive secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia, with resultant hyperplasia of these glands. This disorder is primarily seen in patients with chronic kidney failure. It is sometimes abbreviated "SHPT" in medical literature.

<span class="mw-page-title-main">Bartter syndrome</span> Medical condition

Bartter syndrome (BS) is a rare inherited disease characterised by a defect in the thick ascending limb of the loop of Henle, which results in low potassium levels (hypokalemia), increased blood pH (alkalosis), and normal to low blood pressure. There are two types of Bartter syndrome: neonatal and classic. A closely associated disorder, Gitelman syndrome, is milder than both subtypes of Bartter syndrome.

Milk-alkali syndrome (MAS), also referred to as calcium-alkali syndrome, is the third most common cause of hypercalcemia. Milk-alkali syndrome is characterized by elevated blood calcium levels, metabolic alkalosis, and acute kidney injury.

TRPM is a family of transient receptor potential ion channels (M standing for wikt:melastatin). Functional TRPM channels are believed to form tetramers. The TRPM family consists of eight different channels, TRPM1–TRPM8.

TRPM6 is a transient receptor potential ion channel associated with hypomagnesemia with secondary hypocalcemia.

Familial hypocalciuric hypercalcemia (FHH) is an inherited condition that can cause hypercalcemia, a serum calcium level typically above 10.2 mg/dL; although uncommon. It is also known as familial benign hypocalciuric hypercalcemia (FBHH) where there is usually a family history of hypercalcemia which is mild, a urine calcium to creatinine ratio <0.01, and urine calcium <200 mg/day.

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

↑ "TRPM6 gene: MedlinePlus Genetics". medlineplus.gov. Retrieved 2023-07-02.
1 2 3 4 5 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. S2CID 33192419.
1 2 3 4 5 6 7 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. S2CID 40990544.
↑ 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.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 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.
1 2 3 4 5 6 7 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.
1 2 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.

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[1] "TRPM6 gene: MedlinePlus Genetics". medlineplus.gov. Retrieved 2023-07-02.

[Walder_2002-2] 1 2 3 4 5 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. S2CID 33192419.

[Schlingmann_2002-3] 1 2 3 4 5 6 7 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. S2CID 40990544.

[Chubanov_2004-4] 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_2005-5] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 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_2006-6] 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_2006-7] 1 2 3 4 5 6 7 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_2004-8] 1 2 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.

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