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 ... 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 (reviewed 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.
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 ... 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.
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 ... 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.