Nerve function and dysfunction in acute intermittent porphyria.
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 (I(H)). 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 I(H) in AIPWN axons, whereas porphyric neuropathy may develop when reduced activity of the Na(+)/K(+) pump results in membrane depolarization.
Lin
Cindy S-Y
CS
Prince of Wales Clinical School, Prince of Wales Medical Research Institute, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
Krishnan
Arun V
AV
Lee
Ming-Jen
MJ
Zagami
Alessandro S
AS
You
Hui-Ling
HL
Yang
Chih-Chao
CC
Bostock
Hugh
H
Kiernan
Matthew C
MC
D000293:Adolescent; D000328:Adult; D000368:Aged; D001369:Axons / Q000502:physiology*; D002648:Child; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D008959:Models, Neurological; D009046:Motor Neurons / Q000502:physiology; D009431:Neural Conduction; D017118:Porphyria, Acute Intermittent / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D011166:Porphyrins / Q000097:blood; D012008:Recurrence; D015203:Reproducibility of Results
D011166:Porphyrins