How is it diagnosed?

In spite of the recent important advances in the genetics of the syndrome, it is nevertheless important to bear in mind the clinical and neuroradiological criteria fundamental for a diagnosis of suspected AGS (based on clinical history, laboratory tests of blood and CSF — in particular the interferon signature — and neuroimaging studies, namely new brain MRI and possibly CT techniques). The diagnostic suspicion can then be confirmed by specific genetic testing, which is currently able to identify the majority (over 90%) of affected individuals.
It is also important to emphasise that some criteria are "age-specific" or rather "evolution-specific", meaning that the significance of their presence or absence is different in different stages of the disease: for example, at onset of the symptoms, the presence of cerebral calcification, while very frequent, is not an indispensable diagnostic criterion (if it is absent, patients should be monitored, over time, to see if it appears); similarly, the absence of raised IFN levels in the CSF some years after the clinical onset of the disease does not exclude a diagnosis of AGS.
Since cerebral calcification is not readily identified on MRI (even though this technique is routinely used in the diagnostic work-up), a second aspect to emphasise is the importance of specifically looking for it in all cases of unexplained early-onset leukoencephalopathy, by performing brain MRI with gradient echo/3D gradient echo techniques or brain CT scans.

These considerations apart, the main criteria for a diagnosis of AGS are:
1. Early-onset encephalopathy with psychomotor delay, spasticity, extrapyramidal signs and microcephaly, the latter appearing in the course of the first year of life;
2.Cerebral calcification, particularly visible at basal ganglia level (putamen, pallidus and thalamus) but also extending to the white matter;
3.Cerebral white matter abnormalities;
4.Cerebral atrophy;
5.Exclusion of pre-/perinatal infections, in particular the TORCH complex (toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus);
6.Chronic lymphocytosis (>5 cells/mm3) on CSF examination, not accompanied by any other sign of an infectious process;
7.Raised IFN in the CSF (>2 IU/ml);
8.Increased expression (=transcription into RNA) of the interferon-stimulated genes (positive interferon signature);
9.Elevation of neopterins and, less marked, biopterins in the CSF sometimes associated with decreased folates;
10.Suggestive systemic symptoms in the early stages of the disease, for example irritability, feeding and sleeping difficulties, unexplained fevers, and the appearance of chilblain-like skin lesions on the fingers, toes and ears;
11.Genetic screening for mutations in the seven genes known to cause AGS allows definitive confirmation of the diagnosis in the majority of cases.