Hypomagnesemia and functional hypoparathyroidism due to novel mutations in the Mg-channel TRPM6

Abstract

Primary hypomagnesemia with secondary hypocalcemia (HSH) is an autosomal recessive disorder characterized by neuromuscular symptoms in infancy due to extremely low levels of serum magnesium and moderate to severe hypocalcemia. Homozygous mutations in the magnesium transporter gene transient receptor potential cation channel member 6 (TRPM6) cause the disease. HSH can be misdiagnosed as primary hypoparathyroidism. The aim of this study was to describe the genetic, clinical and biochemical features of patients clinically diagnosed with HSH in a Norwegian cohort. Five patients in four families with clinical features of HSH were identified, including one during a national survey of hypoparathyroidism. The clinical history of the patients and their families were reviewed and gene analyses of TRPM6 performed. Four of five patients presented with generalized seizures in infancy and extremely low levels of serum magnesium accompanied by moderate hypocalcemia. Two of the patients had an older sibling who died in infancy. Four novel mutations and one large deletion in TRPM6 were identified. In one patient two linked homozygous mutations were located in exon 22 (p.F978L) and exon 23 (p.G1042V). Two families had an identical mutation in exon 25 (p.E1155X). The fourth patient had a missense mutation in exon 4 (p.H61N) combined with a large deletion in the C-terminal end of the gene. HSH is a potentially lethal condition that can be misdiagnosed as primary hypoparathyroidism. The diagnosis is easily made if serum magnesium is measured. When treated appropriately with high doses of oral magnesium supplementation, severe hypomagnesemia is uncommon and the long-term prognosis seems to be good.

The influence of spironolactone on the serum electrolytes balance and renal cortical magnesium and calcium contents in cisplatin – treated rabbits

“…12 and a mutation in the TRPM6 gene was shown to cause hypomagnesemia with secondary hypocalcemia. 13 The mechanism underlying this hypomagnesemia was shown to involve impairment of intestinal magnesium absorption as well as renal magnesium wasting.…”

Afebrile seizures in infants: Never forget magnesium!

“…Oral magnesium dosing should be divided to decrease side effects, such as diarrhoea. When treated appropriately, further episodes of severe hypomagnesaemia are uncommon and the long‐term prognosis is good …”

“…When treated appropriately, further episodes of severe hypomagnesaemia are uncommon and the long-term prognosis is good. 12 Multiple Choice Questions 1 Primary hypomagnesaemia with secondary hypocalcaemia (HSH) presentation consists more often on: a) Nephrocalcinosis b) Growth failure c) Afebrile seizure in infancy d) Diarrhoea e) Intellectual disability Answer: c. Since magnesium has membrane-stabilising effects and HSH causes the most severe form of hypomagnesaemia, it results on a brain hyper activation with generalised seizures that mimic epilepsy. a) Nephrocalcinosis is absent, since proximal tubule and Henle's loop are not affected.…”

Functional hypoparathyroidism: causes, pathogenesis, clinical significance in Bone tissue pathology

“…Высказывается предположение, что дефицит магния (Mg) может играть роль в отсутствии повышения ПТГ у пациентов с дефицитом витамина D [27][28][29][30][31][32]. Магний играет центральную роль в регуляции активности аденилатциклазы и в последующем производстве цАМФ [33,34].…”