MDA5-Associated Neuroinflammation and the Singleton-Merten Syndrome: Two Faces of the Same Type I Interferonopathy Spectrum

Abstract

In 1973, Singleton and Merten described a new syndrome in 2 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 6 different genes were described to be associated with Aicardi-Goutières 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 (SMS). IFIH1 encodes for melanoma differentiation-associated gene 5 (MDA5), and all mutations identified to date have been associated with an enhanced interferon response in affected individuals. In this study, 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 SMS. 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.

Keywords: Aicardi–Goutières syndrome; IFIH1; Singleton–Merten syndrome.

FIG. 1.

Clinical features of the proband carrying the Arg822Gln mutation in IFIH1. (A) Well-defined scaly erythematous skin lesion on the left flank at the age of 12 months. (B) Spastic gait and mild right facial palsy at the age of 5 years. (C) Quantitative analysis of interferon stimulated genes (ISGs) in peripheral blood mononuclear cells (PBMCs) of the proband. The expression of IFI27, IFI44L, IFIT1, ISG15, RSAD2, and SIGLEC1 was analyzed by quantitative PCR in 3 technical replicates. The relative expression of each gene in PBMCs from the proband was normalized to controls and represented as a mean ± standard deviation. (D+E) Sagittal and coronal image showing calcification of the globi pallidi bilaterally. PCR, polymerase chain reaction. (Written parental consent obtained to reproduce photo.) Color images available online at www.liebertpub.com/jir

FIG. 2.

Localization and effect of Aicardi–Goutières syndrome- and Singleton–Merten syndrome (SMS)-associated MDA5 variants. (A) MDA5 protein structure and the position of the identified Aicardi–Goutières syndrome and SMS causing variants. (B) Disease-causing mutations in IFIH1 leading to increased MDA5 filament stability and enhanced type I interferon production. MDA5, melanoma differentiation-associated gene 5. Color images available online at www.liebertpub.com/jir