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Table of Contents    
Year : 2018  |  Volume : 66  |  Issue : 6  |  Page : 1795-1800

Case of hypomagnesemia with secondary hypocalcemia with a novel TRPM6 mutation

1 Pediatric Intensive Care Unit, Department of Pediatrics, BL Kapur Super Specialty Hospital, New Delhi, India
2 Division of Pediatric Nephrology, Department of Pediatrics, BL Kapur Super Specialty Hospital, New Delhi, India
3 Department of Critical Care Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
4 Pediatric Intensive Care Unit, Department of Pediatrics, BL Kapur Super Specialty Hospital, New Delhi, India; Epilepsy Program, Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada

Date of Web Publication28-Nov-2018

Correspondence Address:
Dr. Puneet Jain
Epilepsy Program, Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.246240

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How to cite this article:
Lal N, Bhardwaj S, Lalgudi Ganesan S, Sharma R, Jain P. Case of hypomagnesemia with secondary hypocalcemia with a novel TRPM6 mutation. Neurol India 2018;66:1795-800

How to cite this URL:
Lal N, Bhardwaj S, Lalgudi Ganesan S, Sharma R, Jain P. Case of hypomagnesemia with secondary hypocalcemia with a novel TRPM6 mutation. Neurol India [serial online] 2018 [cited 2022 May 20];66:1795-800. Available from: https://www.neurologyindia.com/text.asp?2018/66/6/1795/246240


Hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disorder (OMIM# 602014) characterized by severe hypomagnesemia and moderate-to-severe hypocalcemia.[1] This disorder typically presents within the first few weeks of life with neurological symptoms. Also known as Paunier's disease,[1] it results from mutations in the gene encoding transient receptor potential cation channel member 6 (TRPM6) on chromosome 9q22.[2],[3] The primary defect is impaired intestinal absorption of magnesium[4] with secondary defect in its renal conservation.[5] We report the case of a 17-month old boy presenting with recurrent seizures and severe hypomagnesemia with a novel TRPM6 mutation.

The patient was born to a non-consanguineous couple with no adverse perinatal events. The family history was unremarkable. He presented with a cluster of multifocal seizures on day 28 of his life. He was found to have hypocalcemia (3.4 mg/dL; normal: 8.5–12.5 mg/dL) and was managed with intravenous followed by oral calcium supplements. He continued to have seizures once in 1–2 months, with all episodes associated with hypocalcemia (detailed investigations were not available for review). The child presented to our center at the 17th month of age with recurrent seizures. His seizures were not controlled on two anticonvulsant drugs – valproate and levetiracetam. He was again found to have hypocalcemia (4.8 mg/dL). Other investigations revealed elevated inorganic-phosphorus level (8.4 mg/dL; normal: 2.7–4.5 mg/dL), normal alkaline phosphatase (80 U/L; normal <280 IU/L), low 25-hydroxy-vitamin D3 (28 ng/mL; normal 30–75 ng/mL), normal parathyroid hormone (PTH, 47.2 pg/ml; normal: 12–92 pg/ml), and low serum magnesium (0.36 mg/dL; normal: 1.8–2.4 mg/dL). His fractional excretion of magnesium (FE Mg) was <1.16% (normal range: 1–5%) in the face of severe hypomagnesemia and urine calcium creatinine ratio was 0.17 mg/mg (normal <0.2 mg/mg).

His examination showed a mild central hypotonia. He also showed a global developmental delay. He could sit with support, spoke occasional monosyllables, and had a crude pincer grasp. His inter-ictal-electroencephalogram (EEG) showed diffuse slowing of activity, which was nonspecific. Magnetic resonance imaging (MRI) of the brain revealed mild cortical atrophy and non-specific hyperintensity in bilateral basal ganglia regions. He was treated with intravenous magnesium (up to 12 g/day) and calcium. The seizures subsided after 5 days of hospitalization with normalization of his serum calcium (8.5–10 mg/dL). However, he continued to have hypomagnesemia (0.91–1.28 mg/dL) on magnesium supplements.

He was discharged on oral magnesium (8.5 gm/kg/day) and calcium supplements.

