A Rare Case of Neonatal Hypomagnesemia with Secondary Hypocalcemia Caused by a Novel Homozygous TRPM6 Gene Variant.

BACKGROUND Familial hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disorder (OMIM# 602014) caused by mutations in the gene encoding transient receptor potential melastatin 6 (TRPM6)) on chromosome 9q22, a channel involved in epithelial magnesium resorption. While a plethora of studies have delineated various clinical manifestations pertinent to this mutation, the literature is devoid of connections between TRPM6 mutations and bleeding diathesis, or sudden infant death syndrome (SIDS). This report presents a case of familial HSH associated with the novel homozygous TRPM6 gene variant c.5281C>G p. (Arg1761Gly) chr9: 77354845. CASE REPORT This report details a 26-day-old neonate, born full term with optimal Apgar scores, who experienced an abrupt emergence of apnea, cyanosis, bilateral nasal bleeding, and diminished alertness. Despite the neonate's initially unremarkable clinical birth indicators, a meticulous assessment unveiled a pronounced family history of SIDS, including a sibling previously diagnosed with hypomagnesemia. Laboratory examination of the infant demonstrated severe hypomagnesemia and hypocalcemia, conditions which were promptly ameliorated following intravenous administration of magnesium and calcium. Whole-exome sequencing identified a homozygous TRPM6 gene mutation c.5281C>G p. (Arg1761Gly) at chr9: 77354845. This gene is crucial for magnesium regulation. The mutation involves a cytosine-to-guanine shift, resulting in an arginine to glycine amino acid substitution at position 1761 of the TRPM6 protein. CONCLUSIONS This report has highlighted that infantile hypomagnesemia may be associated with symptoms and signs that can mimic infection, or it can present with seizures. Although familial HSH is a rare genetic disorder that can be identified by genetic testing, correction of hypomagnesemia is the most important and immediate clinical management strategy.

Improving diagnosis and treatment of hypomagnesemia.

Magnesium is one of the most abundant cations in the body and acts as a cofactor in more than 600 biochemical reactions. Hypomagnesemia is a highly prevalent condition, especially in subjects with comorbid conditions, but has received less attention than other electrolyte disturbances. This review will discuss magnesium physiology, absorption, storage, distribution across the body, and kidney excretion. After reviewing the regulation of magnesium homeostasis, we will focus on the etiology and clinical presentation of hypomagnesemia. The role of laboratory medicine in hypomagnesemia will be the main purpose of this review, and we will discuss the laboratory tests and different samples and methods for its measurement. Although free magnesium is physiologically active, total serum magnesium is the most commonly used measurement in laboratory medicine and is apt for clinical purposes; however, it is not appropriately used, and many patients with hypomagnesemia remain undiagnosed and not treated. Using information technologies, laboratory medicine can largely improve the diagnosis and treatment of hypomagnesemia through the design and establishment of automatic demand management and result management interventions by acting in the first and last steps of the laboratory cycle, test requests, and actions taken after test results, to unmask patients with hypomagnesemia and improve the number of patients undergoing treatment.

[Severe hypomagnesemia in a man with alcohol dependence: a forgotten electrolyte in a neglected population]. / Ernstig magnesiumtekort bij alcoholverslaving.

BACKGROUND: Symptoms of acute alcohol withdrawal like tremors, seizures and delirium are commonly treated with benzodiazepines and vitamins. When complaints are not reacting to this treatment, an alternative diagnosis must be considered. Although hypomagnesemia is present in at least 30 percent of the patients with alcohol dependence, it can provoke and maintain these complaints. CASE DESCRIPTION: We present a 43-year-old man with alcohol dependence, who shows neurological, muscular, and cardiac consequences of an undiagnosed hypomagnesemia. CONCLUSION: In daily clinical practice there is not enough attention for magnesium deficits, especially in patients with alcohol dependence. Serious complications can be prevented by recognizing and treating magnesium deficiency more adequately.

Serum magnesium: time for a standardized and evidence-based reference range.

