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The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
Orpha Number: 34526
A rare mineral absorption and transport disorder characterized by a selective defect in renal or intestinal magnesium (Mg) absorption, resulting in a low Mg concentration in the blood.
To date, more than 500 cases of Familial primary hypomagnesemia (FPH) have been described in the literature.
Clinical manifestations include weakness, fatigue, increased neuromuscular excitability (muscle fasciculation, cramps, tremor carpopedal spasms, numbness in the hands and tetany), central nervous system manifestations (lethargy, drowsiness, depression, agitation and generalized seizures), and cardiac manifestations (atrial or ventricular tachycardia, and premature contractions). Chronic hypomagnesemia may be associated with chondrocalcinosis. Hypomagnesemia is frequently accompanied by hypocalcemia and sometimes by hypokalemia. Depending on the renal segment involved, FPH can be associated with hypercalcuria (when the defect of magnesium reabsorption is in the thick ascending limb of Henle's loop) or with hypocalcuria or normocalcuria (when the defect of magnesium reabsorption is in distal convoluted tubule). The severity of the clinical manifestations and the age of onset is variable (depends on the implicated transporter and type of inheritance. Severe and early presentation is observed in primary hypomagnesemia with secondary hypocalcemia (PHSH, recessive inheritance; see this term), while the mild phenotype is observed in older children and adults in dominant diseases. Other hereditary renal diseases are frequently associated with hypomagnesemia such as salt losing tubulopathies: classic Bartter syndrome, Gitelman syndrome, EAST syndrome, renal cysts and diabetes syndrome and autosomal dominant hypocalcemia (see these terms).
Renal reabsorption of Mg occurs in the loop of Henle via a passive paracellular transport process implicating claudin-16 and claudin-19 while in the intestine and in the distal convoluted tubule (DCT), reabsorption is achieved by an active process mediated by TRPM6. FPH is caused by mutations in genes encoding key proteins with direct or indirect involvement in active Mg handling, such as CLDN16 , CLDN19 , CNNM2 , EGF , FXYD2 , KCNA1 , HNF1B and TRPM6.
Clinically, Chvostek's (twitching of facial muscles in response to tapping over the area of the facial nerve) and Trousseau's (carpopedal spasm resulting from ischemia) signs can detect hypomagnesemia in a specific and sensitive manner. Diagnosis is also established by simultaneous evaluation of serum Mg and urinary Mg excretion. Presence of hypomagnesemia with adapted urinary Mg excretion (<1mmol/24h or fractional excretion (FE) < 1%) indicates an extra renal origin. Elevated fecal Mg levels indicate an intestinal defect. In contrast, hypomagnesemia with increased urinary Mg excretion (> 2 mmol/24h or FE >2%) indicates a renal origin. In mixed intestinal and renal hypomagnesemia (PHSH), the renal reabsorption defect is only observed after an intravenous magnesium load test. Diagnosis is confirmed by molecular screening of genes involved in FPH.
Differential diagnosis includes isolated Mg malabsorption, hypoparathyroidism and drug toxicity (diuretics, aminoglycosides, proton pump inhibitors, pentamidin, EGF receptor antagonists, calcineurin inhibitors and platin salts).
Transmission is autosomal recessive or autosomal dominant.
Management and treatment
Treatment of FPH involves substitution with oral Mg. In cases of intolerance, patients may be treated with intramuscular Mg sulfate. Treatment and doses should be adjusted according to gastrointestinal tolerance and clinical manifestations. Intravenous Mg and calcium therapies may be given during symptomatic attacks.
Prognosis is highly dependent on the rapidity of diagnosis and treatment. Complications or death resulting from untreated convulsions or tetany may be observed in certain forms of FPH.
Visit the Orphanet disease page for more resources.
Source: GARD Last updated on 05-01-20
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