MDA5-associated neuroinflammation and the Singleton-Merten syndrome: two faces of the same type I interferonopathy spectrum

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In 1973, Singleton and Merten described a new syndrome in two female probands with aortic and cardiac valve calcifications, early loss of secondary dentition and widened medullary cavities of the phalanges. In 1984, Aicardi and Goutières defined a phenotype resembling congenital viral infection with basal ganglia calcification and increased protein content in the cerebrospinal fluid. Between 2006 and 2012 mutations in six different genes were described to be associated with Aicardi- Goutierès syndrome, specifically - TREX1, RNASEH2A, RNASEH2B, RNASEH2C, ADAR and SAMHD1. More recently, mutations in IFIH1 were reported in a variety of neuroimmunological phenotypes including Aicardi-Goutières syndrome, while a specific Arg822Gln mutation in IFIH1 was described in 3 discrete families with Singleton-Merten syndrome. IFIH1 encodes for MDA5, and all mutations identified to date have been associated with an enhanced interferon response in affected individuals. Here we present a male child demonstrating recurrent febrile episodes, spasticity and basal ganglia calcification suggestive of Aicardi-Goutières syndrome, who carries the same Arg822Gln mutation in IFIH1 previously associated with Singleton-Merten syndrome. We conclude that both diseases are part of the interferonopathy grouping and that the Arg822Gln mutation in IFIH1 can cause a spectrum of disease including neurological involvement.

Bibliographical metadata

Original languageEnglish
Pages (from-to)214-219
Number of pages6
JournalJournal of Interferon & Cytokine Research
Issue number5
Early online date1 May 2017
Publication statusPublished - May 2017