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

Diane Beysen,Julie Dandelooy,Marije M.E Meuwissen,Charlotte Dielman,Chania De Cordt,Katrien Janssens,Benson Ogunjimi,Edwin Reyniers

doi:10.3389/fneur.2021.617813

Abstract

Cerebral palsy (CP) is a non-progressive neurodevelopmental disorder characterized by motor impairments, often accompanied by co-morbidities such as intellectual disability, epilepsy, visual and hearing impairment and speech and language deficits. Despite the established role of hypoxic–ischemic injury in some CP cases, several studies suggest that birth asphyxia is actually an uncommon cause, accounting for <10% of CP cases. For children with CP in the absence of traditional risk factors, a genetic basis to their condition is increasingly suspected. Several recent studies indeed confirm copy number variants and single gene mutations with large genetic heterogeneity as an etiology in children with CP. Here, we report three patients with spastic cerebral palsy and a genetically confirmed diagnosis of Aicardi-Goutières syndrome (AGS), with highly variable phenotypes ranging from clinically suggestive to non-specific symptomatology. Our findings suggest that AGS may be a rather common cause of CP, that frequently remains undiagnosed without additional genetic testing, as in only one case a clinical suspicion of AGS was raised. Our data show that a diagnosis of AGS must be considered in cases with spastic CP, even in the absence of characteristic brain abnormalities. Importantly, a genetic diagnosis of AGS may have significant therapeutic consequences, as targeted therapies are being developed for type 1 interferonopathies, the group of diseases to which AGS belongs. Our findings demonstrate the importance of next generation sequencing in CP patients without an identifiable cause, since targeted diagnostic testing is hampered by the often non-specific presentation.

Highlights

Aicardi-Goutières syndrome (AGS) is a rare hereditary inflammatory disorder which usually presents in early infancy with systemic and central nervous manifestations caused by the inappropriate induction of a type I interferon-mediated immune response [1]
Further interrogation of the read depth suggested a possible deletion of exon 5 of the SAMHD1-gene, that was confirmed by Multiplex Amplicon Quantification (MAQ) analysis and was maternally inherited
We describe three patients with a clinical diagnosis of spastic cerebral palsy in whom genetic testing contributed to a molecular diagnosis of Aicardi-Goutières syndrome

Summary

Introduction

Aicardi-Goutières syndrome (AGS) is a rare hereditary inflammatory disorder which usually presents in early infancy with systemic and central nervous manifestations caused by the inappropriate induction of a type I interferon-mediated immune response [1]. In case of Aicardi-Goutières syndrome, it is hypothesized that self-nucleic acids are no longer recognized as such, leading to an inappropriate immune response with an overactive type 1 interferon signaling, even in the absence of a viral infection. The majority of patients present with this “classical” phenotype, several studies report a broader spectrum of disease presentation, progression and outcome, with even static or slowly progressive forms presenting as cerebral palsy (CP) [3,4,5] Due to this clinical heterogeneity, the actual prevalence of AGS is not known

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