Hypomagnesemia 1, Intestinal

A number sign (#) is used with this entry because of evidence that this form of hypomagnesemia with secondary hypocalcemia (HOMG1) is caused by homozygous or compound heterozygous mutations in the TRPM6 gene (607009) on chromosome 9q21.

Description

Familial hypomagnesemia with secondary hypocalcemia is a rare autosomal recessive disorder characterized by very low serum magnesium levels. Hypocalcemia is a secondary consequence of parathyroid failure and parathyroid hormone resistance as a result of severe magnesium deficiency. The disease typically manifests during the first months of life with generalized convulsions or signs of increased neuromuscular excitability, such as muscle spasms or tetany. Untreated, the disease may be fatal or lead to severe neurologic damage. Treatment includes immediate administration of magnesium, usually intravenously, followed by life-long high-dose oral magnesium (review by Knoers, 2009).

Genetic Heterogeneity of Hypomagnesemia

A form of hypomagnesemia due to kidney defects and high urinary magnesium excretion associated with hypocalciuria (HOMG2; 154020) is caused by mutation in the FXYD2 gene (601814). Renal hypomagnesemia-3 (HOMG3; 248250), associated with hypercalciuria and nephrocalcinosis, is caused by mutation in the CLDN16 gene (603959). Renal hypomagnesemia-4 (HOMG4; 611718), which is normocalciuric, is caused by mutation in the EGF gene (131530). Renal hypomagnesemia-5 (HOMG5; 248190), associated with hypercalciuria, nephrocalcinosis, and severe ocular involvement, is caused by mutation in the CLDN19 gene (610036). Renal hypomagnesemia-6 (HOMG6; 613882) is caused by mutation in the CNNM2 gene (607803).

Patients with Gitelman syndrome (263800) and Bartter syndrome (see 241200) also show hypomagnesemia, and steatorrhea and severe chronic diarrhea states, such as Crohn disease (see 226600) and Whipple disease, that can result in severe hypomagnesemia.

Clinical Features

Vainsel et al. (1970) described a 5-month-old boy who had convulsions and persistent tetany, associated with hypomagnesemia and hypocalcemia. Vitamin D therapy corrected the hypocalcemia without improving the clinical status. Autopsy showed calcinosis of the myocardium, kidneys, and a cerebral artery. Two brothers of the proband had died of a clinically similar disorder and 3 of 4 surviving brothers had convulsions. Others, e.g., Skyberg et al. (1967, 1969), reported cases, all in males, and X-linked recessive inheritance was considered possible.

Teebi (1983) found reports of 10 cases, all male, including 2 brothers.

Walder et al. (1997) described 11 males and 2 females from 3 inbred Bedouin kindreds with familial hypomagnesemia. Most of the patients presented at 2 to 8 weeks of age with restlessness, tremor, neuromuscular hyperexcitability and overt seizures. None of the patients had feeding problems or signs of malabsorption. Serum magnesium levels at initial presentation ranged from 1.2 to 0.8 mg% (normal 1.4-2.6 mg%) and serum calcium levels of 2.7-7.6 mg% (normal 8.4-10.8 mg%). Treatment was delayed in 2 cases. These patients suffered prolonged, intractable seizures which were unresponsive to anticonvulsants. After treatment, these patients continued to suffer from a chronic convulsive disorder and mental retardation. Walder et al. (1997) noted that the predominance in males in their study was at least partially explained by a substantial predominance of male offspring (31) compared with female offspring (13) in these kindreds. Nonpenetrance was not observed in any of the unaffected females. Walder et al. (1997) stated that the low levels of serum magnesium in their patients were probably due to a defect in the intestinal reabsorption of magnesium. Renal magnesium secretion was normal. Normal values were observed for general intestinal absorption of other molecules. They commented that the hypocalcemia is to be expected since it develops in instances of any severe hypomagnesemic state, as a result of unresponsiveness to parathyroid hormone (168450). Restoration of serum magnesium levels to the low normal values with high doses, up to 20 times the normal daily requirement, can overcome the defect in absorption and restore serum calcium levels to normal.

In 2 sibs of consanguineous parents, Minty and Hall (1993) described the concurrence of acromesomelic dysplasia, Maroteaux type (AMDM; 602875) and familial hypomagnesemia.

Cytogenetics

Meyer et al. (1978) reported primary hypomagnesemia in a girl who had a translocation t(9;X)(q12;p22), suggesting that an X-linked gene mutant in this disorder might be situated at Xp22. Mettey and Hoppeler (1982) suggested that mutation in an autosomal gene is responsible for the disorder but that a gene on Xp modulates expression of the autosomal mutation. The patient of Meyer et al. (1978) showed dysmorphic facies and psychomotor retardation in addition to hypomagnesemia.

