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Familial primary hypomagnesemia with normocalciuria and normocalcemia
A form of familial primary hypomagnesemia (FPH), characterized by low serum magnesium (Mg) values but inappropriate normal urinary Mg values (i.e. renal hypomagnesemia). The typical symptoms are weakness of the limbs, vertigo, headaches, seizures, brisk tendon reflexes and mild to moderate psychomotor delay.
ORPHA:34527Classification level: Disorder
To date, less than 20 cases have been described in the literature.
Age of disease onset is variable and ranges from 3 months to 15 years depending on the genes and mutations involved. Clinically, the disease is characterized by weakness of the limbs, vertigo, headaches, seizures, mild to moderate psychomotor delay, intellectual disability, delayed speech and linguistic development and brisk tendon reflexes.
Familial primary hypomagnesemia with normocalciuria and normocalcemia (FPHNN) is caused by mutations in either CNNM2 (10q23.32) or EGF (4q25). CNNM2 encodes cyclin M2, a ubiquitous protein, predominantly expressed in the thick ascending limb of Henle's loop and in the renal distal convoluted tubule where it is thought to contribute to a Mg-sensing mechanism. EGF encodes a magnesiotropic hormone where mutations in the gene lead to impaired basolateral sorting of pro-EGF. As a consequence, the renal EGF receptor (EGFR) is inadequately stimulated, resulting in insufficient activation of the epithelial Mg channel TRPM6 and thereby Mg loss. Thus, a renal Mg reabsorption defect is observed due to the inability of the kidney to reduce urinary Mg excretion under low serum Mg conditions.
Diagnosis relies on laboratory findings revealing severely lowered serum Mg values in the absence of other electrolyte disturbances, normocalcemia, low to normal urinary calcium (Ca) values and normal urinary Mg values. A negative Chvostek's and Trousseau's signs are observed. The diagnosis is confirmed by genetic screening of CNNM2 and EGF.
Differential diagnosis includes the other forms of FPH with normal urinary calcium excretion, as is the case in some patients with classic Bartter syndrome.
Transmission is autosomal recessive for carriers of mutations in the EGF gene. For carriers of mutations in the CNNM2 gene, both autosomal dominant and recessive (1 family) inheritance have been described. Genetic counseling should be offered to at-risk couples informing them of the risk of having an affected child.
Management and treatment
Treatment of FPHNN is mainly symptomatic and includes the Mg substitution therapy.
Severity of the disease is variable.