Sine causa tetraparesis

Abstract

Tetraparesis is usually due to cerebral palsy (CP), inborn errors of metabolism, neurogenetic disorders and spinal cord lesions. However, literature data reported that about 10% of children with tetraparesis show a negative/non-specific neuroradiological findings without a specific etiological cause. Aicardi Goutières Syndrome (AGS) is a genetic encephalopathy that may cause tetraparesis. Interferon signature is a reliable biomarker for AGS and could be performed in sine-causa tetraparesis. The aim of the study was to examine the type I interferon signature and AGS related-genes in children with sine causa tetraparesis, to look for misdiagnosed AGS. A secondary aim was to determine which aspects of the patient history, clinical picture and brain imaging best characterize tetraparesis due to an interferonopathy.Seven out of 78 patients affected by tetraparesis, characterized by unremarkable pre-peri-postnatal history and normal/non-specific brain magnetic resonance imaging (MRI) were selected and underwent anamnestic data collection, clinical examination, brain imaging review, peripheral blood interferon signature and AGS-related genes analysis.At our evaluation time (mean age of 11.9 years), all the 7 patients showed spastic-dystonic tetraparesis. At clinical onset brain MRI was normal in 4 and with non-specific abnormalities in 3; at follow-up 3 patients presented with new white-matter lesions, associated with brain calcification in 1 case. Interferon signature was elevated in one subject who presented also a mutation of the IFIH1 gene.AGS should be considered in sine-causa tetraparesis. Core features of interferonopathy-related tetraparesis are: onset during first year of life, psychomotor regression with tetraparesis evolution, brain white-matter lesions with late calcifications. A positive interferon signature may be a helpful marker to select patients with spastic tetraparesis who should undergo genetic analysis for AGS.

Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review

“…Moreover, we identified in one patient (P44) the c.2471G>A/p. (Arg824Lys), a heterozygous transition which results in the substitution of arginine 824, a positively charged amino acid, with a lysine, positively charged [31]. In our group of patients the p.(Arg779His) was identified in two different patients (P45-46) (one of them, with classic severe infantile phenotype, never described) and p.(Arg720Gln) mutation in one patient (P47).…”

“…The baby girl showed normal early psychomotor development until age 16 months when, following an intercurrent infection the disease manifested with a progressive loss of independent walking. The younger brother showed a mild clinical picture until the age of 13 months when he evolved in a classic phenotype [31]. One patient (P34) in our cohort presented the c.554T>G/p.…”

“…These two variants cause the substitution of an arginine with histidine and glutamine, respectively. All three previous children presented with a classic severe phenotype with predominant infantile onset, but one of them, described in Galli et al [31], presented normal head circumference, and normal non-verbal intelligence quotient. The last patient (P48), never described, carried the missense mutation c.2561T>A/p.…”

“…The expression analysis of six interferon-stimulated genes was performed using the TaqMan Universal PCR Master Mix (Applied Biosystems, Paisley, UK), and cDNA derived from 40 ng total RNA. The relative abundance of target transcripts was measured using TaqMan probes for IFI27 (Hs01086370_m1), IFI44L (Hs00199115_m1), IFIT1 (Hs00356631_g1), ISG15 (Hs00192713_m1), RSAD2 (Hs01057264_m1), and SIGLEC1 (Hs00988063_m1), and normalized to the expression level of HPRT1 (Hs03929096_g1) and 18S (Hs999999001_s1) as described by Rice and collaborators [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]. To perform this assay, the LightCycler 480 (Roche) was used.…”

Genetic Testing Contributes to Diagnosis in Cerebral Palsy: Aicardi-Goutières Syndrome as an Example

“…The highly variable and sometimes rather non-specific phenotype of AGS hampers a swift diagnosis and probably results in underdiagnosis of the condition. A recent study of interferon-related gene expression in seven patients with sine causa spastic-dystonic tetraparesis led to the diagnosis of AGS in one patient by the demonstration of a “type 1 interferon signature,” a specific expression pattern of IFN-related genes identified in type 1-interferonopathies ( 19 , 20 ). While an analysis of interferon-related gene expression may indeed be useful, we suggest performing genetic testing by whole exome sequencing as a first-tier strategy in CP diagnostics due to the wide differential diagnostic considerations in CP.…”