Journal of Inherited Metabolic Disease

, Volume 32, Issue 1, pp 65–72

Tetrahydrobiopterin deficiency in human rabies

  • R. E. Willoughby
  • T. Opladen
  • T. Maier
  • W. Rhead
  • S. Schmiedel
  • J. Hoyer
  • C. Drosten
  • C. E. Rupprecht
  • K. Hyland
  • G. F. Hoffmann
BH4 and PKU

DOI: 10.1007/s10545-008-0949-z

Cite this article as:
Willoughby, R.E., Opladen, T., Maier, T. et al. J Inherit Metab Dis (2009) 32: 65. doi:10.1007/s10545-008-0949-z

Summary

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.

Abbreviations

5-HIAA

5-hydroxyindoleacetic acid

ATG

anti-thymocyte-globulin

BH4

tetrahydrobiopterin

DHPR

dihydropteridine reductase

FLAIR

fluid-attenuated inversion-recovery

GTPCH

GTP cyclohydrolase I

HD

hospital day

HVA

homovanillic acid

MCA

middle cerebral artery

MP

Milwaukee protocol

MRA

MR-angiography

NAA

N-acetyl aspartate

NOS

nitric oxide synthase

NOx

nitrite/nitrate

PAH

phenylalanine hydroxylase

PTPS

6-pyruvoyl-tetrahydrobiopterin synthase

RIG

rabies immunoglobulin

SR

sepiapterin reductase

TCD

transcranial Doppler

TH

tyrosine hydroxylase

TPH

tryptophan hydroxylase

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • R. E. Willoughby
    • 1
    • 8
  • T. Opladen
    • 2
  • T. Maier
    • 3
  • W. Rhead
    • 1
  • S. Schmiedel
    • 4
  • J. Hoyer
    • 3
  • C. Drosten
    • 5
  • C. E. Rupprecht
    • 6
  • K. Hyland
    • 7
  • G. F. Hoffmann
    • 2
  1. 1.Medical College of WisconsinMilwaukeeUSA
  2. 2.University Children’s Hospital HeidelbergHeidelbergGermany
  3. 3.Philipps UniversityMarburgGermany
  4. 4.Hamburg University Medical CenterHamburgGermany
  5. 5.University of Bonn Medical CentreBonnGermany
  6. 6.Centers for Disease Control and PreventionAtlantaUSA
  7. 7.Medical NeurogeneticsAtlantaUSA
  8. 8.Children’s Hospital of Wisconsin Corporate CenterMilwaukeeUSA