Porphyric Neuropathy: Pathophysiology, Diagnosis, and Updated Management
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(2020) 20:56
AUTONOMIC DYSFUNCTION (L.H. WEIMER, SECTION EDITOR)
Porphyric Neuropathy: Pathophysiology, Diagnosis, and Updated Management Mohamed Kazamel 1
&
Robert J. Desnick 2 & John G. Quigley 3
Accepted: 29 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose of Review To review the peripheral neurological complications of the acute hepatic porphyrias, as well as the latest advances in their pathophysiology and management. Recent Findings The diagnosis of porphyric neuropathy remains challenging as varying neuropathic patterns are encountered depending on disease stage, including a non-length-dependent distribution pattern. The major pathophysiologic mechanism is δaminolevulinic acid (ALA)–induced neurotoxicity. The less restrictive blood-nerve barrier in the autonomic ganglia and myenteric plexus may explain the frequency of dysautonomic manifestations. Recently, a prophylactic small interfering RNA (siRNA)-based therapy that reduces hepatic ALA Synthase-1 mRNA was approved for patients with recurrent neuro-visceral attacks. Summary Neurologists should appreciate the varying patterns of porphyric neuropathy. As with most toxin-induced axonopathies, long-term outcomes depend on early diagnosis and treatment. While the short-term clinical and biochemical benefits of siRNA-based therapy are known, its long-term effects on motor recovery, chronic pain, and dysautonomic manifestations are yet to be determined. Keywords ALA . Dysautonomia . Hemin . Neuropathy . Porphyria . Small interfering RNA
Introduction Porphyrias are a group of eight disorders, each resulting from a specific enzymatic defect in the heme biosynthesis pathway, with the resultant accumulation of heme biosynthetic intermediates (Fig. 1) [2, 3]. The four acute hepatic porphyrias (AHPs) are due to hepatic overproduction of the porphyrin precursors, δ-aminolevulinic acid (ALA), and porphobilinogen (PBG). Their symptoms primarily involve the central and peripheral nervous system [4]. They include This article is part of the Topical Collection on Autonomic Dysfunction * Mohamed Kazamel [email protected] 1
Department of Neurology, University of Alabama at Birmingham, 1720 2nd Ave. South, SC271, Birmingham, AL 35294-0017, USA
2
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3
Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
acute intermittent porphyria (AIP), the most common, variegate porphyria (VP), and hereditary coproporphyria (HCP) which are less frequent and often have photosensitive cutaneous lesions (Table 1) [4–7]. ALA-dehydratase deficiency porphyria (ADP) is extremely rare with ≤ 12 reported cases [8, 9]. AIP, VP, and HCP are autosomal dominant disorders, while ADP is autosomal recessive [10]. The Human Gene Mutation Database [11] presently lists > 400 variants in the hydroxymethylbilane synthase (HMBS) gene causing AIP. Pathogenic mutations in the protoporphyrinogen oxidase (PPOX) and coproporphyrino
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