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

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

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 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 (CADD score 10.08 vs. 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
Pages (from-to)1076-1080
Number of pages5
JournalHuman Mutation: Variation, Informatics and Disease
Issue number8
Early online date4 Jun 2018
Publication statusPublished - 12 Jul 2018


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