Long-term Clinical Follow-up of Patients with Familial Hypomagnesemia with Secondary Hypocalcemia

Objective:Familial hypomagnesemia with secondary hypocalcemia (HSH) is an autosomal recessive disease caused by a mutation in the transient receptor potential melastatin 6 (TRPM6) gene and is characterized by selective magnesium malabsorption. Affected cases are usually diagnosed during infancy and usually present with seizures due to hypocalcemia and hypomagnesemia. Irreversible neurological deficits and arrhythmias can be observed without appropriate treatment. The aim was to evaluate the long-term follow-up of patients with genetically confirmed HSH.Methods:A total of six patients with HSH, two of whom were siblings, were included. Age at diagnosis, clinical, laboratory and follow-up data on admission were recorded. All 39 exons of the TRPM6 gene and flanking exon-intron junctions from genomic DNA were amplified and sequenced in all cases.Results:The median (range) follow-up duration was 12.1 (7.6-21.7) years. All cases were diagnosed in infancy. Four different mutations, three of which had not been previously reported, were detected in the TRPM6 gene. Treatment compliance was good and there were no severe complications in the long-term follow-up of cases. However, mental retardation, specific learning difficulty and attention deficit/hyperactive disorder were observed as comorbidities.Conclusion:Of the four different TRPM6 mutations in this small cohort, three had not been previously reported. The long-term prognosis of HSH appears to be good, given early diagnosis and good treatment compliance. This long-term follow-up and prognostic data and the three novel mutations will contribute to the published evidence concerning this rare condition, HSH, and it is hoped will prevent negative outcomes.     

A Novel Homozygous Mutation in the Transient Receptor Potential Melastatin 6 Gene: A Case Report

Hereditary hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disease caused by mutations in the transient receptor potential melastatin 6 (TRPM6) gene. Affected individuals present in early infancy with seizures caused by the severe hypocalcemia and hypomagnesemia. By presenting this case report, we also aimed to highlight the need for molecular genetic analysis in inbred or familial cases with hypomagnesemia. A Turkish inbred girl, now aged six years, had presented to another hospital at age two months with seizures diagnosed to be due to hypomagnesemia. She was on magnesium replacement therapy when she was admitted to our clinic with complaints of chronic diarrhea at age 3.6 years. During her follow-up in our clinic, she showed an age-appropriate physical and neurological development. In molecular genetic analysis, a novel homozygous frame-shift mutation (c.3447delT>p.F1149fs) was identified in the TRPM6 gene. This mutation leads to a truncation of the TRPM6 protein, thereby complete loss of function. We present the clinical follow-up findings of a pediatric HSH case due to a novel mutation in the TRPM6 gene and highlight the need for molecular genetic analysis in inbred or familial cases with hypomagnesemia.     

Altered functional properties of a TRPM2 variant in Guamanian ALS and PD

Two related neurodegenerative disorders, Western Pacific amyotrophic lateral sclerosis (ALS) and parkinsonism–dementia (PD), originally occurred at a high incidence on Guam, in the Kii peninsula of Japan, and in southern West New Guinea more than 50 years ago. These three foci shared a unique mineral environment characterized by the presence of severely low levels of Ca²⁺ and Mg²⁺, coupled with high levels of bioavailable transition metals in the soil and drinking water. Epidemiological studies suggest that genetic factors also contribute to the etiology of these disorders. Here, we report that a variant of the transient receptor potential melastatin 2 (TRPM2) gene may confer susceptibility to these diseases. TRPM2 encodes a calcium-permeable cation channel highly expressed in the brain that has been implicated in mediating cell death induced by oxidants. We found a heterozygous variant of TRPM2 in a subset of Guamanian ALS (ALS-G) and PD (PD-G) cases. This variant, TRPM2^P1018L, produces a missense change in the channel protein whereby proline 1018 (Pro¹⁰¹⁸) is replaced by leucine (Leu¹⁰¹⁸). Functional studies revealed that, unlike WT TRPM2, P1018L channels inactivate. Our results suggest that the ability of TRPM2 to maintain sustained ion influx is a physiologically important function and that its disruption may, under certain conditions, contribute to disease states.     

