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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT  
Year : 2012  |  Volume : 23  |  Issue : 5  |  Page : 1038-1042
Resolving basal ganglia calcification in hereditary hypomagnesemia with secondary hypocalcemia due to a novel TRMP6 gene mutation


1 Pediatric Department, Maternity and Children Hospital, Madinah, Saudi Arabia
2 Pediatric Department, Ohud General Hospital, Madinah, Saudi Arabia
3 Pediatric Nephrology, University Children Hospital, Philipps University, Baldingerstrasse, Marburg, Germany

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Date of Web Publication13-Sep-2012
 

   Abstract 

Hereditary hypomagnesemia with secondary hypocalcemia (HSH) is a rare condi­tion caused by mutations in the Transient Receptor Potential Melastatin 6 (TRMP6) gene. Patients usually present during early infancy with symptomatic hypocalcemia; however, intracranial calcification has not been previously reported in HSH. We report on a three-month-old Saudi girl who presented with hypocalcemic convulsions and was initially treated as nutritional rickets. However, further biochemical analysis of blood and urine were suggestive of HSH. This diagnosis was confirmed by mutation analysis, which identified a novel homozygous frame shift mutation (ins 2999T) of the TRMP6 gene. A computed tomography brain scan, done around the time of diagnosis, identified bilateral basal ganglia calcification (BGC). Her serum calcium and the BGC improved with magnesium replacement. BGC can be added as a new feature of HSH and the case highlights the importance of measuring serum Mg in patients with hypocalcemic convulsions, particularly in children of consanguineous parents.

How to cite this article:
Habeb AM, Al-Harbi H, Schlingmann KP. Resolving basal ganglia calcification in hereditary hypomagnesemia with secondary hypocalcemia due to a novel TRMP6 gene mutation. Saudi J Kidney Dis Transpl 2012;23:1038-42

How to cite this URL:
Habeb AM, Al-Harbi H, Schlingmann KP. Resolving basal ganglia calcification in hereditary hypomagnesemia with secondary hypocalcemia due to a novel TRMP6 gene mutation. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2020 Oct 29];23:1038-42. Available from: https://www.sjkdt.org/text.asp?2012/23/5/1038/100945

   Introduction Top


Hereditary hypomagnesemia with secondary hypocalcemia (HSH OMIM 602014) is a rare autosomal-recessive condition characterized by severe hypomagnesemia leading to low serum calcium levels. The latter is due to either reduced secretion or tissue response to para­thyroid hormone (PTH) as a consequence of persistent hypomagnesemia. [1] The majority of dietary magnesium (Mg) is absorbed in the small intestine either through paracellular sim­ple diffusion or by active transcellular uptake via the Transient Receptor Potential Melastatin 6 (TRPM6). [2] Around 2500 mg of Mg is fil­tered daily and 96% of it is reabsorbed in the distal convolute tubules. The amount of Mg excretion can be altered with Mg intake to maintain a normal plasma Mg level. [2] The dis­order is characterized by a defect in intestinal magnesium (Mg) absorption with renal Mg loss. [2],[3] A few years ago, mutations of the TRPM6 gene have been identified in affected individuals. [4],[5] The TRPM6 gene encodes a protein that forms or is an essential component of an epithelial Mg-permeable ion channel (TRPM6/7 channel complex). This channel is important for active transcellular Mg absorbtion in the intestine and also plays a part in Mg reabsorbtion in the DCT in the kidney.

Patients with HSH usually present within the first few months of life with features of hypocalcemia, such as recurrent seizures or tetany that fail to respond to calcium therapy. However, cranial calcifications have not been reported in this condition. The treatment of HSH involves oral Mg supplement with intermittent use of intravenous Mg in the acute phase. If not diag­nosed and properly managed, the condition can lead to various morbidities, especially neurolo­gical impairment, or can even be fatal. [6]

We herein report an infant with HSH due to a novel TRPM6 gene mutation. The child was also found to have bilateral basal ganglia calci­fication, which improved with Mg therapy.


   Case Report Top


A three-month-old girl of Saudi origin pre­sented with recurrent generalized convulsions with no history of fever or trauma. She was born at term with normal birth weight follo­wing uneventful pregnancy. There were no neo­natal problems or concerns about her develop­ment. The parents were first degree cousins and their only other daughter was admitted in early life to the same hospital with convulsion due to nutritional rickets with normal Mg.

On examination, the patient was apyrexial and thriving, with weight and length at the 50 th and 75 th percentiles, respectively. Her head cir­cumference was at the 75 th percentile, with wide anterior fontanelle of 6 cm × 5 cm and well-separated cranial sutures. She was rather hypotonic but there were no focal neurological signs, dysmorphic features or neuro-cutaneus stigmata. The rest of the examination was un­remarkable.