In a lymphoblastoid cell line derived from the patient with the t(9;X) translocation reported by Meyer et al. (1978), Chery et al. (1994) demonstrated that the normal X chromosome was preferentially inactivated, suggesting that the patient's phenotype was caused by disruption of a gene in Xp22. In an attempt to define more precisely the position of the X-chromosome breakpoint, they constructed a hybrid cell retaining the derivative X chromosome in the absence of the derivative chromosome 9 and the normal X chromosome. Southern blot analysis of this hybrid and in situ hybridization on metaphase chromosomes localized the breakpoint between DXS16 and the cluster (DXS207, DXS43) on Xp22.2.

Inheritance

Pronicka and Gruszczynska (1991) suggested autosomal recessive inheritance of this disorder. They stated that since the first report in 1965, the diagnosis had been made in 30 children (not including their own cases) from 28 families. In 6 families, consanguinity was found. Serum magnesium concentrations in the parents were invariably normal. The disorder could also be suspected in 13 sibs of the patients (5 boys and 8 girls) who died with similar clinical pictures. A preponderance of male patients, initially striking at 10:1, in later reports decreased to lower values and became 1.8:1. Salet et al. (1966), Becker et al. (1979), Garty et al. (1983), Hennekam and Donckerwolcke (1983), and Meyer and Boettger (2001) all suggested autosomal recessive inheritance.

Mapping

In their study of 3 inbred Bedouin kindreds segregating hypomagnesemia with secondary hypocalcemia from Israel, Walder et al. (1997) assumed that the affected individuals shared a chromosomal region inherited from a common ancestor, and used a DNA pooling strategy in a genomewide search for loci that showed homozygosity for shared alleles in those affected. A shift toward homozygosity was observed with marker D9S301 in the affected DNA pool compared with control pools. Genotyping of individual DNA samples using D9S301 and several flanking markers confirmed linkage to chromosome 9 with maximum lod scores of 3.4 (theta = 0.05), 3.7 (theta = 0.0), and 2.3 (theta = 0.0) for the 3 families. Walder et al. (1997) identified a 14-cM interval on chromosome 9 (9q12-q22.2), flanked by proximal marker D9S1874 and distal marker D9S1807, within which all affected individuals from the 3 kindreds were homozygous for a shared haplotype. The disease segregated with a common affected haplotype in the 3 families, suggesting that hypomagnesemia is caused by a common ancestral mutation in these families. Mapping of a chromosomal breakpoint in a somatic cell line established from a patient with HSH and a balanced t(X;9) translocation, previously reported by Meyer et al. (1978), placed the chromosomal breakpoint in a 500-kb region flanked by D9S1844 and D9S273.

Molecular Genetics

Using a positional candidate gene approach, Schlingmann et al. (2002) and Walder et al. (2002) identified homozygous or compound heterozygous mutations in the TRPM6 gene (607009.0001-607009.0010), also known as CHAK2, in patients with hypomagnesemia with secondary hypocalcemia. The TRPM6 protein is a member of the long transient receptor potential channel (TRPM) family and is highly similar to TRPM7 (605692), a bifunctional protein that combines calcium- and magnesium-permeable cation channel properties with protein kinase activity (Nadler et al., 2001; Runnels et al., 2001). TRPM6 is expressed in intestinal epithelia and kidney cells. These findings indicated that TRPM6 is crucial for magnesium homeostasis.

In 7 patients with hypomagnesemia and secondary hypocalcemia from 5 unrelated families, Lainez et al. (2014) sequenced the TRPM6 gene and identified homozygous or compound heterozygous mutations in all (see, e.g., 607009.0012). The mutations segregated fully with disease in the 3 families for which DNA from unaffected family members was available. All of the patients presented in infancy with generalized seizures as the predominant symptom, and laboratory analysis revealed the characteristic combination of profound hypomagnesemia, hypoparathyroidism, and resultant hypocalcemia. Lainez et al. (2014) noted that diagnosis of this disorder is sometimes delayed because renal Mg(2+) wasting is not detectable during periods of profound hypomagnesemia.

History

Familial hypomagnesemia with secondary hypocalcemia was formerly thought to be an X-linked recessive disorder based on its occurrence predominantly in males and on the report of a single female patient with the disorder and a balanced t(X;9) chromosomal translocation by Meyer et al. (1978) and Chery et al. (1994). The study of Walder et al. (1997) convincingly demonstrated that the disorder is autosomal recessive and is determined by mutation in a gene located on chromosome 9.