Primary hypomagnesemia with secondary hypocalcemia,diarrhea and insensitivity to parathyroid hormone

That diarrhea may be associated with hypomagnesemia and/or hypocalcemia is clearly shown by the relationship of magnesium, calcium and gut function in a 2-month-old male hospitalized with seizures, diarrhea, anasarca, hypoalbuminemia, hypocalcemia and hypomagnesemia. Calcium, phosphorus, sodium, potassium and nitrogen balances were positive, but magnesium balance was negative with fecal excretion approximating oral intake. Urinary protein loss was 40 mg/24 hr;⁵¹Cr albumin loss was 1.8%. Administration of parathyroid hormone during magnesium depletion did not produce any rise in serum calcium, but a normal response was observed after magnesium repletion. All clinical abnormalities cleared when magnesium was given, first parenterally and later orally. Thus, hypomagnesemia appears to have resulted from a selective defect in magnesium absorption. Hypocalcemia resulted from parathyroid hormone unresponsiveness during magnesium deficiency. No explanation for diarrhea, other than hypomagnesemia and/or hypocalcemia, was found. The presence of hypoalbuminemia in the face of a positive nitrogen balance suggests that albumin was not synthesized at its usual rate while the patient was depleted of magnesium.     

Cation Interdependency in Acute Stressor States

Acute stressor states are inextricably linked to neurohormonal activation which includes the adrenergic nervous system. Consequent elevations in circulating epinephrine and norepinephrine unmask an interdependency that exists between K⁺, Mg²⁺ and Ca²⁺. Catecholamines, for example, regulate the large number of Mg²⁺-dependent Na/K ATPase pumps present in skeletal muscle. A hyperadrenergic state accounts for a sudden translocation of K⁺ into muscle and rapid appearance of hypokalemia. In the myocardium, catecholamines promote Mg²⁺ efflux from cardiomyocytes, whereas intracellular Ca²⁺ influx and overloading account for the induction of oxidative stress and necrosis of these cells with leakage of their contents, including troponins. Accordingly, acute stressor states can be accompanied by nonischemic elevations in serum troponins, together with the concordant appearance of hypokalemia, hypomagnesemia and ionized hypocalcemia, causing a delay in myocardial repolarization and electrocardiographic QTc prolongation raising the propensity for arrhythmias, including atrial fibrillation and polymorphic ventricular tachycardia. In this review, we focus on the interdependency between K⁺, Mg²⁺ and Ca²⁺ which are clinically relevant to acute stressor states.     

Alteration in Mg2+ content of red blood cells from patients with diuretic therapy

Hypomagnesemia can cause ventricular tachycardia, cardiac necrosis, or torsades de pointes. Diuretic treatment can result in Mg²⁺ depletion, as many diuretics inhibit the reabsorption of filtered Mg²⁺ in the proximal or distal tubule. As plasma Mg²⁺ constitutes only about 3% of total body Mg²⁺ stores, intracellular Mg²⁺ determinations may be more useful for assessing total body Mg²⁺ content. Therefore we studied the effect of a thiazide diuretic (trichlormethiazide 4 mg/day), a combination of a thiazide and a potassium-sparing diuretic (trichlormethiazide and amiloride 2 mg/day each), and the loop diuretic piretanide (6 mg/day) on intracellular Mg²⁺ in patients with mild essential hypertension before and after 6 and 10 weeks of therapy. Mg²⁺ measurements were performed in blood plasma and in red blood cells by atomic absorption spectroscopy, using a Video 12 apparatus. There was a significant decrease in intracellular Mg²⁺ content under trichlormethiazide therapy (p<0.05). Furthermore, our results show that diuretic treatment with a combination of a thiazide and a potassium-sparing diuretic or with the loop diuretic piretanide may have the advantage of avoiding intracellular Mg²⁺ depletion.Presented at The 35th World Congress, International College of Angiology, Copenhagen, Denmark, July 1993     

