Elevated pterins in cerebral spinal fluid– biochemical marker of Aicardi–Goutières syndrome

SIR–Dale et al.1 reported elevated neopterin in cerebrospinal fluid (CSF) as a useful marker of inflammation in a broad range of acute and chronic central nervous system (CNS) disorders. Like Blau et al.2 we have found CSF pterins a useful indicator of CNS inflammation in Aicardi–Goutières syndrome.3 Here, we report a child with Aicardi–Goutières syndrome, where the elevated CSF neopterin was the clue to diagnosis as the characteristic CNS inflammatory makers, IFN-α, and CSF pleocytosis for this syndrome were normal. A female of non-consanguineous Caucasian parents was born at term after an uneventful pregnancy with a normal occipitofrontal circumference. She first presented at 4 months of age with regression, encephalopathy, hypotonia, and transient myoclonus. She improved initially before regressing again a month later in her motor skills over a 2-week period. She stabilized and started to make developmental progress again. At 2 years of age she was sitting with support and saying her first words. On examination she had microcephaly (46.5 cm) and truncal hypotonia. Investigations for common vertically transmitted infections, plasma and CSF lactate, plasma and urine amino acids, serum very long chain fatty acids, urine organic acids, carnitines, chitotriosidase, urine vanil-mandelic acid, and CSF dopamine metabolites were normal. However, CSF pterins (neopterin and biopterin) were elevated; CSF neopterin was 920nmol/L (normal 7–65nmol/L), CSF biopterin 240nmol/L (normal 23–55nmol/L), and CSF dihydrobiopterin 74nmol/L (normal 0.4–13.9nmol/L). Neuroimaging at 5 months of age showed slightly delayed myelination on magnetic resonance imaging (MRI) and punctate periventricular calcification on computed tomography (Fig. 1). CSF interferon-alpha (IFN-α) titres and cell count were normal. Repeat MRI at 13 months of age showed hypomyelination with dysmyelination (Fig. 2). Sequence analysis confirmed that the child was homozygous for the recurrent c.529G>A/pA177T mutation in RNASEH2B (AGS2). Computed tomography with punctate periventricular calcification. Magnetic resonance imaging with hypomyelination with dysmyelination. Aicardi–Goutières syndrome is a genetic encephalopathy phenotypically similar to in utero viral infection with calcifications of the basal ganglia and white matter on neuroimaging. CSF pleocytosis and elevated CSF IFN-α are characteristic, but inconstant findings. We have previously documented that CSF pterins, most particularly neopterin, to be raised in the encephalopathic phase of the disease.3 Severe neurological dysfunction usually becomes clinically apparent in infancy, and manifests as progressive microcephaly, spasticity, dystonic posturing, profound psychomotor retardation, and often death in early childhood. Outside the nervous system, thrombocytopenia, hepatosplenomegaly, and elevated hepatic transaminases have been described. Our case illustrates the tremendous diagnostic challenge in recognizing those cases of Aicardi–Goutières syndrome associated with a milder phenotype, and where there is an absence of a tell-tale CSF pleocytosis. Our experience is that during the active stage of the disease, IFN-α is a reliable disease marker. However, in this case the IFN-α was normal so that the intrathecal overproduction of pterins was the only biochemical abnormality suggesting an inflammatory process and leading to a diagnosis of Aicardi–Goutières syndrome.