Acute porphyrias - A neurological perspective

Abstract

Acute hepatic porphyrias (AHP) can cause severe neurological symptoms involving the central, autonomic, and peripheral nervous system. Due to their relative rarity and their chameleon-like presentation, delayed diagnosis and misdiagnosis are common. AHPs are genetically inherited disorders that result from heme biosynthesis enzyme deficiencies and comprise four forms: acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and ALA-dehydratase porphyria (ALADP). Depending on the clinical presentation, the main differential diagnoses are Guillain-Barré syndrome and autoimmune encephalitis. Red flags that could raise the suspicion of acute porphyria are neurological symptoms starting after severe (abdominal) pain, in association with reddish urine, hyponatremia or photodermatitis, and the presence of encephalopathy and/or axonal neuropathy. We highlight the diagnostic difficulties by presenting three cases from our neurological intensive care unit and give a comprehensive overview about the diagnostic findings in imaging, electrophysiology, and neuropathology.

Keywords: Guillain-Barré syndrome; acute porphyria; autoimmune encephalitis; porphyric encephalopathy; porphyric neuropathy.

FIGURE 1

Heme biosynthesis pathway and the four acute hepatic porphyrias, clinical manifestations, precipitating factors and therapies. In the liver, heme regulates the first enzyme ALAS1 via a negative feedback loop. In contrast to the liver enzyme ALAS1, the rate‐limiting enzyme ALAS2 in the bone marrow is regulated by iron and erythropoietin instead of heme. *A lead intoxication can mimic the clinical and biochemical constellation found in ALADP and should therefore always be excluded. AIP, acute intermittent porphyria; ALA, 5‐aminolaevulinic acid; ALAD, ALA‐dehydratase; ALADP, ALA‐dehydratase porphyria; ALAS, ALA‐synthase; CPOX, coproporphyrinogen oxidase; Fe2+, ferrous iron; FECH, ferrochelatase; HCP, hereditary coproporphyria; HMB, hydroxymethylbilane; Pb, lead; PBG, porphobilinogen; PBGD, porphobilinogen deaminase; PPOX, protoporphyrinogen oxidase; UROD, uroporphyrinogen decarboxylase; UROS, uroporphyrinogen III synthase; siRNA, small interfering RNA; SuccinylCoA, succinyl‐coenzyme‐A; VP, variegate porphyria

FIGURE 2

Overview of the clinical neurological manifestations of acute hepatic porphyrias. AHPs, acute hepatic porphyrias; HCP, hereditary coproporphyria; VP, variegate porphyria

FIGURE 3

Diagnostic workup and therapeutic strategies in AHPs. +If laboratory results are available as metabolites normalized per gram creatinine, spot urine is sufficient. Otherwise, a 24 h urine collection is recommended. *ALADP, tyrosinemia type I and lead intoxication may be missed if only PBG is analyzed because they cause raised ALA and raised porphyrins only. ^#Hemin is available in Europe as heme arginate (stable form of human hemin in a complex with arginine; NormosangÂ^®, Orphan Europe, Puteaux, France) and in the United States and other countries as lyophilized human hemin (PanhematinÂ^®, Recordati Rare Diseases, Lebanon, NJ, USA). AHP, acute hepatic porphyrias; AIP, acute intermittent porphyria; ALA, 5‐aminolaevulinic acid; HCP, hereditary coproporphyria; VP, variegate porphyria; PBG, porphobilinogen

FIGURE 4

ALA‐induced toxicity or heme deficiency? Proposed overview of main hypotheses of pathophysiological mechanisms of neurotoxicity. For detailed explanation, please refer to main text. ALA, 5‐aminolaevulinic acid; ANS, autonomic nervous system; cGMP, cyclic guanosine monophosphate; CNS, central nervous system; GABA, gamma amino butyric acid; 5HT, serotonin; NO, nitric oxide; PEPT2, peptide transporter 2; PNS, peripheral nervous system