K+ and Mg2+ Dyshomeostasis in Acute Hyperadrenergic Stressor States

Acute stressor states are linked to neurohormonal activation that includes the adrenergic nervous system. Elevations in circulating epinephrine and norepinephrine unmask an interdependency that exists between K⁺ and Mg²⁺ based on their regulation of a large number of Mg²⁺-dependent Na⁺-K⁺-ATPase pumps present in skeletal muscle. The hyperadrenergic state accounts for a sudden translocation of cations into muscle with the rapid appearance of hypokalemia and hypomagnesemia. The resultant hypokalemia and hypomagnesemia will cause a delay in myocardial repolarization and electrocardiographic QTc prolongation raising the propensity for supraventricular and ventricular arrhythmias. In this review, we focus on the interdependency between K⁺ and Mg²⁺, which is clinically relevant to acute hyperadrenergic stressor states found in patients admitted to intensive care units.     

Extreme hypomagnesemia: characteristics of 119 consecutive inpatients

Extreme hypomagnesemia (hypoMg) can be encountered in many situations, but little data currently exist. Our aim is to describe the epidemiological, clinical, etiological characteristics, and the biological abnormalities of consecutive inpatients with extreme hypomagnesemia. In our observational monocentric study, between 1st July 2000 and April 2015, all inpatients with extreme hypomagnesemia, defined by at least one plasma magnesium concentration (P_Mg) below 0.3 mmol/L, were included. Demographic, clinical, biological characteristics and the drugs prescribed before the qualifying P_Mg measurement were retrospectively collected. 41,069 patients had at least one P_Mg assessment. The prevalence of extreme hypomagnesemia is 0.3% (119 inpatients). The median age is 70 years, 52% are women. The patients were mainly hospitalized in intensive care (n?=?37, 31.1%), oncology (n?=?21, 17.6%), gastroenterology (n?=?18, 15.1%) and internal medicine (n?=?16, 13.4%) departments. One hundred patients (84%) had a medical history of gastrointestinal disease (39% with bowel resections, 24% with stoma), and 50 (42%) had a cancer history. The drugs most commonly prescribed (known to induce hypoMg) are proton pump inhibitors (PPI) (n?=?77, 70%), immunosuppressive regimens (n?=?25, 22.5%), platinum salt-based chemotherapies (n?=?19, 17.1%), and diuretics (n?=?22, 19.8%). The suspected causes of hypomagnesemia are often multiple, but drugs (46%, including PPI in 19%) and chronic gastrointestinal disorders (37%) are prominent. Associated electrolyte disturbances include hypocalcemia (77%) and mild hypokalemia (51%). The 1-month mortality from all causes is 16%. Extreme hypomagnesemia is rare in inpatients, and is frequently associated with severe hypocalcemia. Digestive disorders and drugs are the main contributory causes.     

Quadriparesis in diabetes due to dyselectrolytemia

A tendency for magnesium deficiency in patients with diabetes mellitus is well established. Hypomagnesemia is commonly associated with hypokalemia and hypocalcemia. Here, we report a case of a 55 yr old woman with diabetes mellitus, presenting with acute onset quadriparesis, paresthesia and muscle cramps, associated with hypokalemia, hypomagnesemia and hypocalcemia, with total recovery on correction of electrolytes for which no other secondary cause could be ascertained.     

Parathyroid Hormone, A Crucial Mediator of Pathologic Cardiac Remodeling in Aldosteronism

Aldosteronism, or chronic elevation in plasma aldosterone (ALDO) (inappropriate for dietary Na⁺ intake), is accompanied by an adverse structural remodeling of the heart and vasculature. Herein, we bring forward a new perspective in which parathyroid hormone (PTH) is identified as a crucial mediator of pathologic cardiac remodeling in aldosteronism. Secondary hyperparathyroidism (SHPT) appears because of the marked urinary and fecal losses of Ca²⁺ and Mg²⁺ that accompany aldosteronism which creates ionized hypocalcemia and hypomagnesemia, providing major stimuli to the parathyroids' enhanced secretion of PTH. Invoked to restore extracellular Ca²⁺ and Mg²⁺ homeostasis, elevations in plasma PTH lead to paradoxical intracellular Ca²⁺ overloading of diverse tissues. In the case of cardiomyocytes, the excessive intracellular Ca²⁺ accumulation involves both cytosolic free and mitochondrial domains with a consequent induction of oxidative stress by these organelles and lost ATP synthesis. The ensuing opening of their inner membrane permeability transition pore (mPTP) accounts for the osmotic swelling and structural degeneration of mitochondria followed by programed cell necrosis. Tissue repair, invoked to preserve the structural integrity of myocardium accounts for a replacement fibrosis, or scarring, which is found scattered throughout the right and left heart; it represents a morphologic footprint of earlier necrosis. Multiple lines of evidence are reviewed that substantiate the PTH-mediated paradigm and the mitochondriocentric signal-transducer-effector pathway to cardiomyocyte necrosis.     

