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.

Renal diseases that course with hypomagnesemia. Comments on a new hereditary hypomagnesemic tubulopathy.

Renal diseases associated with hypomagnesemia are a complex and diverse group of tubulopathies caused by mutations in genes encoding proteins that are expressed in the thick ascending limb of the loop of Henle and in the distal convoluted tubule. In this paper, we review the initial description, the clinical expressiveness and etiology of four of the first hypomagnesemic tubulopathies described: type 3 Bartter and Gitelman diseases, Autosomal recessive hypomagnesemia with secondary hypocalcemia and Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The basic biochemical patterns observed in renal tubular hypomagnesemias and the modalities of transport and interaction that occur between the transporters involved in the reabsorption of magnesium in the distal convoluted tubule are described below. Finally, the recent report of a new renal disease with hypomagnesemia, type 2 hypomagnesemia with secondary hypocalcemia caused by reduced TRPM7 channel activity is described.

Hereditary hypomagnesemia with secondary hypocalcemia caused by a novel mutation in TRPM6 gene.

OBJECTIVES: Hereditary hypomagnesemia with secondary hypocalcemia (HSH), which results from variations in the transient receptor potential melastatin 6 (TRPM6) genes, is a rare hereditary cause of extremely low serum magnesium levels. We describe an infant with triggered seizures due to hypomagnesemia and a novel mutation in TRPM6 gene was identified. CASE PRESENTATION: A 10-month-old boy presented with multidrug resistant seizures, and axial hypotonia due to severe hypomagnesemia. Electroencephalography and neuroimaging of the patient was normal. He had a favorable outcome with magnesium supplement. In this study, the patient underwent clinical exome sequencing (CES) which detected a novel homozygous variant in the TRPM6 gene: NM_017662.5: c.5571-3C>G. After replacing his magnesium orally, he was free from seizures and had an encouraging outcome at the twelfth-month follow-up. CONCLUSIONS: HSH often presents with developmental issues, treatment-resistant seizures, and increased neuromuscular excitability. Untreated hypomagnesemia can potentially be fatal and severely impair cognitive function. Clinical suspicion is essential for early diagnosis and treatment.

A functional study for verifying the pathogenicity of a TRPM6 variant of uncertain significance: A novel non-canonical splicing-site variant in primary hypomagnesemia with secondary hypocalcemia.

INTRODUCTION: Primary hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disease caused by biallelic variants in TRPM6 gene. METHODS: In this study, we reported a Chinese patient diagnosed with HSH in Tianjin Children's Hospital. Detailed clinical examination and laboratory test were performed and whole exome sequencing (WES) was applied to detect the pathogenic gene in the proband. The suspected compound heterozygous variant in TRPM6 gene was verified by Sanger sequencing and quantitative real-time PCR technology. Minigene assay was performed to verify the function of the variant suspected to affect splicing process. RESULTS: The patient presented with seizure and markedly decreased levels of serum magnesium and calcium. WES combined with functional study diagnosed a pediatric patient with HSH caused by a compound heterozygous variant in TRPM6 gene, containing a novel non-canonical splicing-site variant c.5058-26A > G and a heterozygous deletion in exons 27-33 (chr9q21.13: 77357467-77376734). CONCLUSIONS: The compound heterozygous variant in TRPM6 gene is the pathogenic cause of the proband. The combined application of WES and functional study contribute to validating the effect of an uncertain genetic variant on splicing, improving the pathogenicity evidence and identifying the etiology of the disease. It is helpful for early diagnosis and treatment of HSH.

A novel synonymous homozygous variant [c.2538G>A (p.Thr846Thr)] in TRPM6 in a patient with hypomagnesemia with secondary hypocalcemia.

OBJECTIVES: Hypomagnesemia 1, intestinal (HOMG1) is characterized by neurological symptoms that occur due to hypocalcemia and hypomagnesemia and caused by mutations in the TRPM6. Most of the identified variants in TRPM6 lead to premature termination: nonsense, frameshift, deletion, and splice site mutations. CASE PRESENTATION: Herein, we report a 1.5 month-old case who presented with convulsion due to hypocalcemia and hypomagnesemia in the early infancy. Sequencing of TRPM6 revealed a novel homozygous synonymous variant [c.2538G > A (p.Thr846Thr)] in the last codon of exon 19, which is most likely to affect the splicing. We report a novel homozygous synonymous variant in the TRPM6 leading to HOMG1, expanding the mutational spectrum. CONCLUSIONS: Synonymous mutations that were previously considered as harmless should be evaluated at the nucleotide level, keeping in mind that they may affect splicing and cause to the disease.

Novel mutations in TRPM6 gene associated with primary hypomagnesemia with secondary hypocalcemia. Case report.

