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 rem...

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Bibliographic Details
Published in:Brain (London, England : 1878) England : 1878), 2008-09, Vol.131 (9), p.2510-2519
Main Authors: Lin, Cindy S.-Y., Krishnan, Arun V., Lee, Ming-Jen, Zagami, Alessandro S., You, Hui-Ling, Yang, Chih-Chao, Bostock, Hugh, Kiernan, Matthew C.
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Axons - physiology
Biological and medical sciences
Child
Electric Stimulation - methods
Female
haem
Humans
Injuries of the nervous system and the skull. Diseases due to physical agents
inward rectification (IH)
ischaemia
Male
Medical sciences
Membrane Potentials
Middle Aged
Models, Neurological
Motor Neurons - physiology
nerve excitability
Neural Conduction
Neurology
porphyria
Porphyria, Acute Intermittent - blood
Porphyria, Acute Intermittent - genetics
Porphyria, Acute Intermittent - physiopathology
Porphyrins - blood
Recurrence
Reproducibility of Results
Traumas. Diseases due to physical agents
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Summary: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.
ISSN:0006-8950
1460-2156
DOI:10.1093/brain/awn152