Predictors of clinical hypomagnesemia. Hypokalemia, hypophosphatemia, hyponatremia, and hypocalcemia

Four studies were conducted, each determining the frequency of hypomagnesemia in patients already found to have one abnormal electrolyte determination. Hypomagnesemia occurred in 42% of patients with hypokalemia, 29% of patients with hypophosphatemia, 27% of patients with hyponatremia, and 22% of patients with hypocalcemia. These observations suggest that detection of either hypokalemia, hypophosphatemia, hyponatremia, or hypocalcemia, all of which are routinely available determinations, should alert the clinician to order serum magnesium determinations because of the frequent association of hypomagnesemia with these electrolyte perturbations. Optimally, levels of serum Mg should be determined on a routine basis because of the frequency of the occurrence of hypomagnesemia in hospitalized patients.     

Persistent severe hypomagnesemia caused by proton pump inhibitor resolved after laparoscopic fundoplication

Magnesium deficiency can cause a variety of symptoms, including potentially life-threatening complications such as seizures, cardiac arrhythmias and secondary electrolyte disturbances. Hypomagnesemia can be a serious adverse effect to proton pump inhibitor(PPI) therapy, which is worrying due to the widespread use of PPIs. Current evidence suggest that the mechanism of PPI induced hypomagnesemia is impaired intestinal magnesium absorption. In this report, we present the case of a long-term PPI user with persistent hypomagnesemia with severe symptoms at presentation. He was unable to stop PPI treatment because of severe reflux symptoms, and was dependent on weekly intravenous magnesium infusions, until his magnesium levels finally normalized without the need for supplementation after a successful laparoscopic fundoplication.     

Loss of high-frequency glucose-induced Ca2+ oscillations in pancreatic islets correlates with impaired glucose tolerance in Trpm5?/? mice

Glucose homeostasis is critically dependent on insulin release from pancreatic β-cells, which is strictly regulated by glucose-induced oscillations in membrane potential (V_m) and the cytosolic calcium level ([Ca²⁺]_cyt). We propose that TRPM5, a Ca²⁺-activated monovalent cation channel, is a positive regulator of glucose-induced insulin release. Immunofluorescence revealed expression of TRPM5 in pancreatic islets. A Ca²⁺-activated nonselective cation current with TRPM5-like properties is significantly reduced in Trpm5^−/− cells. Ca²⁺-imaging and electrophysiological analysis show that glucose-induced oscillations of V_m and [Ca²⁺]_cyt have on average a reduced frequency in Trpm5^−/− islets, specifically due to a lack of fast oscillations. As a consequence, glucose-induced insulin release from Trpm5^−/− pancreatic islets is significantly reduced, resulting in an impaired glucose tolerance in Trpm5^−/− mice.     

