Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026
Familial hypomagnesemia with secondary hypocalcemia: a novel TRPM6 mutation associated with treatment-resistant migraine in a North African family.
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Paola Perini Maria, Gianni Cutillo, Emanuele Micaglio, Sara Benedetti, Tiziano Dallavilla, Monica Zanussi, Soeren Rossi Sergio, Gianluca Stufano, Salvatore Mazzeo, Alessandro Bombaci, Luigi Anastasia, Carlo Pappone, Massimo Filippi, Maria Salsone
Аннотация
BACKGROUND: Familial hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disorder caused by TRPM6 loss-of-function variants, leading to impaired magnesium absorption and systemic deficiency. Neurological manifestations are typically dominated by seizures and neuromuscular hyperexcitability, whereas headache manifestations have been less characterized.
METHODS: We performed a clinical, biochemical, and genetic characterization of a consanguineous Moroccan family with hypomagnesemia. The proband underwent neurological assessment, neuroimaging, and electrophysiological studies. Serum electrolytes were evaluated in available relatives. Genetic testing was conducted using a targeted next-generation sequencing panel, followed by segregation analysis. In silico modeling was used to assess the structural impact of the identified variant.
RESULTS: The proband, an 18-year-old woman with lifelong hypomagnesemia, presented with a severe migraine attack associated with paresthesias and muscle cramps. Laboratory findings showed marked hypomagnesemia and hypocalcemia. Oral supplementation was insufficient, whereas intravenous magnesium led to rapid clinical and biochemical normalization. Genetic analysis identified a novel homozygous TRPM6 frameshift variant (c.902dup; p.Ser302Valfs*16), predicted to cause premature protein truncation. Family screening confirmed autosomal recessive inheritance, identifying one similarly affected sibling and multiple heterozygous carriers.
CONCLUSIONS: We report a novel homozygous TRPM6 frameshift variant in a patient with profound hypomagnesemia who experienced a severe migraine attack initially unresponsive to treatment. The rapid response to IV magnesium is consistent with a possible contribution of magnesium depletion to the acute headache phenotype. Our observations raise the possibility of an association between TRPM6-related hypomagnesemia and migraine susceptibility in selected individuals. Additional cases are required better refine TRPM6-related neurological phenotypes.
METHODS: We performed a clinical, biochemical, and genetic characterization of a consanguineous Moroccan family with hypomagnesemia. The proband underwent neurological assessment, neuroimaging, and electrophysiological studies. Serum electrolytes were evaluated in available relatives. Genetic testing was conducted using a targeted next-generation sequencing panel, followed by segregation analysis. In silico modeling was used to assess the structural impact of the identified variant.
RESULTS: The proband, an 18-year-old woman with lifelong hypomagnesemia, presented with a severe migraine attack associated with paresthesias and muscle cramps. Laboratory findings showed marked hypomagnesemia and hypocalcemia. Oral supplementation was insufficient, whereas intravenous magnesium led to rapid clinical and biochemical normalization. Genetic analysis identified a novel homozygous TRPM6 frameshift variant (c.902dup; p.Ser302Valfs*16), predicted to cause premature protein truncation. Family screening confirmed autosomal recessive inheritance, identifying one similarly affected sibling and multiple heterozygous carriers.
CONCLUSIONS: We report a novel homozygous TRPM6 frameshift variant in a patient with profound hypomagnesemia who experienced a severe migraine attack initially unresponsive to treatment. The rapid response to IV magnesium is consistent with a possible contribution of magnesium depletion to the acute headache phenotype. Our observations raise the possibility of an association between TRPM6-related hypomagnesemia and migraine susceptibility in selected individuals. Additional cases are required better refine TRPM6-related neurological phenotypes.