Initial laboratory investigations revealed nor­mal blood glucose, blood gas and electrolytes; however, her total serum calcium was low at 1.6 mmol/L (2.10-2.24), with a phosphate of 2.4 mmol/L (1.0-2.5) and alkaline phosphatase (ALP) of 421 (50-136). Her convulsions were successfully treated by administration of intra­venous diazepam and calcium gluconate, but her serum calcium was only slightly increased after few hours to 1.76 mmol. Her wrist X-ray showed no radiological evidence of rickets; however, it was felt that the picture was sug­gestive of mild nutritional rickets and was treated accordingly. Prior to discharge, the results of her serum Mg came back low at 0.24 mmol/L (0.74-0.9). She was given one dose of intravenous Mg sulfate, which raised the Mg level to 0.52 mmol. At that time, her hypomagnesemia was thought to be transient or nutritional and the patient was discharged on vitamin D and calcium syrup with outpatient follow-up.

One month later, she was reviewed in the clinic and the family reported no symptoms. At that point, her calcium and phosphate were normal at 2.4 and 1.8 mmol/L, respectively. The ALP fell to 191 IU; however, her Mg remained low at 0.20 mmol/L and serum PTH was within the normal range. Her vitamin D and calcium were discontinued and she was commenced on intravenous Mg infusions fol­lowed by oral Mg supplement.

Further investigations to elucidate the etio­logy of hypomagnesemia revealed a fractional excretion of Mg of 4.6%. Although in the nor­mal range, the urinary excretion of magnesium can be considered inappropriately high in the presence of severe hypomagnesemia, indica­ting the presence of a renal magnesium leak. She had normal urinary Ca/creatinine ratio of 0.2 with no evidence of nephrocalcinosis on abdominal ultrasound (in keeping with HSH). Both parents and the sister had normal magne­sium and calcium levels.

Because of the wide anterior fontanelle and dilated sutures she had cranial ultrasound scan, which was inconclusive. Therefore, a computed tomography (CT) brain scan was done to rule out the possibility of hydrocephalus, which surprisingly showed basal ganglia calcification (BGC) [Figure 1]a. Congenital infection scree­ning, including cytomegalovirus and toxoplasmosis, was negative.
Figure 1: (a and b): CT brain scan of the affected child: (a) at 5 months showing bilateral basal ganglia calcification, (b) after 13 months of Mg therapy (18 months old) showing an improvement of the bilateral basal ganglia calcification

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As the clinical picture and the laboratory findings in serum and urine pointed toward HSH as the underlying genetic defect, the TRMP6 gene was screened for mutations, which identified a novel homozygous frame shift mutation (ins 2999T), confirming the cli­nical diagnosis of HSH.

At the age of 18 months, the patient remained well and her developmental milestones were appropriate for age. Her calcium, phosphate and ALP levels remained normal and the com­bination of oral Mg and intermittent intra­venous Mg sulfate maintained her serum Mg levels close to the normal range [Table 1]. A repeat CT brain scan, done on the family's request, showed an improvement of the BGC [Figure 1]b.
Table 1: Biochemical results over 18 months period since starting treatment.

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   Discussion Top


The diagnosis of children with hereditary hypomagnesemia can be a challenge for pediatri­cians as the condition is rare, symptoms are non-specific and it is eventually associated with more common biochemical abnormalities such as hypocalcaemia. As a result, late or misdiagnosis have been reported in some patients. [7],[8],[9]

Our patient presented with hypocalcemic convulsions and slightly raised ALP. She lived in an area where nutritional rickets still com­mon and her elder sister indeed had a history of convulsions due to infantile rickets (with normal serum Mg levels). These factors had influenced the initial management and led to a relative delay in making the diagnosis. The initial high ALP, which improved with vitamin D treatment and calcium, could indicate the presence of a coexisting mild vitamin D defi­ciency, which can be either nutritional or due to impaired synthesis as a result of severe hypomagnesemia. [10] Although the initial results showed low Mg, this finding was considered a transient phenomenon. The persistent hypomagnesemia during the follow-up triggered further investigations, which led to the correct diagnosis.

Hypomagnesemia in infancy can also be se­condary to other conditions such as malabsorp­tion, persistent diarrhea or short bowel syn­drome. In rare occasions, however, it can be due to hereditary defects of magnesium hand­ling in either gut or kidneys. In our child, the absence of diarrhea and the normal weight gain ruled out the possibility of malabsorption, and the parental consanguinity pointed toward hereditary hypomagnesemia. The next step in our management was to identify which sub­type of familial hypomagnesemia this patient had. Measurement of urinary magnesium and calcium as well as blood pH and serum elec­trolytes are crucial in this aspect. In our infant, the normal pH and serum potassium ruled out the possibilities of Gitelman and Bartter syn­dromes and the normal urinary calcium excre­tion excluded familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). The history of infantile convulsions together with the laboratory findings of hypomagnesemia, hypocalcaemia and inappropriate uri­nary Mg excretion were suggestive of HSH.

A genetic linkage analysis using polymorphic microsatellites showed homozygosity for the TRPM6 locus in our patient and the subsequent sequence analysis of the TRPM6 gene in the four family members identified a novel homozygous frame shift mutation (ins2999T) in the affected child, while both parents and the un­affected sister were found to be heterozygous for the same mutation. The identified mutation leads to a shift in the reading frame, a prema­ture stop of translation and a truncated TRPM6 protein (S1000fsX1016). The mutation disrupts the TRPM6 protein within the pore region of the ion channel domain and therefore, presu­mably, leads to a complete loss of function. So far, a number of mutations in the TRPM6 gene have been detected in individuals with HSH from different ethnic groups; [11] however, to the best of our knowledge, no case of HSH has been reported from Saudi Arabia.

