To report two sisters with late diagnosis of Aicardi-Goutières Syndrome 2.

Aicardi-Goutières Syndrome (AGS) is a rare encephalopathy characterized by neuroimaging findings of basal ganglia calcification, leukoencephalopathy and cerebral atrophy. Laboratory investigation shows increased IFN-α and lymphocytosis in the cerebrospinal fluid. It presents with progressive microcephaly, spasticity and cognitive impairment (CI). Seven genetic subtypes are known for AGS (I-VII), caused by mutations on TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SAMHD1, ADAR1 or IFIH1, respectively, all associated with abnormal type I interferon-mediated innate immune response. Pathogenic variants of the RNASEH2B gene are associated with Aicardi-Goutières Syndrome 2 (AGS2), an autosomal recessive disturbance related to milder forms of the disease, later onset of symptoms and less childhood mortality.

Case Report.

Patient 1 is a 32-year-old female, born from non-consanguineous parents, who started presenting seizures/status epilepticus at 5-months-old. She evolved with focal seizures with secondary generalization until the age of 4. Magnetic resonance imaging showed no alterations. She was diagnosed with cerebral palsy until the birth of her sister (Patient 2), 10 years later. Patient 2 is a 22-year-old female, who also started presenting focal seizures with secondary generalization at the age of 1 year and 3 months, until the age of 13. Computed tomography revealed basal ganglia and periventricular calcifications. Both kids failed to reach normal developmental milestones, and presented gait spasticity, ataxia, hyperreflexia and plantar responses. Patient 1 presented CI and became non-ambulatory. At the age of 20, Patient 2 underwent whole-exome sequencing, which revealed the homozygous c.529G>A, p.(Ala177Thr) variant on RNASEH2B gene, compatible with AGS2.

AGS2 should be investigated in patients presenting developmental delay, spasticity, CI and seizures, even in the absence of prototypical brain imaging. Because of its similarity with congenital infection and cerebral palsy, a high level of suspicion is necessary. Early diagnosis may influence genetic counseling and therapeutic interventions.