Atormac
Neurology India
Open access journal indexed with Index Medicus
  Users online: 612  
 Home | Login 
About Current Issue Archive Ahead of print Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
 Search
 
  
 Resource Links
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Article in PDF (653 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this Article
   References
   Article Tables

 Article Access Statistics
    Viewed88    
    Printed0    
    Emailed0    
    PDF Downloaded10    
    Comments [Add]    

Recommend this journal

 


 
Table of Contents    
LETTERS TO EDITOR
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

Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.246240

Rights and Permissions



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 2018 Dec 14];66:1795-800. Available from: http://www.neurologyindia.com/text.asp?2018/66/6/1795/246240




Sir,

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*

Click here to view


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

Click here to view


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.

Acknowledgments

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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
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
    
2.
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
    
3.
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
    
4.
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
    
5.
Matzkin H, Lotan D, Boichis H. Primary hypomagnesemia with a probable double magnesium transport defect. Nephron 1989;52:83-6.  Back to cited text no. 5
    
6.
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
    
7.
Viering DHHM, de Baaij JHF, Walsh SB, Kleta R, Bockenhauer D. Genetic causes of hypomagnesemia, a clinical overview. Pediatr Nephrol 2017;32:1123-35.  Back to cited text no. 7
    
8.
Schlingmann KP, Sassen MC, Weber S, Pechmann U, Kusch K, Pelken L, et al. Novel TRPM6 mutations in 21 families with primary hypomagnesemia and secondary hypocalcemia. J Am Soc Nephrol 2005;16:3061-9.  Back to cited text no. 8
    
9.
Chubanov V, Mittermeier L, Gudermann T. Role of kinase-coupled TRP channels in mineral homeostasis. Pharmacol Ther 2018;184:159-76.  Back to cited text no. 9
    
10.
Visudhipan P, Visudtibhan A, Chiemchanya S, Khongkhatuthum C. Neonatal seizures and familial hypomagnesemia with secondary hypocalcemia. Pediatric Neurology 2004;33:202-5.  Back to cited text no. 10
    
11.
Jalkanen R, Pronicka E, Tyynismaa H, Hanauer A, Walder R, Alitalo T. Genetic background of HSH in three Polish families and a patient with X; 9 translocation. Eur J Hum Genet.2006;14:55-62.  Back to cited text no. 11
    
12.
Apa H, Kayserili E, Agin H, Hizarcioglu M, Gulez P, Berdeli A. A case of hypomagnesemia with secondary hypocalcemia caused by Trpm6 gene mutation. Indian J Pediatr 2008;75:632-4.  Back to cited text no. 12
    
13.
Esteban-Oliva D, Pintos-Morell G, Konrad M. Long-term follow-up of a patient with primary hypomagnesaemia and secondary hypocalcaemia due to a novel TRPM6 mutation. Eur J Pediatr 2009;168:439-42.  Back to cited text no. 13
    
14.
Joshi R, Phatarpekar A. Hypomagnesaemia with secondary hypocalcaemia due to TRPM6 gene mutation. Sri Lanka J Child Health 2012;41:205-6.  Back to cited text no. 14
    
15.
Guran T, Akcay T, Bereket A, Atay Z, Turan S, Haisch L, et al. Clinical and molecular characterization of Turkish patients with familial hypomagnesemia: Novel mutations in TRPM6 and CLDN16 genes. Nephrol Dial Transpl 2012;27:667-73.  Back to cited text no. 15
    
16.
Habeb AM, Al-Harbi H, Schlingmann KP. Resolving basal ganglia calcification in hereditary hypomagnesemia with secondary hypocalcemia due to a novel TRPM6 gene mutation. Saudi J Kidney Dis Transpl 2012;23:1038-42.  Back to cited text no. 16
  [Full text]  
17.
Zhao Z, Pei Y, Huang X, Liu Y, Yang W, Sun J, et al. Novel TRPM6 mutations in familial hypomagnesemia with secondary hypocalcemia. Am J Nephrol 2013;37:541-8.  Back to cited text no. 17
    
18.
Katayama K, Povalko N, Yatsuga S, Nishioka J, Kakuma T, Matsuishi T, et al. New TRPM6 mutation and management of hypomagnesemia with secondary hypocalcemia. Brain Dev 2015;37:292-8.  Back to cited text no. 18
    
19.
Lainez S, Schlingmann KP, van der Wijst J, Dworniczak B, van Zeeland F, Konrad M, et al. New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia. Eur J Hum Genet. 2014;22:497-504.  Back to cited text no. 19
    
20.
Kamate M, Singh N, Patil S. Familial Hypomagnesemia with Secondary Hypocalcemia Mimicking Neurodegenerative Disorder. Indian Pediatr 2015;52:521-2.  Back to cited text no. 20
    
21.
Coulter M, Colvin C, Korf B, Messiaen L, Tuanama B, Crowley M, et al. Hypomagnesemia due to two novel TRPM6 mutations. J Pediatr Endocrinol Metab 2015;28:1373-8.  Back to cited text no. 21
    
22.
Astor MC, Løvås K, Wolff AS, Nedrebø B, Bratland E, Steen-Johnsen J, et al. Hypomagnesemia and functional hypoparathyroidism due to novel mutations in the Mg-channel TRPM6. Endocr Connect 2015;4:215-22.  Back to cited text no. 22
    
23.
Altincik A, Schlingmann KP, Tosun MS. A novel homozygous mutation in the transient receptor potential melastatin 6 gene: A case report. J Clin Res Pediatr Endocrinol 2016;8:101-4.  Back to cited text no. 23
    
24.
Shimizu M, Niida Y, Koizumi S, Yachie A. An infant with recurrent convulsive seizures of 3 weeks duration: questions. Pediatr Nephrol 2014;29:1951, 1953-5.  Back to cited text no. 24
    
25.
Patel S, Rayanagoudar G, Gelding S. Familial hypomagnesaemia with secondary hypocalcaemia. BMJ Case Reports 2016. doi:10.1136/bcr-2016-216870.  Back to cited text no. 25
    
26.
Tej A, Dworniczak B, Marzouk A, Soyah N, Tilouche S, Gribaa M, et al. Hypomagnesemia with secondary hypocalcemia linked to a novel TRPM6 gene mutation. Open J Pediatr 2016;6:290-4.  Back to cited text no. 26
    
27.
Kekatpure MV, Gaur S, Dash GK, Kannan S. TRPM6 mutation: A novel cause of “reversible” infantile epileptic encephalopathy. Neurol India 2016;64:1037-8.  Back to cited text no. 27
[PUBMED]  [Full text]  



 
 
    Tables

  [Table 1], [Table 2]



 

Top
Print this article  Email this article
   
Online since 20th March '04
Published by Wolters Kluwer - Medknow