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 Volume 61, Number 5, September 09, 2003
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NEUROLOGY 2003;61:642-647
© 2003 American Academy of Neurology

Cerebrospinal fluid pterins and folates in Aicardi-Goutières syndrome

A new phenotype

N. Blau, PhD, L. Bonafé, MD PhD, I. Krägeloh-Mann, MD, B. Thöny, PhD, L. Kierat, BSc, M. Häusler, MD and V. Ramaekers, MD

From the Division of Clinical Chemistry and Biochemistry (Drs. Blau and Thöny, and L. Kierat), University Children’s Hospital, Zurich; Division of Molecular Pediatrics (Dr. Bonafé), Centre Hospitalier Universitaire Vaudois Lausanne, Switzerland; Department of Pediatric Neurology (Dr. Krägeloh-Mann), University Hospital Tübingen; and Division of Pediatric Neurology (Drs. Häusler and Ramaekers), University Hospital Aachen, Germany.

Address correspondence and reprint requests to Prof. Dr. Nenad Blau, Division of Clinical Chemistry and Biochemistry, University Children’s Hospital, Steinwiesstrasse 75, 8032 Zurich, Switzerland; e-mail: nenad.blau{at}kispi.unizh.ch

Objective: To describe three unrelated children with a distinctive variant of Aicardi-Goutières syndrome (AGS) characterized by microcephaly, severe mental and motor retardation, dyskinesia or spasticity, and occasional seizures.

Results: Neuroimaging showed bilateral calcification of basal ganglia and white matter. CSF glucose, protein, cell count, and interferon alpha were normal. Abnormal CSF findings included extremely high neopterin (293 to 814 nmol/L; normal 12 to 30 nmol/L) and biopterin (226 to 416 nmol/L; normal 15 to 40 nmol/L) combined with lowered 5-methyltetrahydrofolate (23 to 48 nmol/L; normal 64 to 182 nmol/L) concentrations in two patients. The absence of pleocytosis and normal CSF interferon alpha was a characteristic finding compared to the classic AGS syndrome. Genetic and enzymatic tests excluded disorders of tetrahydrobiopterin metabolism, including mutation analysis of GTP cyclohydrolase feed-back regulatory protein. CSF investigations in three patients with classic AGS also showed increased pterins and partially lowered folate levels.

Conclusions: Intrathecal overproduction of pterins is the first biochemical abnormality identified in patients with AGS variants. Long-term substitution with folinic acid (2-4 mg/kg/day) resulted in substantial clinical recovery with normalization of CSF folates and pterins in one patient and clinical improvement in another. The underlying defect remains unknown.

Received March 3, 2003. Accepted in final form May 19, 2003.




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