Ion channel-kinase TRPM7 is required for maintaining cardiac automaticity

Sick sinus syndrome and atrioventricular block are common clinical problems, often necessitating permanent pacemaker placement, yet the pathophysiology of these conditions remains poorly understood. Here we show that Transient Receptor Potential Melastatin 7 (TRPM7), a divalent-permeant channel-kinase of unknown function, is highly expressed in embryonic myocardium and sinoatrial node (SAN) and is required for cardiac automaticity in these specialized tissues. TRPM7 disruption in vitro, in cultured embryonic cardiomyocytes, significantly reduces spontaneous Ca²⁺ transient firing rates and is associated with robust down-regulation of Hcn4, Ca_v3.1, and SERCA2a mRNA. TRPM7 knockdown in zebrafish, global murine cardiac Trpm7 deletion (KO^αMHC-Cre), and tamoxifen-inducible SAN restricted Trpm7 deletion (KO^HCN4-CreERT2) disrupts cardiac automaticity in vivo. Telemetered and sedated KO^αMHC-Cre and KO^HCN4-CreERT2 mice show episodes of sinus pauses and atrioventricular block. Isolated SAN from KO^αMHC-Cre mice exhibit diminished Ca²⁺ transient firing rates with a blunted diastolic increase in Ca²⁺. Action potential firing rates are diminished owing to slower diastolic depolarization. Accordingly, Hcn4 mRNA and the pacemaker current, I_f, are diminished in SAN from both KO^αMHC-Cre and KO^HCN4-CreERT2 mice. Moreover, heart rates of KO^αMHC-Cre mice are less sensitive to the selective I_f blocker ivabradine, and acute application of the recently identified TRPM7 blocker FTY720 has no effect on action potential firing rates of wild-type SAN cells. We conclude that TRPM7 influences diastolic membrane depolarization and automaticity in SAN indirectly via regulation of Hcn4 expression.Sinus node dysfunction and atrioventricular node block (AVB) are common causes of bradyarrhythmias in patients, often requiring treatment with permanent pacemakers (1). However, the pathophysiology of sinus node failure and the physiology underlying sinoatrial node (SAN) automaticity remains incompletely understood. The currently held paradigm is that cardiac automaticity arises from the integrated activity of voltage-gated ionic currents (Hcn2/Hcn4, Ca_v3.1, Ca_v1.3), transporters (NCX), and sarcoplasmic reticulum (SR) Ca²⁺ release (2–4). In addition to these “classic” ion currents, some members of the transient receptor potential (TRP) superfamily of ion channels are also expressed in myocardium (TRPC1/3/4/6, TRPM4, TRPM7) (5, 6), but the contribution of these channels to myocardial function remains relatively unexplored.Among these TRP channels, TRPM7 is especially abundant in both human and murine heart (5, 6) and is concentrated in myocardium during embryonic development (7). TRPM7, and its homolog TRPM6, are unique in that they are ion channels containing a carboxyl terminal kinase of unknown function. TRPM7 channel is divalent-permeant and forms an outwardly rectifying current that is inhibited by both cytoplasmic and extracellular Mg²⁺ (8). TRPM7 current was recently shown to be up-regulated in human atrial fibroblasts in the context of atrial fibrillation and was hypothesized to provide a Ca²⁺ influx pathway inducing TGF-β1–mediated fibroblast proliferation and differentiation, thereby contributing to atrial fibrosis in the pathogenesis of atrial fibrillation (9). In addition to atrial fibroblasts, ventricular fibroblasts also have a large TRPM7 current (10), and a TRPM7-like current has been recorded from human atrial myocytes (11). Thus, TRPM7 represents a heretofore unstudied ionic current and signaling molecule in cardiac biology that may participate in arrhythmogenesis in human heart disease or contribute to normal myocardial Ca²⁺ signaling.In this study we show that TRPM7 is required for maintaining cardiac automaticity. TRPM7 current is largest in myocardial cells that exhibit automaticity, such as cultured embryonic ventricular cardiomyocytes (EVM) and isolated SAN cells, compared with the quiescent adult ventricular cardiomyocyte (AVM). Trpm7 deletion in both EVM and SAN slows spontaneous Ca²⁺ transient frequency, thereby disrupting cardiac automaticity in vitro. In vivo, Trpm7 loss of function slows heart rate in embryonic zebrafish and induces sinus pauses (SPs) and AVB in both global cardiac-targeted Trpm7 knockout mice (KO^αMHC-Cre) and in tamoxifen-inducible SAN/atrioventricular node cell (AVN)-restricted Trpm7 knockout mice (KO^Hcn4-CreERT2). We show that these effects are associated with shallowing of the diastolic depolarization slope (DDSL) due to TRPM7-dependent down-regulation of Hcn4 and pacemaker current, I_f.     

