Late diagnosis and atypical brain imaging of Aicardi–Goutières syndrome: are we failing to diagnose Aicardi–Goutières syndrome‐2?

Abstract

Aicardi–Goutières syndrome (AGS) is a rare disorder with in utero or postnatal onset of encephalopathy and progressive neurological deterioration. The seven genetic subtypes of AGS are associated with abnormal type I interferon-mediated innate immune response. Most patients with AGS present with progressive microcephaly, spasticity, and cognitive impairment. Some, especially those with type 2 (AGS2), manifest milder phenotypes, reduced childhood mortality, and relative preservation of physical and cognitive abilities. In this report, we describe two siblings (sister and brother), diagnosed with AGS2 in their second decade, who exhibited static encephalopathy since 1 year of age, with spastic quadriplegia and anarthria but preserved intellect. Both were homozygous for the common pathogenic RNASEH2B allele (c.529G>A, p.Ala177Thr). Rather than manifesting calcifications and leukoencephalopathy, both had increased iron signal in the basal ganglia. Our report broadens the clinical and imaging spectrum of AGS2 and emphasizes the importance of including AGS2 in the differential diagnosis of idiopathic spastic cerebral palsy.

Relapsing–remitting clinical course expands the phenotype of Aicardi–Goutières syndrome

“…We report a patient whose initial presentation in infancy resembling hereditary spastic paraplegia with extensive white matter abnormalities and residual neurological deficits was in keeping with the known history of AGS, 3 as was the presence of the RNASEH2B missense mutation c.529G>A. 2 However, her subsequent clinical course was highly unusual.…”

“…The natural history of milder presentations of AGS has only been partially delineated. While fewer than 200 cases of c.529G>A RNASEH2B mutations have been described, the predicted prevalence of AGS due to biallelic c.529G>A mutations is 1 in 250,000 in the general population and 1 in 120,000 in the European population, suggesting that the condition may be largely underdiagnosed . The increasing availability of whole‐exome sequencing and subsequent genotype‐first diagnostic approach may facilitate an increase in the recognition of AGS and, in turn, the spectrum of phenotypes associated with the disease .…”

“…3 The increasing availability of whole-exome sequencing and subsequent genotype-first diagnostic approach may facilitate an increase in the recognition of AGS and, in turn, the spectrum of phenotypes associated with the disease. 3 The identification of an RNA-SEH2B mutation in this patient through whole-exome sequencing, with no secondary variants identified, confirmed a diagnosis of AGS that had until that point remained elusive despite extensive investigation. Intriguingly, although RNASEH2B mutations comprise the majority of mutations in milder disease, they have also been frequently observed in the "typical" phenotype of the disease.…”

“…A subset of AGS patients with pathogenic variants in ADAR, SAMHD1, IFIH1, and RNASEH2B have been reported to exhibit a more variable phenotype, with later symptom onset, better preservation of motor and cognitive function, and partial or complete absence of classical neuroimaging features. [3][4][5][6][7][8][9] Herein, we describe a patient whose relapsing clinical course further broadens the phenotype of AGS associated with pathogenic RNASEH2B variants.…”

Aicardi–Goutières Syndrome Type 2: A Report on Two Cases with Different Phenotypes Caused by RNASEH2B Gene Mutations

“…It has been reported more rarely than the c.529G > A in particular in two unrelated Italian families, and (curiously) in compound heterozygosis with c.529G > A, in members of a family of mixed European Canadian and Hungarian descent. 13 Clinically, both the two groups of patients presented with a "complete" and severe form of the disease (immunological deficit, mental impairment, movement disorder, and brain calcifications).…”