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.

What this paper adds: We identified two siblings (sister and brother) with atypical Aicardi-Goutières syndrome type 2 due to RNASEH2B mutation. Manifestations included spastic quadriplegia and anarthria but preserved intellect and increased iron signal in the basal ganglia. RNASEH2B-related Aicardi-Goutières syndrome type 2 can have present with a variable phenotype, including idiopathic spastic cerebral palsy.

Figure 1

(a) Neuroimaging results. (i) Magnetic resonance imaging (T2, T2-FLAIR and T2*) and CT of patients 1 (II-1) and 2 (II-3) revealed grossly normal anatomy, nonspecific small white matter lesions, and globus pallidus hypointensity on T2* and T2-FLAIR (arrows), consistent with abnormal metal deposition. Computed tomography scans demonstrated no evident brain parenchymal calcifications. (ii) T2, T2-FLAIR and T2* from an age-matched normal control is shown for comparison. (iii) Axial FLAIR images from patient 2 (II-3) showing red nucleus and substantia nigra, which are iron containing and appear hypointense on FLAIR imaging. Magnetic resonance images were obtained using a 3.0 T Philips Achieva scanner. Acquisition parameters were: T2 (repetition time 5400ms; echo time 100ms; echo train length 26; acquisition time 90s); T2-FLAIR (repetition time 11 000ms; inversion time 2700ms; echo time, 120ms; echo train length 20; acquisition time 90s); and T2* (repetition time 600ms; echo time 15ms; echo train length 5; acquisition time 30s). Age-matched control was scanned on the same scanner with the same acquisition parameters. (b) Family pedigree and molecular data. Affected patients are shown in black. Unaffected family members are shown in white. Chromatogram images show that patients 1 (II-1) and 2 (II-3) are homozygous for the c.529G>A in RNASEH2B, while their father (I-1) mother (I-2), and unaffected brother (II-2) are heterozygous for the mutation. CT, computed tomography; FLAIR, fluid-attenuated inversion recovery.