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

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 intellectu...

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Bibliographic Details
Published in:Human mutation 2018-08, Vol.39 (8), p.1076-1080
Main Authors: Ruaud, Lyse, Rice, Gillian I., Cabrol, Christelle, Piard, Juliette, Rodero, Mathieu, Eyk, Lien, Boucher‐Brischoux, Elise, Noordhout, Alain Maertens, Maré, Ricardo, Scalais, Emmanuel, Pauly, Fernand, Debray, François‐Guillaume, Dobyns, William, Uggenti, Carolina, Park, Ji Woo, Hur, Sun, Livingston, John H., Crow, Yanick J., Maldergem, Lionel
Format: Article
Language:English
Subjects:
Algorithms
brain calcification
Brain Diseases - genetics
Calcification
Calcification (ectopic)
Calcinosis - genetics
Female
Gain of Function Mutation - genetics
Gait
Genetics & genetic processes
Génétique & processus génétiques
HEK293 Cells
Heterozygote
Humans
IFIH1
Interferon
Interferon-Induced Helicase, IFIH1 - genetics
interferonopathy
Life Sciences
Male
Mutation, Missense - genetics
Neuroimaging
Paraparesis, Spastic - genetics
Pedigree
Reflexes
Sciences du vivant
Spastic paraparesis
Spastic paraplegia
Spasticity
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Description
Summary: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. By describing a family where three individuals over two generations present progressive isolated spastic paraparesia, associated in one of them with extensive brain calcification on CT scan, we came to the conclusion that it relates to an IFIH1‐associated interferonopathy. Interestingly, prediction softwares were non‐contributive in establishing pathogenicity of the corresponding c.2445T>G missense variant, only demonstrated through a construct in HEK293T cells. Two relatives with a strong interferon signature were completely asymptomatic, illustrating how clinical expression can be highly variable in interferonopathies.
ISSN:1059-7794
1098-1004
1098-1004
DOI:10.1002/humu.23554