BACKGROUND: Primary hypomagnesemia with secondary hypocalcemia (HSH) is a rare genetic disorder. Dysfunctional transient receptor potential melastatin 6 causes impaired intestinal absorption of magnesium, leading to low serum levels accompanied by hypocalcemia. Typical signs at initial manifestation are generalized seizures, tetany, and/or muscle spasms. CASE REPORT: We present a 5 w/o female manifesting tonic-clonic seizures. Laboratory tests detected severe hypomagnesemia and hypocalcemia. The molecular genetic analysis revealed two novel mutations within the TRPM6 gene c.3308dupC (p.Pro1104Thrfs*28) (p.P1104Tfs*28) and c.3958C>T (p.Gln1302*) (p.Q1302*) and the patient was successfully treated with Mg supplementation. CONCLUSION: Ion disbalance should be taken into account in the differential diagnosis of infantile seizures. Accurate diagnosis of HSH together with appropriate treatment are crucial to prevent irreversible neurological outcomes.

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.

Multiple electrolyte imbalances and mixed acid-base disorder posing a diagnostic dilemma: a case report.

BACKGROUND: In clinical practice, both the history and laboratory testing are paramount to making an accurate diagnosis. Situations in which laboratory findings and patient history are not congruent pose a diagnostic dilemma. We report a case of a young woman presenting with a myriad of electrolyte and acid-base disorders. Difficulty in reaching a unifying diagnosis persisted due to discordant patient history. We believe this case shows that lab findings will clearly portray the problems a patient has and should be given more credence in a case where the history is discordant with lab findings. CASE PRESENTATION: A 28-year-old Hispanic American woman presented to the emergency room of our institution with a complaint of painless and sudden onset of stiffness in her upper and lower limbs. Associated weakness worse in the distal limbs was also reported. She experienced shortness of breath with minimal exertion, diaphoresis, and anxiety. Her vital signs revealed tachycardia without corresponding fever. She was conscious, oriented, and alert. Her physical exam revealed dry mucous membranes and warm extremities. She denied recent consumption of a large carbohydrate meal, diarrhea, vomiting, use of laxatives, and use of alcohol or recreational drugs. She vaguely described two previous similar episodes in the last 7 months that spontaneously resolved. Her medical history was significant only for hypothyroidism treated with daily levothyroxine tablets. Laboratory analysis revealed the following abnormalities: an elevated anion gap with significant lactate, hypokalemia, hypomagnesemia, elevated mean corpuscular volume, elevated mean cell hemoglobin, and elevated liver enzymes with aspartate aminotransferase/alanine aminotransferase ratio > 2. She was hydrated with balanced crystalloids, and her electrolyte deficiencies corrected. The etiology of her multiple electrolyte abnormalities was unclear because alcohol use was vehemently denied. Extensive evaluation for causes of electrolyte disorder was undertaken, which was unrevealing. On further interrogation, she admitted to recent alcohol intoxication and several episodes of vomiting before presentation. She was advised to refrain from alcohol use and discharged afterward. CONCLUSION: Both patient history and laboratory analysis have a role in identifying and confirming a diagnosis. In cases in which laboratory tests are incongruous with reported history, making a unifying diagnosis can be challenging or delayed. The importance of taking a comprehensive history cannot be overemphasized, but history provided by patients may be prone to intentional or unintentional distortion, whereas laboratory findings are more objective. The case presented underscores why the lab findings should be given credence in cases in which there is discordance between lab results and the provided patient history.

[Clinical features and TRPM6 mutations of an infant with hypomagnesemia with secondary hypocalcemia].

OBJECTIVE: To explore the clinical features and mutations of the TRPM6 gene in an infant featuring hypomagnesemia and secondary hypocalcemia. METHODS: Clinical data of the patient was collected. Genomic DNA was extracted from peripheral blood samples from the patient and her parents. Targeted exome sequencing was carried out to screen the potential mutations. Suspected mutations were verified by Sanger sequencing. RESULTS: A novel homozygous c.5538delA (p.Q1846Qfs*2) mutation in the TRPM6 gene was identified in the proband, for which both of her parents were heterozygous carriers. CONCLUSION: The homozygous frameshift mutation of TRPM6 gene (c.5538delA) probably underlies the disease in the proband. The finding has expanded the mutation spectrum of TRPM6 gene.

[Familial hypomagnesaemia with secondary hypocalcaemia as a cause of seizures in children].

This case report presents a three-month-old girl, previously healthy, who was admitted to the hospital due to a cyanotic episode during breastfeeding. The episode was initially interpreted as aspiration. She had recurrent generalised seizures, and blood tests revealed hypomagnesaemia and hypocalcaemia. The electrolyte abnormalities were corrected by intravenous magnesium with subsequent normalisation of the calcium level. Genetic testing discovered a deletion in the TRPM6, which is associated with familial hypomagne-s-aemia with secondary hypocalcaemia. It is important to identify electrolyte disturbances in infants with afebrile seizures.

Exome sequencing identifies a novel frameshift variant causing hypomagnesemia with secondary hypocalcemia.

