Tetrahydrobiopterin deficiency in human rabies
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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 (www.mcw.edu/rabies) 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 (BH4) and associated pathological decrease of dopaminergic and serotoninergic neurotransmission in three successive patients with rabies. CSF levels of BH4 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 BH4 deficiency. Neuronal nitric oxide synthase is BH4-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.
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- Tetrahydrobiopterin deficiency in human rabies
Journal of Inherited Metabolic Disease
Volume 32, Issue 1 , pp 65-72
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- Springer Netherlands
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- 1. Medical College of Wisconsin, Milwaukee, WI, USA
- 8. Children’s Hospital of Wisconsin Corporate Center, C450, PO Box 1997, Milwaukee, WI, 53201-1997, USA
- 2. University Children’s Hospital Heidelberg, Heidelberg, Germany
- 3. Philipps University, Marburg, Germany
- 4. Hamburg University Medical Center, Hamburg, Germany
- 5. University of Bonn Medical Centre, Bonn, Germany
- 6. Centers for Disease Control and Prevention, Atlanta, GA, USA
- 7. Medical Neurogenetics, Atlanta, GA, USA