Porphyria, Neurology, and Neuropathy

Abstract & Commentary

Synopsis: The severity of the neuropathy and the availability of potential treatments, including avoidance of provocative factors, make identification important.

Source: Albers JW, et al. Porphyric Neuropathy. Muscle Nerve. 2004;30;410-422.

Heme biosynthesis, the primary objective of porphyrin metabolism, begins in the mitochondria, where glycine binds succinyl coenzyme A to form delta-amino-levulinic acid (ALA) catalyzed by the rate-limiting enzyme, ALA synthase. ALA then enters the cell cytoplasm, and sequentially, is transformed into porphobilinogen (catalyzed by ALA dehydratase), uroporphyrinogen (catalyzed by porphobilinogen deaminase and composed of 4 porphobilinogen molecules), and finally, coproporphyrinogen (catalyzed by uroporphyrinogen decarboxylase). Coproporphyrinogen returns to the mitochondria, where oxidase enzymes convert it, sequentially, into protoporphyrinogen and protoporphyrin IX. Iron is then added by ferrochelatase to form heme.

Acute intermittent porphyria, the most common hepatic porphyria, hereditary coproporphyria, variegate porphyria, and least commonly, ALA dehydratase deficiency constitute the acute hepatic porphyrias associated with neuropsychiatric complications, including neuropathy. Diagnosis may be confusing, but is usually achieved, during an attack, by measuring heme precursors in a 24-hour collection of urine and feces and determining, by the pattern of their elevation, which enzyme is deficient (see Table).

Table 1: ALADD ALA dehydratase deficiency, AIP acute intermittent
porphyria, HCP hereditary coproporphyria, VP variegate porphyria,
PBG porphobilinogen, Copro coproporphyrinogen, Proto protoporphyrinogen,
Uro uroporphyrinogen

Genetic mutation analysis is available for definitive diagnosis. Unlike most hereditary enzyme deficiencies, hepatic porphyrias are autosomal dominant, with the exception of autosomal recessive ALA dehydratase deficiency.

Extrahepatic manifestations of the hepatic porphyrias, involving both the central and peripheral nervous system, are similar except that skin lesions do not occur in acute intermittent porphyria, whereas they are seen in hereditary coproporphyria and variegate porphyria. Abdominal pain, psychosis, and neuropathy compose the classic triad of the porphyrias, and most attacks follow a predictable course. Medications usually precipitate an attack, as may starvation and altered hormonal levels. Abdominal pain, typically dramatically severe, poorly localized, and associated with nausea and vomiting, is usually followed by nonspecific psychiatric and mental status changes. Restlessness, insomnia, and agitation may be followed by hysteria, delirium, or hallucinations, even coma. Posterior leukoencephalopathy can be seen, with cortical blindness due to occipital infarcts.

Up to 40% develop combined autonomic (hence the abdominal pain) and peripheral neuropathy, the latter typically within 1 month of the abdominal pain, which may render the patient quadriplegic and ventilatory dependant. Typically, areflexic motor neuropathy resembling Guillain-Barre syndrome (GBS), including cytoalbuminogenic dissociation, is seen, with labile hypertension and tachycardia, implicating autonomic neuropathy. Curiously, 50% have an upper extremity onset, and 80% are worse proximally. One-third have leg weakness initially, and the remainder are diffusely weak at onset. Lack of symmetry is common. Differential diagnosis usually includes, in addition to GBS, vasculitis, heavy metal poisoning, and polio. Unlike GBS, electrodiagnostic studies demonstrate acute axonal neuropathy with loss of motor amplitudes, but retained distal latency and velocity measurements. Conduction block and temporal dispersion are not seen, and sensory responses are relatively spared. A needle electromyographic study shows abundant positive sharp waves with decreased recruitment.

Prognosis is good, with neuropathy recovering last, as it requires axonal regeneration. With repeated attacks, recovery may be incomplete, and a fixed deficit may result. Treatment is primarily preventive and abortive, and supportive in the acute phase. Medications, which activate the cytochrome P450 enzyme system, are to be avoided, and lists of safe medications should be consulted as needed. The American Porphyria Association is a good source of up-to-date safe-drug information.


What are the magnetic resonance imaging and cerebrospinal fluid findings between attacks of acute intermittent porphyria (AIP)? Among 16 AIP gene carriers who were not experiencing an acute event, ages 30 to 62 years, half with and half without any previous episode, 2 patients in each group had several high-signal, white matter lesions on T2 weighted images, but fewer (< 5) were seen in those with no previous attack (Bylesjo I, et al. Eur Neurol. 2004;51:1-5). No patient demonstrated oligoclonal bands, and cerebrospinal fluid protein was elevated in only one. Interestingly, 10 patients had elevated (n = 7), or borderline (n = 3), levels of hemoglobin A1c.

Cure is not yet available, but liver transplantation may be an option in severe cases of porphyria (Soonawalla ZF, et al. Lancet. 2004,363;705-706). Urine concentrations of heme precursors returned to normal, and quality of life was improved in a 19- year-old woman with acute intermittent porphyria who underwent such surgery in an attempt to replace her enzyme deficiency, holding out hope for future patients. — Michael Rubin

Dr. Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.