Brain Advance Access published online on July 17, 2008
Brain, doi:10.1093/brain/awn152
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Nerve function and dysfunction in acute intermittent porphyria
1Prince of Wales Clinical School, 2Prince of Wales Medical Research Institute, 3School of Medical Sciences, University of New South Wales, Randwick, Sydney, New South Wales, Australia, 4Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan and 5Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, Queen Square, London, UK
Correspondence to:
Matthew C. Kiernan, Associate Professor, Prince of Wales Medical Research Institute, Barker Street, Randwick, Sydney, New South Wales 2031, Australia E-mail: m.kiernan{at}unsw.edu.au
Acute intermittent porphyria (AIP) is a rare metabolic disorder characterized by mutations of the porphobilinogen deaminase gene. Clinical manifestations of AIP are caused by the neurotoxic effects of increased porphyrin precursors, although the underlying pathophysiology of porphyric neuropathy remains unclear. To further investigate the neurotoxic effect of porphyrins, excitability measurements (stimulus-response, threshold electrotonus, current–threshold relationship and recovery cycle) of peripheral motor axons were undertaken in 20 AIP subjects combined with the results of genetic screening, biochemical and conventional nerve conduction studies. Compared with controls, excitability measurements from five latent AIP patients were normal, while 13 patients who experienced acute porphyric episodes without clinical neuropathy (AIPWN) showed clear differences in their responses to hyperpolarizing currents (e.g. reduced hyperpolarizing I/V slope, P < 0.01). Subsequent mathematical simulation using a model of human axons indicated that this change could be modelled by a reduction in the hyperpolarization-activated, cyclic nucleotide-dependent current (IH). In contrast, in one patient tested during an acute neuropathic episode, axons of high threshold with reduced superexcitability, consistent with membrane depolarization and reminiscent of ischemic changes. It is proposed that porphyrin neurotoxicity causes a subclinical reduction in IH in AIPWN axons, whereas porphyric neuropathy may develop when reduced activity of the Na+/K+ pump results in membrane depolarization.
Key Words: porphyria; haem; nerve excitability; inward rectification (IH); ischaemia
Abbreviations:
AIPWN, acute intermittent porphyria without neuropathy; AIPN, acute intermittent prophyric neuropathy; ALA, 
-aminolevulanic acid; ATP, adenosine triphosphate; APB, abductor pollicis brevis; CMAP, compound muscle action potential; Cr, creatinine; GBS, Guillain Barré syndrome; GH, inward rectifying conductance; HMBS, hydroxymethylbilane synthase gene; IH, hyperpolarizing activated conductance/inward rectification; PBGD, porphobilinogen deaminase; PN, porphyric neuropathy; TA, tibialis anterior; TE, threshold electrotonus
Received November 26, 2007. Revised May 8, 2008. Accepted June 20, 2008.