Aicardi-Goutieres Syndrome 3 is a rare disorder with severe neurological and immune system manifestations. Affected individuals suffer from encephalopathy which results in brain deformities such as delayed myelination, white matter abnormalities, a thin corpus callosum and intracranial calcifications. Patients exhibit extreme irritability, intermittent fevers (sterile pyrexias), progressive microcephaly, hypotonia, dystonia, and psychomotor regression. Immune system anomalies include increased alpha-interferon levels in the serum and CSF as well as CSF lymphocytosis. Chilblains are another hallmark of AGS3. These are puffy, red, itchy and painful lesions that occur on the fingers, toes or ears and are caused by the inflammation of small blood vessels. AGS3 is a progressive disorder with an onset in early infancy. About 80% of the patients presenting with severe forms of AGS die within the first decade of life. So far, AGS does not appear to have a gender or racial bias.
Diagnosis can be made based on MRI scans that help identify brain anomalies and by spinal taps which allow cerebrospinal fluid to be analyzed for lymphocytosis and an increase in interferon alpha activity. While there is currently no cure for the disorder, supportive and symptomatic treatments such as physical therapy may help patients based on their individual needs.
Al-Shamsi et al. (2016) identified a cohort of 85 patients that failed to be diagnosed at a metabolic center in Abu Dhabi. Whole Exome Sequencing (WES) was carried out and this approach helped to definitively diagnose 50% of the cases in the cohort. One patient belonging to a consanguineous family suffered from global developmental delay, central hypotonia, peripheral hypertonia, opisthotonus, microcephaly, failure to thrive, diffuse white matter hyperintensity, cortical brain atrophy, and dilated ventricles. WES uncovered a homozygous variant of unknown significance (c.205C>T, p.R69W) in the patient’s RNASEH2C gene. It was confirmed to be pathogenic due to a consistent phenotype, biochemical findings and reported pathogenicity. WES also found a homozygous variant in the CDK5RAP2 gene (that was shared by an unaffected sibling) and a pathogenic heterozygous mutation in the BUB1B gene