His genetic testing revealed a novel homozygous frame shift mutation, p. Leu1476Cysfs*75, that leads to a truncated TRPM6 protein. Both the parents were heterozygous for the same mutation and were asymptomatic. This confirmed the diagnosis of hereditary HSH.

We describe the clinical phenotype of a patient with HSH. As reported previously, our patient had the onset of symptoms during early infancy. The diagnosis was delayed until serum magnesium was measured. Hyperphosphatemia in this case could be explained by a decreased secretion as well as resistance to PTH action in the presence of hypomagnesemia. Hypocalcemia and low or low-normal PTH values can often be confused with hypoparathyroidism, unless serum magnesium is measured. [Table 1] describes the clinical and biochemical features of various inherited hypomagnesemia disorders.[6],[7] A combination of presentation in infancy, severe hypomagnesemia, and hypocalcemia with normal urinary calcium excretion helped us reach the diagnosis of HSH.
Table 1: Clinical and biochemical characteristics of inherited hypomagnesemia disorders*

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HSH is a rare disorder, with fewer than 100 cases reported worldwide. To date, TRPM6 mutations have been identified in 40 kindreds, mainly truncating mutations, though a number of missense mutations have also been described[8] and complete loss of function is a prerequisite for the development of the typical HSH phenotype. No definitive genotype–phenotype correlation has been established. TRPM6 protein is vital in maintaining the cellular magnesium homeostasis and its role has been reviewed recently.[9] [Table 2] summarizes the clinical details and TRPM6 mutations of HSH cases reported till date.[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27] The condition in our patient was caused by a homozygous frame-shift mutation, p. Leu1476Cysfs*75 in TRPM6 gene leading to truncated protein. This mutation has not been reported previously.
Table 2: Transient Receptor Potential Mealstatin-6 (TRPM6) Channel defects presenting as hypomagnesemia with secondary hypocalcemia - Review of case reports and case series

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Our patient required very high doses of intravenous magnesium sulfate, up to 12 g/day. Following stabilization, oral magnesium supplementation was continued with 50% injection magnesium sulfate, given the nonavailability of liquid formulations in our setting. Patient tolerated it well barring a few episodes of loose stools. After 1 year of follow up, there has been no seizure recurrence; serum calcium and magnesium levels are 9.4 mg/dL and 1.5 mg/dL, respectively. These patients require life-long oral magnesium supplementation. Failure to thrive and intellectual disability may be encountered in patients with delayed diagnosis or inappropriate treatment/compliance.

In conclusion, this case highlights the importance of measuring serum magnesium in cases of persistent hypocalcemia. Otherwise, the diagnosis of HSH is challenging. Hypomagmesemia with hypocalcemia are simple pointers to this disease. Early diagnosis and treatment is important to prevent irreversible neurological damage.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.


The authors are grateful to Dr Karlpeter Schlingmann (Department of General Pediatrics, University Hospital Münster, Münster, Germany) for performing the genetic testing for this patient.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Paunier L, Radde IC, Kooh SW, Conen PE, Fraser D. Primary hypomagnesemia with secondary hypocalcemia in an infant. Pediatrics 1968;41:385-402.  Back to cited text no. 1
Schlingmann KP, Weber S, Peters M, Niemann Nejsum L, Vitzthum H, et al. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet 2002;31:166-70.  Back to cited text no. 2
Wlader RY, Landau D, Meyer P, Shalev H, Tsolia M, Borochowitz Z, et al. Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet 2002;31:171-4.  Back to cited text no. 3
Milla PJ, Aggett PJ, Wolff OH, Harries JT. Studies in primary hypomagnesemia: Evidence for defective carrier-mediated small intestinal transport of magnesium. Gut 1979;20:1028-33.  Back to cited text no. 4
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Konrad M, Schlingmann KP. Disorders of calcium and magnesium metabolism. In: Geary DF, Schaefer F, editors. Pediatric kidney disease. 2nd ed. Heidelberg Germany: Springer; 2016. pp 921-52.  Back to cited text no. 6
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  [Table 1], [Table 2]

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