Acute Hepatic Porphyria: Pathophysiological Basis of Neuromuscular Manifestations

Souza, Paulo Victor Sgobbi de; Badia, Bruno de Mattos Lombardi; Farias, Igor Braga; Pinto, Wladimir Bocca Vieira de Rezende; Oliveira, Acary Souza Bullé

doi:10.3389/fnins.2021.715523

Cited by 22 publications

(20 citation statements)

References 80 publications

(213 reference statements)

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“…A novel siRNA-based agent, givosiran, exploits the native RNA-induced silencing complex (RISC) to specifically modulate liver ALAS1 mRNA translation [ 10 , 11 , 12 ]. Givosiran has shown excellent results in terms of reduction in acute attacks per year and an overall improvement of quality of life in symptomatic patients with AHP [ 10 , 11 ].…”

Section: Givosiran and Pakdmentioning

confidence: 99%

“…In recent years, a novel siRNA-based drug, givosiran, has been approved for the treatment of acute hepatic porphyrias [ 10 , 11 ]: by specifically inhibiting the liver isoform of ALA synthase (ALAS1), the first and rate-limiting enzyme of the heme biosynthetic pathway, givosiran has shown to be highly efficacious in reducing the frequency of porphyric attacks and improving the quality of life of patients with AHPs [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications

Ricci

Guida²,

Manzini

et al. 2021

Diagnostics

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Porphyrias are a group of rare disorders originating from an enzyme dysfunction in the pathway of heme biosynthesis. Depending on the specific enzyme involved, porphyrias manifest under drastically different clinical pictures. The most dramatic presentation of the four congenital acute hepatic porphyrias (AHPs: acute intermittent porphyria—AIP, ALAD deficiency, hereditary coproporphyria—HCP, and porphyria variegata—VP) consists of potentially life-threatening neurovisceral attacks, for which givosiran, a novel and effective siRNA-based therapeutic, has recently been licensed. Nonetheless, the clinical manifestations of acute porphyrias are multifaceted and do not limit themselves to acute attacks. In particular, porphyria-associated kidney disease (PAKD) is a distinct, long-term degenerating condition with specific pathological and clinical features, for which a satisfactory treatment is not available yet. In PAKD, chronic tubule-interstitial damage has been most commonly reported, though other pathologic features (e.g., chronic fibrous intimal hyperplasia) are consistent findings. Given the relevant role of the kidney in porphyrin metabolism, the mechanisms possibly intervening in causing renal damage in AHPs are different: among others, δ-aminolevulinic acid (ALA)-induced oxidative damage on mitochondria, intracellular toxic aggregation of porphyrins in proximal tubular cells, and derangements in the delicate microcirculatory balances of the kidney might be implicated. The presence of a variant of the human peptide transporter 2 (PEPT2), with a greater affinity to its substrates (including ALA), might confer a greater susceptibility to kidney damage in patients with AHPs. Furthermore, a possible effect of givosiran in worsening kidney function has been observed. In sum, the diagnostic workup of AHPs should always include a baseline evaluation of renal function, and periodic monitoring of the progression of kidney disease in patients with AHPs is strongly recommended. This review outlines the role of the kidney in porphyrin metabolism, the available evidence in support of the current etiologic and pathogenetic hypotheses, and the known clinical features of renal involvement in acute hepatic porphyrias.

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Section: Givosiran and Pakdmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications

Ricci

Guida²,

Manzini

et al. 2021

Diagnostics

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“…Heme is derived from porphyrins and several enzymes play a key role in the synthesis of heme [1]. If any of the enzymes is defective the precursors start to accumulate and result in an acute attack [2]. The type of porphyria depends on the type of affected enzyme.…”

Section: Introductionmentioning

confidence: 99%

A Case of Acute Intermittent Porphyria Leading to Severe Disability in a Young 21-Year-Old Female

Ramzan¹,

Cao²,

Frazer³

et al. 2023

Cureus

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Acute intermittent porphyria (AIP) is a rare metabolic disorder that is challenging to diagnose and treat. Symptoms are nonspecific and severe acute attacks may be life-threatening. This is a case of a previously healthy 21-year-old woman diagnosed with an acute attack of AIP following recurrent hospitalizations with undiagnosed abdominal pain over a 12-month period with gradual onset of motor neuropathy which resulted in complete paralysis and respiratory failure. Through our case, we will highlight the challenges in AIP diagnosis and management, its potential severity, and how an early diagnosis could have prevented severe disability.

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“…Deficiency of enzymes of the heme biosynthetic pathway causes a category of human metabolic diseases called porphyrias, characterized by different modes of inheritance and clinical manifestations, with signs and symptoms manifesting in different organ systems [ 1 , 2 , 3 ]. Porphyrias are associated with build-up and undue excretion of heme pathway intermediates, such as the heme precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) and their oxidized products, such as porphirins [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Circadian Genes Expression Patterns in Disorders Due to Enzyme Deficiencies in the Heme Biosynthetic Pathway

et al. 2022

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Heme is a member of the porphyrins family of cyclic tetrapyrroles and influences various cell processes and signalling pathways. Enzyme deficiencies in the heme biosynthetic pathway provoke rare human inherited metabolic diseases called porphyrias. Protein levels and activity of enzymes involved in the heme biosynthetic pathway and especially 5′-Aminolevulinate Synthase 1 are featured by 24-h rhythmic oscillations driven by the biological clock. Heme biosynthesis and circadian pathways intermingle with mutual modulatory roles. Notably, heme is a ligand of important cogs of the molecular clockwork, which upon heme binding recruit co-repressors and inhibit the transcription of numerous genes enriching metabolic pathways and encoding functional proteins bringing on crucial cell processes. Herein, we assessed mRNA levels of circadian genes in patients suffering from porphyrias and found several modifications of core clock genes and clock-controlled genes expression, associated with metabolic and electrolytic changes. Overall, our results show an altered expression of circadian genes accompanying heme biosynthesis disorders and confirm the need to deepen the knowledge of the mechanisms through which the alteration of the circadian clock circuitry could take part in determining signs and symptoms of porphyria patients and then again could represent a target for innovative therapeutic strategies.

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Acute Hepatic Porphyria: Pathophysiological Basis of Neuromuscular Manifestations

Cited by 22 publications

References 80 publications

Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications

Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications

A Case of Acute Intermittent Porphyria Leading to Severe Disability in a Young 21-Year-Old Female

Circadian Genes Expression Patterns in Disorders Due to Enzyme Deficiencies in the Heme Biosynthetic Pathway

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