Autosomal dominant early‐onset spastic paraparesis with brain calcification due to IFIH1 gain‐of‐function

Lyse Ruaud, Gillian Rice, Christelle Cabrol, Juliette Piard, Mathieu Rodero, Lien van Eyk, Elise Boucher-Brischoux, Alaiin Maertens de Noordhout, Ricardo Mare, Emmanuel Scalais, Fernand Pauly, François Guillaume Debray, William B Dobyns, Carolina Uggenti, Ji Woo Park, Sun Hur, John H Livingstone, Yanick Crow, Lionel Van Maldergem

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We describe progressive spastic paraparesis in two male siblings and the daughter of one of these individuals. Onset of disease occurred within the first decade, with stiffness and gait difficulties. Brisk deep tendon reflexes and extensor plantar responses were present, in the absence of intellectual disability or dermatological manifestations. Cerebral imaging identified intracranial calcification in all symptomatic family members. A marked upregulation of interferon stimulated gene (ISG) transcripts was recorded in all three affected individuals and in two clinically unaffected relatives. A heterozygous IFIH1 c.2544T > G missense variant (p.Asp848Glu) segregated with interferon status. Although not highly conserved (Supporting figure 1; CADD score 10.08 versus MSC‐CADD score of 19.33) and predicted as benign by in silico algorithms, this variant is not present on publically available databases of control alleles, and expression of the D848E construct in HEK293T cells indicated that it confers a gain‐of‐function. This report illustrates, for the first time, the occurrence of autosomal dominant spastic paraplegia with intracranial calcifications due to an IFIH1‐related type 1 interferonopathy.
Original languageEnglish
JournalHuman Mutation
Issue number8
Early online date21 May 2018
Publication statusPublished - 2018


  • IFIH1
  • interferonopathy
  • spastic paraparesis
  • brain calcification


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