Purple pigments: The pathophysiology of acute porphyric neuropathy

The porphyrias are inherited metabolic disorders arising from disturbance in the haem biosynthesis pathway. The neuropathy associated with acute intermittent porphyria (AIP) occurs due to mutation involving the enzyme porphobilinogen deaminase (PBGD) and is characterised by motor-predominant features. Definitive diagnosis often encompasses a combination of biochemical, enzyme analysis and genetic testing, with clinical neurophysiological findings of a predominantly motor axonal neuropathy. Symptomatic and supportive treatment are the mainstays during an acute attack. If administered early, intravenous haemin may prevent progression of neuropathy. While the pathophysiology of AIP neuropathy remains unclear, axonal dysfunction appears intrinsically linked to the effects of neural energy deficits acquired through haem deficiency coupled to the neurotoxic effects of porphyrin precursors. The present review will provide an overview of AIP neuropathy, including discussion of recent advances in understanding developed through neurophysiological approaches that have further delineated the pathophysiology of axonal degeneration.

► Acute intermittent porphyria (AIP) is the most common porphyria associated with neuropathy. ► AIP neuropathy occurs due to mutation in the hydroxymethylbilane synthase gene (HMBS), although 90% of carriers of such mutations may remain asymptomatic. ► The development of porphyric neuropathy appears related to energy failure due to lack of haem, combined with direct neurotoxicity of porphyrin precursors, potentially leading to dysfunction of the axonal membrane Na+/K+ ATPase.