Primary hypomagnesemia with secondary hypocalcemia (ORPHA:30924)
Primary hypomagnesemia with secondary hypocalcemia (PHSH) is a form of familial primary hypomagnesemia (FPH, see this term), characterized by severe hypomagnesemia and secondary hypocalcemia associated with neurological symptoms, including generalized seizures, tetany and muscle spasms. PHSH may be fatal or may result in chronic irreversible neurological complications.
Epidemiology
To date, approximately 100 cases have been described in the literature. Both sexes are equally affected.
Clinical description
Disease onset is often in the neonatal period and always before the end of the first year of life. The predominant symptom at initial presentation is generalized and recurrent seizures which are refractory to the conventional convulsive therapy. Additional features that are observed in the newborn period include tetany (that fails to respond to calcium therapy), failure to thrive, restlessness, tremors, muscle spasms, and perioral cyanosis. Cardiac arrhythmia may be observed.
Etiology
Mutations in the gene TRPM6 (9q21.13), encoding the transient receptor potential cation channel subfamily M, member 6, have been found to be responsible for this disease The pathophysiological hallmark of PHSH is the impaired intestinal absorption of magnesium (Mg) accompanied by renal Mg wasting as a result of a reabsorption defect in the distal convoluted tubule. The renal defect is only detected after an intravenous Mg load test. Hypocalcemia seems to be caused by diminished parathyroid hormone (PTH) release as a result of profound hypomagnesemia.
Diagnostic methods
Diagnosis relies on laboratory findings which reveal severely reduced serum Mg levels accompanied by hypocalcemia and barely detectable PTH levels. Urinary calcium (Ca) values are normal. Renal defects may be detected after an intravenous Mg load test. The diagnosis is confirmed by genetic screening of TRPM6. One case of bilateral basal ganglia calcification has been detected by computed tomography brain scan.
Differential diagnosis
Differential diagnosis includes Gitelman and Bartter syndromes, familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis without severe ocular involvement (see these terms), and nutritional rickets.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.
Management and treatment
Management is mainly symptomatic and the standard treatment consists of the exclusive and lifelong administration of Mg. During manifestations, intravenous or intramuscular administrations are preferred, whereas maintenance therapy usually consists of an oral administration of high doses of Mg. However, because of gastrointestinal side effects, some patients require additional parenteral Mg.
Prognosis
Prognosis of PHSH depends on the rapidity of diagnosis. Indeed, delayed diagnosis, or delayed administration of the appropriate treatment may result in convulsions that can be fatal or that may result in chronic, irreversible neurological complications.

                            Last update: 
                            February 2014


                            - Expert reviewer(s): 
                            Dr Rosa VARGAS-POUSSOU