Journal Article

Nerve function and dysfunction in acute intermittent porphyria

Cindy S.-Y. Lin, Arun V. Krishnan, Ming-Jen Lee, Alessandro S. Zagami, Hui-Ling You, Chih-Chao Yang, Hugh Bostock and Matthew C. Kiernan

in Brain

Published on behalf of The Guarantors of Brain

Volume 131, issue 9, pages 2510-2519
Published in print September 2008 | ISSN: 0006-8950
Published online July 2008 | e-ISSN: 1460-2156 | DOI:
Nerve function and dysfunction in acute intermittent porphyria

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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.

Keywords: porphyria; haem; nerve excitability; inward rectification (IH); ischaemia

Journal Article.  5587 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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