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.

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.

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 Hypomagnesemia with Secondary Hypocalcemia Mimicking Neurodegenerative Disorder.

BACKGROUND: Familial hypomagnesemia with secondary hypocalcemia is a genetic disorder of magnesium metabolism that presents with refractory seizures in infancy. CASE CHARACTERISTICS: We herein report an infant with familial hypomagnesemia who presented as medically-refractory seizures and had cerebral atrophy on neuroimaging. Interestingly he had lost previous two siblings because of lack of correct diagnosis. INTERVENTION: Child was given oral magnesium supplementation and the seizures got controlled. MESSAGE: Familial hypomagnesemia should be considered in any child with recurrent or refractory hypocalcemic seizures.

New TRPM6 mutation and management of hypomagnesaemia with secondary hypocalcaemia.

BACKGROUND: TRPM6 gene mutation has been reported to cause hypomagnesemia with secondary hypocalcemia (HSH). However, the genotype-phenotype correlation for TRPM6 gene mutations has not been clarified. OBJECTIVE: To elucidate the factors underlying the severe neurological complications in HSH and evaluate the potential association between the location of TRPM6 gene mutations and clinical data of HSH. METHODS: A Japanese patient diagnosed with HSH at 10 weeks of age exhibited neurological damage and failed to thrive. Magnesium supplements were therefore started at 12 weeks of age. Mutational analysis of the TRPM6 gene was performed using a direct sequencing method to determine the position and type of mutation. Using the data of 29 HSH patients reported in the literature, linear regression analysis was also performed to examine the association between TRPM6 gene mutation location and HSH onset age, initial serum magnesium and calcium concentrations, and dose of oral magnesium. RESULTS: A novel stop-codon homozygous mutation [c.4190 G>A] W1397X was identified in exon 26 of the patient's TRPM6 gene. No statistical correlation was found between the location of mutations in the TRPM6 gene and the clinical data for 4 clinical indicators of HSH. CONCLUSIONS: We identified the first Japanese HSH patient with a novel nonsense mutation in the TRPM6 gene. Regression analysis of mutation locations in the protein-coding region of TRPM6 and the reported clinical data for 4 clinical indicators of HSH in 30 HSH patients did not detect a genotype-phenotype correlation.

[Familial congenital hypomagnesemia revealed by neonatal convulsions]. / Convulsions néonatales révélant une hypomagnésémie congénitale familiale.

Congenital hypomagnesemia is a rare disease, with an impact on cognitive and neurological development. We report on three familial cases of congenital hypomagnesemia, two boys and one girl who belong to the same consanguineous family. They all presented neonatal seizures and a psychomotor developmental delay. Cerebral computed tomography showed cerebral atrophy and calcifications in one case and magnetic resonance imaging found predominant cerebellar atrophy in the two other cases. All three patients also had hypocalcemia, hyperphosphoremia, and hypomagnesemia. The parathyroid hormone blood level was low in two cases and normal in the third. One 7-month old patient died. The others received a supplementation of calcium and magnesium, which normalized calcemia, phosphatemia but not magnesemia, which remained low despite high doses. They have both developed cognitive and behavioral impairments.

Primary infantile hypomagnesaemia: report of two cases.

OBJECTIVE: To present case reports of two siblings with primary hypomagnesaemia both presenting with seizures, and one also with a cardiac arrhythmia. To briefly review the pathophysiology, clinical features, diagnosis, management and genetics of this disorder. METHODOLOGY: Published literature reports of primary hypomagnesaemia and studies of hypomagnesaemia in humans. Reports of the clinical features and inheritance of primary hypomagnesaemia. RESULTS: The information is descriptive of the pathophysiology, clinical features, diagnostic criteria, and management. Considered modes of inheritance are presented. Two cases of primary hypomagnesaemia in brothers of consanguineous parents are described. Cardiac arrhythmia at presentation has not previously been reported. Diagnosis and adequate magnesium supplementation controls the biochemical disorder and the neurological development is normal. CONCLUSIONS: Primary hypomagnesaemia should be considered in infants with seizures, as failure to identify this metabolic disorder can result in death. Subsequent siblings, particularly male, should be closely monitored.

Primary hypomagnesemia with secondary hypocalcemia. Report of a case and review of the world literature.

Primary hypomagnesemia with secondary hypocalcemia (PHSH) is a rare type of hypocalcemic disorder which occurs in early infancy and is clinically characterized by recurrent tetany and/or convulsion. In this paper, a male infant with PHSH who had frequent seizures at the age of 9 days is described. Besides PHSH, several illnesses in infancy are manifested by hypomagnesemia and hypocalcemia, i.e. transient neonatal hypomagnesemic hypocalcemia, congenital renal or hepatic insufficiencies, magnesium-losing nephropathy, combined impairments of intestinal absorption and renal reabsorption of magnesium. PHSH is to be differentiated from these illnesses by the demonstration of a combination of the following findings; hypocalcemia refractory to calcium but responsive to magnesium, continuous requirement for magnesium supplementation to maintain normocalcemia, lack of hypermagnesiuria and/or impaired intestinal absorption of magnesium. Twenty cases from the literature were found to exhibit these characteristics. The clinical, biochemical, and endocrine features of PHSH are summarized on the basis of a review of the data of these and the present case. No associated illness was known in the afflicted infants or mothers. Both male and female infants were afflicted at a male to female ratio of 15:6. Some siblings were afflicted but none of the parents or relatives. The onset of tetany and/or convulsion was between the 9th day and 4th month, which is later than that of other neonatal hypocalcemic illnesses. Hypocalcemia was more pronounced than other infantile hypocalcemic illnesses. The role of the parathyroid hormone in the pathogenesis of hypocalcemia has been studied in several studies but no unifying concepts have yet been established.