Magnesium deficiency can have serious health consequences. Low magnesium intake or low serum levels are risk factors for e.g. type 2 diabetes and cardiovascular diseases. Despite its scientifically recognized importance, too little attention is paid to magnesium in clinical practice. This may be due to the fact that there is no uniform and evidence-based reference range for serum magnesium as is the case for other electrolytes such as sodium and potassium. The serum magnesium concentration is also of a limited informative value, as it is maintained for a long time by releasing magnesium from body pools. A low serum magnesium is a definite sign of magnesium deficiency; however, values within the reference range do not rule out deficiencies. Nevertheless, serum magnesium should become part of routine diagnostics in order to be able to better detect deficiency states. For serum magnesium, a reference range of 0.75 to 0.95 mmol/L (1.82 to 2.31 mg/dL) can often be found. However, according to the current data situation, serum magnesium values of less than 0.85 mmol/L are associated with increased health risks. Therefore, the lower limit of the reference range should be raised to 0.85 mmol/L (2.07 mg/dL).

Migraine and Its Association with Hyperactivity of Cell Membranes in the Course of Latent Magnesium Deficiency-Preliminary Study of the Importance of the Latent Tetany Presence in the Migraine Pathogenesis.

So far, there is no consistent and convincing theory explaining the pathogenesis of migraines. Vascular disorders, the effect of oxidative stress on neurons, and the contribution of magnesium-calcium deficiencies in triggering cortical depression and abnormal glutaminergic neurotransmission are taken into account. However, there are no reliable publications confirming the role of dietary deficits of magnesium and latent tetany as factors triggering migraine attacks. The aim of the study was to evaluate the influence of latent magnesium deficiency assessed with the electrophysiological tetany test on the course of migraine. The study included: a group of 35 patients (29 women and six men; in mean age 41 years) with migraine and a control group of 24 (17 women and seven men; in mean age 39 years) healthy volunteers. Migraine diagnosis was based on the International Headache Society criteria, 3rd edition. All patients and controls after full general and neurological examination were subjected to a standard electrophysiological ischemic tetany test. Moreover, the level of magnesium in blood serum was tested and was in the normal range in all patients. Then, the incidence of a positive tetany EMG test results in the migraine group and the results in the subgroups with and without aura were compared to the results in the control group. Moreover, the relationship between clinical markers of spasmophilia and the results of the tetany test was investigated in the migraine group. As well as the relationship between migraine frequency and tetany test results. There was no statistically significant difference in the occurrence of the electrophysiological exponent of spasmophilia between the migraine and control group. Neither correlation between the occurrence of clinical symptoms nor the frequency of migraine attacks and the results of the tetany test was stated (p > 0.05). However, there was an apparent statistical difference between the subgroup of migraine patients with aura in relation to the control group (p < 0.05). The result raises hope to find a trigger for migraine attacks of this clinical form, the more that this factor may turn out to be easy to supplement with dietary supplementation.

Hypomagnesemia Is a Risk Factor for Infections after Kidney Transplantation: A Retrospective Cohort Analysis.