Severe Hypomagnesemia Associated with the Long-term Use of the Potassium-competitive Acid Blocker Vonoprazan

Hypomagnesemia caused by a proton pump inhibitor (PPI) was first reported in 2006. We herein report a case of hypomagnesemia due to the long-term use of vonoprazan, a potassium-competitive acid blocker (P-CAB). A 66-year-old man was admitted to our hospital complaining of disturbance of consciousness with evidence of hypomagnesemia noted on blood testing. The long-term use of vonoprazan was considered the cause of his hypomagnesemia, so it was discontinued, after which the hypomagnesemia improved. Hypomagnesemia can be induced not only by PPI treatment but also following the long-term use of P-CAB.     

Intracellular calcium activates TRPM2 and its alternative spliced isoforms

Melastatin-related transient receptor potential channel 2 (TRPM2) is a Ca²⁺-permeable, nonselective cation channel that is involved in oxidative stress-induced cell death and inflammation processes. Although TRPM2 can be activated by ADP-ribose (ADPR) in vitro, it was unknown how TRPM2 is gated in vivo. Moreover, several alternative spliced isoforms of TRPM2 identified recently are insensitive to ADPR, and their gating mechanisms remain unclear. Here, we report that intracellular Ca²⁺ ([Ca²⁺]_i) can activate TRPM2 as well as its spliced isoforms. We demonstrate that TRPM2 mutants with disrupted ADPR-binding sites can be activated readily by [Ca²⁺]_i, indicating that [Ca²⁺]_i gating of TRPM2 is independent of ADPR. The mechanism by which [Ca²⁺]_i activates TRPM2 is via a calmodulin (CaM)-binding domain in the N terminus of TRPM2. Whereas Ca²⁺-mediated TRPM2 activation is independent of ADPR and ADPR-binding sites, both [Ca²⁺]_i and the CaM-binding motif are required for ADPR-mediated TRPM2 gating. Importantly, we demonstrate that intracellular Ca²⁺ release activates both recombinant and endogenous TRPM2 in intact cells. Moreover, receptor activation-induced Ca²⁺ release is capable of activating TRPM2. These results indicate that [Ca²⁺]_i is a key activator of TRPM2 and the only known activator of the spliced isoforms of TRPM2. Our findings suggest that [Ca²⁺]_i-mediated activation of TRPM2 and its alternative spliced isoforms may represent a major gating mechanism in vivo, therefore conferring important physiological and pathological functions of TRPM2 and its spliced isoforms in response to elevation of [Ca²⁺]_i.     

Growth regulation, reverse transformation, and adaptability of 3T3 cells in decreased Mg2+ concentration

A nontransformed and a spontaneously transformed clone of BALB/c 3T3 cells were compared for their capacity to multiply in decreased concentrations of Mg²⁺. Cells of the nontransformed clone were flat, formed regularly patterned, nonoverlapping arrays, required high serum concentration for multiplication, had a low saturation density, and did not make colonies in agar. Cells of the transformed clone were slender and spiky, formed random, overlapping arrays, multiplied in low serum concentrations, and had no fixed saturation density, and 20-30% of them formed colonies in agar. The saturation density of the nontransformed clone was decreased in a growth-limiting supply of Mg²⁺ in proportion to the reduction in initial rate of multiplication. At very low Mg²⁺ concentrations, saturation occurred when less than half of the surface of the dish was covered with cells. The transformed cells did not reach a stable saturation density in low Mg²⁺ concentrations, but their growth rate did slow down when they became crowded, and a transient saturation density was reached at the lowest Mg²⁺ concentrations that allowed multiplication. Limiting the supply of Mg²⁺ caused the transformed cells to flatten and to assume a regularly patterned, non-overlapping relationship to one another, resembling that of the nontransformed cells. This also occurred in BALB/c 3T3 cells transformed by infection with Moloney mouse sarcoma virus. After 1 week in low concentrations of Mg²⁺, the nontransformed cells began to multiply and to incorporate [³H]thymidine at a rapid rate. The transformed cells did so also and, in addition, reverted to their transformed appearance. The intracellular content of Mg²⁺ was not significantly decreased when the extracellular concentration was decreased to 1/50th. The results suggest that: (a) limited contact among cells already multiplying at a reduced rate is sufficient to halt further multiplication; (b) a very small decrease in intracellular Mg²⁺ content or in membrane-associated Mg²⁺ causes transformed cells to assume aspects of the appearance and behavior of nontransformed cells (i.e., Mg²⁺-regulated reactions may be involved in determining the transformed phenotype); and (c) cells multiplying at a slow rate in low concentrations of Mg²⁺ begin to multiply faster after about 1 week, due either to an adaptation of the cells or to a change in the cellular microenvironment.     

