Hypomagnesemia with secondary hypocalcemia
Encyclopedia
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 spasm
s in early infancy which, if left untreated, can lead to mental retardation
or death. HSH is caused by mutations in the TRPM6
gene.
, and seizure
s. 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.
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.
.
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
magnesium
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
absorption. Decreased intestinal magnesium reabsorption and the resulting decrease in serum magnesium levels is believed to cause lowered parathyroid hormone
Parathyroid hormone
Parathyroid hormone , parathormone or parathyrin, is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids...
(PTH) output by the parathyroid gland
Parathyroid gland
The parathyroid glands are small endocrine glands in the neck that produce parathyroid hormone. Humans usually have four parathyroid glands, which are usually located on the rear surface of the thyroid gland, or, in rare cases, within the thyroid gland itself or in the chest...
. This results in decreased PTH and decreased serum calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
levels (hypocalcemia). This manifests in convulsions and spasm
Spasm
In medicine a spasm is a sudden, involuntary contraction of a muscle, a group of muscles, or a hollow organ, or a similarly sudden contraction of an orifice. It is sometimes accompanied by a sudden burst of pain, but is usually harmless and ceases after a few minutes...
s in early infancy which, if left untreated, can lead to mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
or death. HSH is caused by mutations in the TRPM6
TRPM6
TRPM6 is a transient receptor potential ion channel associated with hypomagnesemia with secondary hypocalcemia....
gene.
Diagnosis
Diagnosis typically occurs during the first 6 months of life due to characteristic neurological symptoms. These symptoms include muscle spasms, tetanyTetany
Tetany has two meanings, though both are related to the muscular system.* Tetany * Tetany The terms "tetany" and "tetanus" are distinct....
, and seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s. Laboratory testing indicates hypomagnesemia (decreased serum magnesium levels), hypocalcemia (decreased serum calcium levels), and little to no measurable parathyroid hormone
Parathyroid hormone
Parathyroid hormone , parathormone or parathyrin, is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids...
levels. Diagnosis is confirmed with these symptoms and can be further solidified with genetic sequencing
Sequencing
In genetics and biochemistry, sequencing means to determine the primary structure of an unbranched biopolymer...
of 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+Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
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
Parathyroid gland
The parathyroid glands are small endocrine glands in the neck that produce parathyroid hormone. Humans usually have four parathyroid glands, which are usually located on the rear surface of the thyroid gland, or, in rare cases, within the thyroid gland itself or in the chest...
secretion of PTH
Parathyroid hormone
Parathyroid hormone , parathormone or parathyrin, is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids...
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.
| Mutation | Location | Functional? | Reference | |
|---|---|---|---|---|
| Nucleotide Nucleotide Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions... |
Amino Acid Amino acid Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen... |
|||
| c.C166T | R56X | N-terminus | ||
| c.C422T | S141L | N-terminus | No | ,,, |
| c.G469T | E157X | N-terminus | ||
| c.T521G | I174R | N-terminus | ||
| c.668delA | D223fsX263 | N-terminus | ||
| c.1010+5G→C | Splicing | N-terminus | ||
| c.A1060C | T354P | N-terminus | ||
| c.1134+5G→A | Splicing | N-terminus | ||
| c.1208-1G→A | Splicing | N-terminus | ||
| c.1280delA | H427fsX429 | N-terminus | No | , |
| c.1308+1G→A | Splicing | N-terminus | ||
| c.C1437A | Y479X | N-terminus | ||
| c.C1450T | R484X | N-terminus | ||
| c.C1769G | S590X | N-terminus | No | ,, |
| c.del1796-1797 | P599fsX609 | N-terminus | ||
| c.2009+1G→A | Splicing | N-terminus | , | |
| c.G2120A | C707Y | N-terminus | ||
| c.2207delG | R736fsX737 | N-terminus | No | ,, |
| c.2537-2A→T | Splicing | N-terminus | ||
| c.2667+1G→A | Splicing | , | ||
| c.C2782T | R928X | M3 | No | |
| c.del Ex 21 | M4 | |||
| c.Del2831-2832insG | I944fsX959 | M4-M5 | ||
| c.3209-68A→G | Splicing | |||
| c.del Ex 22 + 23 | M5-6 | |||
| C.3537-1G→A | Splicing | , | ||
| c.3779-91del | Q1260fsX1283 | C-terminus | , | |
| c.del Ex 25 - 27 | C-terminus | |||
| c.del Ex 26 | Y1533X | C-terminus | No | |
| c.5017-18delT | L1673fsX1675 | C-terminus | No | |
| c.del Ex 31 + 32 | C-terminus | No | ||
| c.5057+2T→C | Splicing | C-terminus | ||
| c.A5775G | Splicing | C-terminus |
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 XX chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
.