INTRODUCTION: Magnesium (Mg2+) deficiency is a common finding in the early phase after kidney transplantation (KT) and has been linked to immune dysfunction and infections. Data on the association of hypomagnesemia and the rate of infections in kidney transplant recipients (KTRs) are sparse. METHODS: We conducted a single-center retrospective cohort study of KTRs transplanted between 2005 and 2015. Laboratory data, including serum Mg2+ (median time of the Mg2+ measurement from KT: 29 days), rate of infections including mainly urinary tract infections (UTI), and common transplant-related viral infections (CMV, polyoma, EBV) in the early phase after KT were recorded. The primary outcome was the incidence of infections within one year after KT, while secondary outcomes were hospitalization due to infection, incidence rates of long-term (up to two years) infections, and all-cause mortality. RESULTS: We enrolled 376 KTRs of whom 229 patients (60.9%) suffered from Mg2+ deficiency defined as a serum Mg2+ < 0.7 mmol/L. A significantly higher incidence rate of UTIs and viral infections was observed in patients with versus without Mg2+ deficiency during the first year after KT (58.5% vs. 47.6%, p = 0.039 and 69.9% vs. 51.7%, p < 0.001). After adjustment for potential confounders, serum Mg2+ deficiency remained an independent predictor of both UTIs and viral infections (odds ratio (OR): 1.73, 95% CI: 1.04-2.86, p = 0.035 and OR: 2.05, 95% CI: 1.23-3.41, p = 0.006). No group differences according to Mg2+ status in hospitalizations due to infections and infection incidence rates in the 12-24 months post-transplant were observed. In the Cox regression analysis, Mg2+ deficiency was not significantly associated with all-cause mortality (HR: 1.15, 95% CI: 0.70-1.89, p = 0.577). CONCLUSIONS: KTRs suffering from Mg2+ deficiency are at increased risk of UTIs and viral infections in the first year after KT. Interventional studies investigating the effect of Mg2+ supplementation on Mg2+ deficiency and viral infections in KTRs are needed.

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.

Risk factors and comorbidities associated with magnesium deficiency in pregnant women and women with hormone-related conditions: analysis of a large real-world dataset.

BACKGROUND: An accumulating body of literature indicates that magnesium deficiency is associated with a number of hormone-related conditions (HRC) in women, and epidemiological studies are needed to assess its prevalence and risk factors. Here, we present a secondary analysis of data pooled from four large observational studies that assessed magnesium deficiency among pregnant women and women with HRC across the Russian Federation. METHODS: The main objective of this analysis was to estimate the prevalence of magnesium deficiency in this population and to describe risk factors and comorbidities associated with low serum magnesium. Univariate logistic regression analysis was performed to identify the risk factors and comorbid conditions associated with an increased risk of low serum magnesium level. RESULTS: A total of 983 pregnant women and 9444 women with HRC were eligible for analysis. Prevalence of hypomagnesemia (magnesium serum level cut-off < 0.66 mmol/L/< 0.8 mmol/L) was 34.0%/78.9% in pregnant women and 21.4%/54.8% in women with HRC. The highest prevalence of magnesium deficiency was observed for osteoporosis and climacteric syndrome. Risk factors included diastolic blood pressure, previous pregnancy complications, infections and edema for pregnant women, and age, body mass index, and various comorbidities for women with HRC. CONCLUSIONS: These results confirm the high prevalence of hypomagnesemia in pregnant women and women with HRC and underline the importance of routine screening, since risk factors are mostly non-specific.

Does fludrocortisone treatment cause hypomagnesemia in children with primary adrenal insufficiency?

Background/aim: Aldosterone is a mineralocorticoid that secreted from adrenal glands and a known factor to increase magnesium excretion by direct and indirect effects on renal tubular cells. Although the frequency of hypomagnesemia was found to be approximately 5% in adult studies, there is no study in the literature investigating the frequency of hypomagnesemia in children by using fludrocortisone, which has a mineralocorticoid activity. Materials and methods: A multi-center retrospective study was conducted, including children who were under fludrocortisone treatment for primary adrenal insufficiency and applied to participant pediatric endocrinology outpatient clinics. Results: Forty-three patients (58.1% male, 41.9% prepubertal) included in the study, whose median age was 9.18 (0.61-19) years, and the most common diagnosis among the patients was a salt-wasting form of congenital adrenal hyperplasia (67.4%). Mean serum magnesium level was 2.05 (±0.13) mg/dL, and hypomagnesemia was not observed in any of the patients treated with fludrocortisone. None of the patients had increased urinary excretion of magnesium. Conclusion: Unlike the studies performed in adults, we could not find any evidence of magnesium wasting effect of fludrocortisone treatment with normal or even high doses in children and adolescents.

[Neurological symptoms of hypomagnesemia]. / Neurologische symptomen bij hypomagnesiëmie.