BGC is a rare abnormality with unknown pathophysiology. It can be idiopathic or secon­dary to other conditions. In infants, it is often linked to abnormalities in serum calcium and/or PTH levels and can also be seen with some congenital infections. [12] The BGC in our patient was accidentally detected while inves­tigating her for wide anterior fontanelle. Congenital infections were excluded in our patient by serology and are usually not confined to basal ganglia. The improvement in BGC with Mg treatment rather ruled out idiopathic BGC and indicated that the etiology might, in fact, be linked to HSH. It appears possible that the BGC in our patient was due to prolonged hypocalcaemia and abnormal PTH levels prior to diagnosis. Although PTH was not measured when calcium was low during the initial presentation, it was normal when the diagnosis was made, i.e. before starting Mg treatment. Alternatively, BGC could be a direct conse­quence of persistent hypomagnesemia. The link between low Mg and tissue calcification has been well documented in animal studies, [13] and a recent report indicated that hypomagnesemia is an independent risk factor for vascular calci­fication in dialysis patients. [14] Although brain calcification has been reported in few patients with FHHNC, [15] to the best of our knowledge, tissue calcifications have not been previously reported in patients with HSH. In conclusion, we report this case as the first Saudi child with HSH caused by a novel TRMP6 gene mutation. The case adds BGC as a new feature of HSH and indicates that tissue calcification in HSH can improve with Mg therapy. It also highlights the importance of measuring serum Mg in patients with hypocalcemic convulsions, particularly in children of consanguineous parents.

 
   References Top

1.Fatemi S, Ryzen E, Floris J, Endres DB, Rude RK. Effect of experimental human Mg depletion on PTH secretion and 1,25-dihydroxyvitamin D metabolism. J Clin Endocrinol Metab 1991;73: 1067-72.  Back to cited text no. 1
    
2.Knoers NV. Inhereted forms of renal hypomagnesemia: An update. Pediatr Nephrol 2009;24:697-705  Back to cited text no. 2
    
3.Schlingmann KP, Gudermann T. A critical role of TRMP channel-kinase for human magnesium transport. J Physiol 2005;566:301-8.  Back to cited text no. 3
[PUBMED]    
4.Schlingmann KP, Weber S, Peters M, et al. Hypomagnesemia with secondary hypocalcaemia 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. 4
[PUBMED]    
5.Walder RY, Landu D, Meyer P, et al. Mutations of TRPM6 causes familial hypomagnesemia with secondary hypocalcaemia, Nat Genet 2002;31:171-4.  Back to cited text no. 5
    
6.Leicher CR, Mezoff AG, Hyams JS. focal cerebral deficits in severe hypomagnesemia. Pediatr Neurol 1991;7:380-1.  Back to cited text no. 6
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7.Shalve H, Philip M, Galil A, Carmi R, Landau D. Clinical presentation and outcome of primary familial hypomagnesimea. Arch Dis Child 1999;78: 127-30.  Back to cited text no. 7
    
8.Al-Elq AH. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis in 2 sisters. Saudi Med J 2008;29:447-51.  Back to cited text no. 8
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9.Visudhiphan P, Visudtibhan A, Chiemchanya S, Khongkhatithum C. Neonatal seizures and familial hypomagnesmia with secondary hypocalcemia. Pediatr Neurolo 2005;33:202-5.  Back to cited text no. 9
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10.Rude RK, Adams JS, Ryzen E, et al. Low serum concentration of 1,25-dihydroxyvitamin D in human magnesium deficiency. J Clin Endocrinol Metab 1985;61:933-40.  Back to cited text no. 10
[PUBMED]    
11.Schlingmann KP, Sassen MC, Weber S, 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. 11
[PUBMED]    
12.Dahnert W. Differential diagnosis of brain disorders. In Radiology review manual, (5 th ed), Lippincott William & Wilkins; 2002. pp. 241.  Back to cited text no. 12
    
13.Planells E, Liopis J, Peran E, Aranda P. Changes in tissue calcium and phosphorus content and plasma concentration of para­thyroid hormone and calcitonin after long-term magnesium deficiency in rates. J Am Coll Nutr 1995;14:292-8.  Back to cited text no. 13
    
14.Ishimura E, Okuno S, Kitatani K, et al. Signi­ficant association between the presence of peripheral vascular calcification and lower serum magnesium in hemodialysis patients. Clin Nephrol 2007;68:222-7.  Back to cited text no. 14
[PUBMED]    
15.Lodha R, Hari P, Bagga A. Syndrome of renal magnesium wasting and nephrocalcinosis. Indian Pediatr 1999;36:1046-8.  Back to cited text no. 15
[PUBMED]    

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Correspondence Address:
Abdelhadi M Habeb
Department of Pediatrics, Maternity and Children Hospital, P.O. Box 25374, Madinah
Saudi Arabia
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DOI: 10.4103/1319-2442.100945

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