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Tetrahydrobiopterin deficiency in human rabies. J Inherit Metab Dis 2009 Feb;32(1):65-72



Pubmed ID




Scopus ID

2-s2.0-59749105128   23 Citations


Rabies is a fatal viral encephalitis characterized by a clinically acute and progressive course. With rare exceptions, there is a discrepancy between clinical outcome and frank histological alterations in rabies. Investigators have postulated that rabies virus may modify neurotransmission through occupancy of cellular receptors or alteration of ion channels. We took advantage of these observations to improvise a successful therapy for rabies. The Milwaukee protocol ( ) was further modified to treat two German patients. We measured pterins and monoamine neurotransmitter metabolites in the CSF of patients with rabies by HPLC with electrochemical or fluorescent detection. We report loss of tetrahydrobiopterin (BH(4)) and associated pathological decrease of dopaminergic and serotoninergic neurotransmission in three successive patients with rabies. CSF levels of BH(4) and neurotransmitter metabolites increased in two patients who were supplemented. Our findings support the long-standing speculation of modified neurotransmission in the pathogenesis of rabies, but by another mechanism. Brain turnover of dopamine and serotonin is reduced following rabies-acquired BH(4) deficiency. Neuronal nitric oxide synthase is BH(4)-dependent and may also be involved, possibly causing cerebrovascular insufficiency in one patient. This work must be carefully replicated in animal models and future patients. We are cautiously optimistic at the prospect of readily available, metabolically specific, enteral therapy for rabies.

Author List

Willoughby RE, Opladen T, Maier T, Rhead W, Schmiedel S, Hoyer J, Drosten C, Rupprecht CE, Hyland K, Hoffmann GF


Rodney E. Willoughby MD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Diagnosis, Differential
Middle Aged
Movement Disorders
Speech Disorders
jenkins-FCD Prod-468 69a93cef3257f26b866d455c1d2b2d0f28382f14