BACKGROUND: An epileptic seizure is a common neurological presentation in the Emergency Department (ED). Electrolyte disturbances are an important cause of neurological symptoms like seizures and hypomagnesemia is one of them. PPI's can cause hypomagnesemia and are readily prescribed. Therefore patients taking PPI's are at risk of developing neurological symptoms due to hypomagnesemia. CASE: A 82-year old woman was seen in ED with a history of nausea, vomiting and vertigo. A vertical nystagmus was observed with attacks of mydriasis followed by a phase of encephalopathy and restlessness. These were recognized as epilepsy. Hypokaliemia, hypocalcemia and a deep hypomagnesemia were present. The PPI accounted for hypomagnesemia. After 2 days of intravenous magnesium suppletion all symptoms disappeared. CONCLUSION: PPI's can cause hypomagnesemia and magnesium levels should be obtained in patients presenting with encephalopathy or atypical neurological symptoms.

Monitoring and parenteral administration of micronutrients, phosphate and magnesium in critically ill patients: The VITA-TRACE survey.

BACKGROUND & AIMS: Despite the presumed importance of preventing and treating micronutrient and mineral deficiencies, it is still not clear how to optimize measurement and administration in critically ill patients. In order to design future comparative trials aimed at optimizing micronutrient and mineral management, an important first step is to gain insight in the current practice of micronutrient, phosphate and magnesium monitoring and administration. METHODS: Within the metabolism-endocrinology-nutrition (MEN) section of the European Society of Intensive Care Medicine (ESICM), the micronutrient working group designed a survey addressing current practice in parenteral micronutrient and mineral administration and monitoring. Invitations were sent by the ESICM research department to all ESICM members and past members. RESULTS: Three hundred thirty-four respondents completed the survey, predominantly consisting of physicians (321 [96.1%]) and participants working in Europe (262 [78.4%]). Eighty-one (24.3%) respondents reported to monitor micronutrient deficiencies through clinical signs and/or laboratory abnormalities, and 148 (44.3%) reportedly measure blood micronutrient concentrations on a routine basis. Two hundred ninety-two (87.4%) participants provided specific data on parenteral micronutrient supplementation, of whom 150 (51.4%) reported early administration of combined multivitamin and trace element preparations at least in selected patients. Among specific parenteral micronutrient preparations, thiamine (146 [50.0%]) was reported to be the most frequently administered micronutrient, followed by vitamin B complex (104 [35.6%]) and folic acid (86 [29.5%]). One hundred twenty (35.9%) and 113 (33.8%) participants reported to perform daily measurements of phosphate and magnesium, respectively, whereas 173 (59.2%) and 185 (63.4%) reported to routinely supplement these minerals parenterally. CONCLUSION: The survey revealed a wide variation in current practices of micronutrient, phosphate and magnesium measurement and parenteral administration, suggesting a risk of insufficient prevention, diagnosis and treatment of deficiencies. These results provide the context for future comparative studies, and identify areas for knowledge translation and recommendations.

[Hypomagnesemia in newborns with hypoxic ischemic encephalopathy and whole-body hypothermia]. / Hipomagnesemia en recién nacidos con encefalopatía hipóxico isquémica en hipotermia corporal total.

INTRODUCTION: In newborns with the diagnosis of hypoxic-ischemic encephalopathy (HIE) treated with hypother mia, metabolic alterations are observed, which are associated with neurological prognosis. Hypo magnesemia has been reported frequently in the literature in these patients, but it is not measured or corrected in all neonatal healthcare centers. OBJECTIVE: To evaluate the frequency of hypomag nesemia and hypocalcemia in newborns with HIE treated with whole-body hypothermia and to evaluate the response to the magnesium sulfate administration. PATIENTS AND METHOD: Prospective, observational and descriptive study in hospitalized newborns with the diagnosis of HIE and trea ted with whole-body hypothermia between the years 2016 and 2017. Serial blood measurement of magnesemia (Mg) and calcemia (Ca) was performed. When presenting an Mg level < 1.8 mg/dl, supplementation with magnesium sulfate was administered to maintain levels between 1.9 and 2.8 mg/dl. The frecuency of hypomagnesemia, hypocalcemia and clinical evolution was registered. A descriptive statistical analysis was performed, with central tendency measures. RESULTS: Sixteen ca ses were included, 13 of them presented hypomagnesemia (81.3%), with early-onset (6-36 hours of life), which was normalized with magnesium sulfate treatment, receiving a second dose 4 patients. Six of 16 patients presented hypocalcemia (37.5 %). CONCLUSIONS: Hypomagnesemia is frequent (80%), similar to that described in the literature, and should be controlled and corrected early, given its physiological role, in the same way that calcium is controlled.

