CNNM2 homozygous mutations cause severe refractory hypomagnesemia, epileptic encephalopathy and brain malformations

Andrea Accogli, Marcello Scala, Annalisa Calcagno, Flavia Napoli, Natascia Di Iorgi, Serena Arrigo, Maria Margherita Mancardi, Giulia Prato, Livia Pisciotta, Mato Nagel, Mariasavina Severino, Valeria Capra

Research output: Contribution to journalArticlepeer-review


Magnesium (Mg2+) plays a crucial role in many biological processes especially in the brain, heart and skeletal muscle. Mg2+ homeostasis is regulated by intestinal absorption and renal reabsorption, involving a combination of different epithelial transport pathways. Mutations in any of these transporters result in hypomagnesemia with variable clinical presentations. Among these, CNNM2 is found along the basolateral membrane of distal tubular segments where it is involved in Mg2+ reabsorption. To date, heterozygous mutations in CNNM2 have been associated with a variable phenotype, ranging from isolated hypomagnesemia to intellectual disability and epilepsy. The only homozygous mutation reported so far, is responsible for hypomagnesemia associated with a severe neurological phenotype characterized by refractory epilepsy, microcephaly, severe global developmental delay and intellectual disability. Here, we report the second homozygous CNNM2 mutation (c.1642G > A,p.Val548Met) in a Moroccan patient, presenting with hypomagnesemia and severe epileptic encephalopathy. Thus, we review and discuss the phenotypic spectrum associated with CNNM2 mutations.

Original languageEnglish
Pages (from-to)198-203
Number of pages6
JournalEuropean Journal of Medical Genetics
Issue number3
Publication statusPublished - Mar 2019


  • Abnormalities, Multiple/genetics
  • Adolescent
  • Brain/abnormalities
  • Cyclins/genetics
  • Epilepsy/genetics
  • Homozygote
  • Humans
  • Magnesium Deficiency/congenital
  • Male
  • Mutation, Missense
  • Phenotype


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