Pseudohypoparathyroidism presenting with ventricular arrhythmia: a case report

Pseudohypoparathyroidism (PHP) is a rare disorder characterized by varying degrees of unresponsiveness to parathyroid hormone. Patients usually present with hypocalcemia-induced seizures or tetany, whereas no case of hypocalcemia-induced cardiac arrhythmia in PHP has been described to date. In this paper, we report the case of a male adolescent with PHP type 1a who presented with hypocalcemia-induced ventricular extrasystoles (bigeminy, trigeminy) and mild corrected QT interval prolongation. The patient had brachydactyly and his second fingers and toes were longer than the others, a finding consistent with PHP. Laboratory tests detected hypomagnesemia, as well as elevated levels of creatine kinase and lactate dehydrogenase. Ventricular arrhythmia and abnormal laboratory tests improved with calcium supplementation and vitamin D treatment. The findings in this patient suggest that hypomagnesemia may make patients with PHP more susceptible to hypocalcemia and may thus prompt a state of hypocalcemia-induced arrhythmia or other cardiac complications.     

Mammalian MagT1 and TUSC3 are required for cellular magnesium uptake and vertebrate embryonic development

Magnesium (Mg²⁺) is the second most abundant cation in cells, yet relatively few mechanisms have been identified that regulate cellular levels of this ion. The most clearly identified Mg²⁺ transporters are in bacteria and yeast. Here, we use a yeast complementary screen to identify two mammalian genes, MagT1 and TUSC3, as major mechanisms of Mg²⁺ influx. MagT1 is universally expressed in all human tissues and its expression level is up-regulated in low extracellular Mg²⁺. Knockdown of either MagT1 or TUSC3 protein significantly lowers the total and free intracellular Mg²⁺ concentrations in mammalian cell lines. Morpholino knockdown of MagT1 and TUSC3 protein expression in zebrafish embryos results in early developmental arrest; excess Mg²⁺ or supplementation with mammalian mRNAs can rescue the effects. We conclude that MagT1 and TUSC3 are indispensable members of the vertebrate plasma membrane Mg²⁺ transport system.     

Identification of p.Arg205Cys in CASR in an autosomal dominant hypocalcaemia type 1 pedigree: A case report

Rationale:Autosomal dominant hypocalcaemia type 1 (ADH1) is a genetic disease characterized by benign hypocalcemia, inappropriately low parathyroid hormone levels and mostly hypercalciuria. It is caused by the activating mutations of the calcium-sensing receptor gene (CASR), which produces a left-shift in the set point for extracellular calcium.Patient concerns:A 50-year-old man presenting with muscle spasms was admitted into the hospital. He has a positive familial history for hypocalcemia. Auxiliary examinations demonstrated hypocalcemia, hyperphosphatemia, normal parathyroid hormone level and nephrolithiasis. A missense heterozygous variant in CASR, c 613C > T (p. Arg205Cys) which has been reported in a familial hypocalciuric hypercalcemia type 1 patient was found in the patient''s genotype. It is the first time that this variant is found associating with ADH1. The variant is predicted vicious by softwares and cosegregates with ADH1 in this pedigree. CASR Arg205Cys was deduced to be the genetic cause of ADH1 in the family.Diagnosis:The patient was diagnosed with ADH1 clinically and genetically.Interventions:Oral calcitriol, calcium and hydrochlorothiazide were prescribed to the patient.Outcomes:After the treatments for 1 week, the patient''s symptom was improved and the re-examination revealed serum calcium in the normal range. A 3-month follow-up showed his symptom was mostly relieved.Lessons:The variant of CASR Arg205Cys, responsible for ADH1 in this family, broadened the genetic spectrum of ADH1. Further and more studies are required to evaluate the correlation between genotype and phenotype in ADH1 patients.