Magnesium Deficiency Questionnaire: A New Non-Invasive Magnesium Deficiency Screening Tool Developed Using Real-World Data from Four Observational Studies.

Due to the high estimated prevalence of magnesium deficiency, there is a need for a rapid, non-invasive assessment tool that could be used by patients and clinicians to confirm suspected hypomagnesemia and substantiate laboratory testing. This study analyzed data from four large observational studies of hypomagnesemia in pregnant women and women with hormone-related conditions across Russia. Hypomagnesemia was assessed using a 62-item magnesium deficiency questionnaire (MDQ-62) and a serum test. The diagnostic utility (sensitivity/specificity) of MDQ-62 was analyzed using area under the receiver operating characteristic curve (AUROC). A logistic regression model was applied to develop a shorter, optimized version of MDQ-62. A total of 765 pregnant women and 8836 women with hormone-related conditions were included in the analysis. The diagnostic performance of MDQ-62 was "fair" (AUROC = 0.7-0.8) for women with hormone-related conditions and "poor" for pregnant women (AUROC = 0.6-0.7). The optimized MDQ-23 (23 questions) and MDQ-10 (10 questions) had similar AUROC values; for all versions of the questionnaire, there was a significant negative correlation between score and changes in total serum magnesium levels (p < 0.0001 for all comparisons; correlation coefficients ranged from -0.1667 to -0.2716). This analysis confirmed the value of MDQ in identifying women at risk of hypomagnesemia.

Relationship Between Dietary Magnesium Intake and Incident Heart Failure Among Older Women: The WHI.

Background Women represent a large proportion of the growing heart failure (HF) epidemic, yet data are lacking regarding optimal dietary and lifestyle prevention strategies for them. Specifically, the association between magnesium intake and HF in a multiracial cohort of women is uncertain. Methods and Results We included 97 725 postmenopausal women from the WHI (Women's Health Initiative) observational studies and placebo arms of the hormone trial. Magnesium intake was measured at baseline by a 122-item validated food-frequency questionnaire and stratified into quartiles based on diet only, total intake (diet with supplements), and residual intake (calibration by total energy). Incident hospitalized HF (2153 events, median follow-up 8.1 years) was adjudicated by medical record abstraction. In Cox proportional hazards models, we evaluated the association between magnesium intake and HF adjusting for potential confounders. Analyses were repeated on a subcohort (n=18 745; median-follow-up, 13.2 years) for whom HF cases were subclassified into preserved ejection fraction (526 events), reduced ejection fraction (291 events) or unknown (168 events). Most women were white (85%) with a mean age of 63. Compared with the highest quartile of magnesium intake, women in the lowest quartile had an increased risk of incident HF, with adjusted hazard ratios of 1.32 (95% CI, 1.02-1.71) for diet only (P trend=0.03), 1.26 (95% CI, 1.03-1.56) for total intake, and 1.31 (95% CI, 1.02-1.67) for residual intake. Results did not significantly vary by race. Subcohort analyses showed low residual magnesium intake was associated with HF with reduced ejection fraction (hazard ratio, 1.81, lowest versus highest quartile; 95% CI, 1.08-3.05) but not HF with preserved ejection fraction. Conclusions Low magnesium intake in a multiracial cohort of postmenopausal women was associated with a higher risk of incident HF, especially HF with reduced ejection fraction.