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

Background: Aicardi-Goutières Syndrome (AGS) is a rare encephalopathy characterized by basal ganglia calcification, leukodystrophy, cerebrospinal fluid lymphocytosis and white matter abnormalities [1]. It is associated to a broad clinical spectrum, presenting with progressive microcephaly, spasticity and cognitive impairment (CI). There are seven known genetic subtypes for AGS (I-VII), caused by mutations on TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SAMHD1, ADAR1 or IFIH1 [2], 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 autonomic recessive disturbance related to milder forms of the disease, later onset of symptoms and less childhood mortality [3].

Method: Case Report

Results: 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 then 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 her last seizure at 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. They underwent investigation for several diseases, all of which resulted negative. When admitted to the movement disorders’ service, both received the diagnosis of complex Hereditary Spastic Paraplegia at the ages of 22 and 12. 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.

Conclusion: AGS2 should be investigated in patients presenting with 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.

References: 1. Aicardi J, Goutières F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol 1984; 15: 49–54 2. Crow YJ, Chase DS, Lowenstein Schmidt J, et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A. 2015; 167A:296–312 3. Rice G, Patrick T, Parmar R, et al. Clinical and molecular phenotype of Aicardi–Goutieres syndrome. Am J Hum Genet. 2007; 81:713–25.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-case-report-of-two-siblings-aicardi-goutieres-syndrome-type-2/