Hypomagnesemia with secondary hypocalcemia is a rare autosomal-recessive disorder characterized by intense hypomagnesemia associated with hypocalcemia (HSH). Mutations in the TRPM6 gene, encoding the epithelial Mg2+ channel TRPM6, have been proven to be the molecular cause of this disease. This study identified causal mutations in a 2-month-old male patient of hypomagnesemia from a consanguineous marriage. Biochemical analyses indicated the diagnosis of HSH due to primary gastrointestinal loss of magnesium. Whole exome sequencing of the trio (i.e. proband and both parents) was carried out with mean coverage of > 150×. ANNOVAR was used to annotate functional consequences of genetic variation from exome sequencing data. After variant filtering and annotation, a number of single nucleotide variants (SNVs) and 2 bp deletion at exon26:c.4402_4403delCT in TRPM6 gene were identified. This deletion which resulted in a novel frameshift mutation in exon 26 of this gene was confirmed by Sanger sequencing. With these investigations in hand, the patient was managed with magnesium sulphate. The patient remained asymptomatic and was developmentally and neurologically normal till his last follow up.

CNNM2 homozygous mutations cause severe refractory hypomagnesemia, epileptic encephalopathy and brain malformations.

Magnesium (Mg2+) plays a crucial role in many biological processes especially in the brain, heart and skeletal muscle. Mg2+ homeostasis is regulated by intestinal absorption and renal reabsorption, involving a combination of different epithelial transport pathways. Mutations in any of these transporters result in hypomagnesemia with variable clinical presentations. Among these, CNNM2 is found along the basolateral membrane of distal tubular segments where it is involved in Mg2+ reabsorption. To date, heterozygous mutations in CNNM2 have been associated with a variable phenotype, ranging from isolated hypomagnesemia to intellectual disability and epilepsy. The only homozygous mutation reported so far, is responsible for hypomagnesemia associated with a severe neurological phenotype characterized by refractory epilepsy, microcephaly, severe global developmental delay and intellectual disability. Here, we report the second homozygous CNNM2 mutation (c.1642G > A,p.Val548Met) in a Moroccan patient, presenting with hypomagnesemia and severe epileptic encephalopathy. Thus, we review and discuss the phenotypic spectrum associated with CNNM2 mutations.

Dietary Magnesium Alleviates Experimental Murine Colitis Through Upregulation of the Transient Receptor Potential Melastatin 6 Channel.

Background: Magnesium (Mg) is essential for human health and is absorbed mainly in the intestine. In view of the likely occurrence of an Mg deficit in inflammatory bowel disease (IBD) and the documented role of Mg in modulating inflammation, the present study addresses whether Mg availability can affect the onset and progression of intestinal inflammation. Methods: To study the correlation between Mg status and disease activity, we measured magnesemia by atomic absorption spectroscopy in a cohort of IBD patients. The effects of dietary Mg modulation were assessed in a murine model of dextran sodium sulfate (DSS)-induced colitis by monitoring magnesemia, weight, fecal occult blood, diarrhea, colon length, and histology. Expression of the transient receptor potential melastatin (TRPM) 6 channel was assessed by real-time reverse transcription polymerase chain reaction and immunohistochemistry in murine colon tissues. The effect of Mg on epithelial barrier formation/repair was evaluated in human colon cell lines. Results: Inflammatory bowel disease patients presented with a substantial Mg deficit, and serum Mg levels were inversely correlated with disease activity. In mice, an Mg-deficient diet caused hypomagnesemia and aggravated DSS-induced colitis. Colitis severely compromised intestinal Mg2+ absorption due to mucosal damage and reduction in TRPM6 expression, but Mg supplementation resulted in better restoration of mucosal integrity and channel expression. Conclusions: Our results highlight the importance of evaluating and correcting magnesemia in IBD patients. The murine model suggests that Mg supplementation may represent a safe and cost-effective strategy to reduce inflammation and restore normal mucosal function.

Familial hypomagnesaemia with secondary hypocalcaemia.

Magnesium is the second most abundant intracellular cation and plays an essential role in neuronal, skeletal and cardiac tissue. Hypomagnesaemia can cause hypocalcaemia by inhibiting parathyroid hormone release and inducing resistance at its receptor sites. Untreated hypomagnesaemia can lead to tetany, recurrent seizures, status epilepticus and life-threatening arrhythmias. Primary hypomagnesaemia with secondary hypocalcaemia (HSH) is a rare metabolic disorder of intestinal magnesium absorption. The condition typically presents in the neonatal period with neuromuscular excitability and seizures refractory to antiepileptic therapy. Early diagnosis and prompt magnesium replacement are essential to prevent death or long-term neurodevelopmental sequelae. Fewer than a hundred cases are reported in the literature. Recent advances have added significantly to our understanding of the genetic basis of HSH. We report the presentation and long-term follow-up of an affected female who was found to have a mutation in the transient receptor potential melastatin 6 (TRPM6) gene, encoding a transient receptor potential cation channel.

Mechanisms and causes of hypomagnesemia.

PURPOSE OF REVIEW: Identification of the mechanisms of magnesium absorption and reabsorption has markedly enhanced our understanding of the causes of hypomagnesemia. RECENT FINDINGS: New gastrointestinal and renal causes of hypomagnesemia have been recently documented. SUMMARY: The recognition of new mechanisms and causes of magnesium absorption and reabsorption should enhance the ability to monitor patients at risk for hypomagnesemia and improve our ability to mitigate the serious symptoms associated with this disorder.

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.