The Porphyrias

Genetic Traits ◽

Molecular Defects ◽

Clinical Presentations ◽

Hereditary Coproporphyria

The porphyrias are uncommon disorders caused by deficiencies in the activities of enzymes of the heme biosynthetic pathway. The enzymatic defects that cause porphyrias are inherited, with the exception of porphyria cutanea tarda, which is primarily acquired. In all porphyrias, there is significant interplay between genetic traits and acquired or environmental factors in the expression of clinical symptoms. This review discusses the classification, pathophysiology, and clinical presentations of the porphyrias. These include those associated with neurovisceral attacks (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and δ-aminolevulinic acid dehydratase [alad] deficiency porphyria) and the porphyrias associated with cutaneous photosensitivity (porphyria cutanea tarda, hepatoerythropoietic porphyria, erythropoietic protoporphyria, and congenital erythropoietic porphyria). Specific emphasis on the epidemiology, molecular defects and pathophysiology, clinical features, diagnosis, and treatment are discussed for each of these disorders. A table lists the safe and unsafe drugs for patients with porphyrias. Figures illustrate the genetic pathways of the disorders and the activities of enzymes of the heme biosynthetic pathway. This review contains 2 highly rendered figures, 1 table, and 96 references.

The Porphyrias

10.2310/neuro.1162 ◽

2010 ◽

Author(s):

Karl E Anderson ◽

Attallah Kappas

Keyword(s):

Porphyria Cutanea Tarda ◽

Genetic Defect ◽

Molecular Defects ◽

Psychiatric Disturbances ◽

Clinical Presentations ◽

Life Threatening ◽

Substantial Morbidity ◽

Enzymatic Defect

The porphyrias are uncommon disorders caused by deficiencies in the activities of the enzymes of the heme biosynthetic pathway. The enzymatic defects that cause porphyrias may be either inherited or acquired, and there is significant interplay between the genetic defect and acquired or environmental factors. Acute forms of the porphyrias may be life threatening and may be misdiagnosed because of the nonspecific nature of the clinical presentation (e.g., acute abdominal pain, psychiatric disturbances, and polyneuropathies). The course of the acute forms of disease is characterized by long latent periods interrupted by acute attacks, which are associated with substantial morbidity and mortality. Porphyrias may be classified as neurovisceral or photosensitive, depending on their prominent clinical characteristic, but in some cases of porphyria, both symptoms are present. Alternatively, the porphyrias can be classified as hepatic or erythropoietic, depending on the principal site of expression of the specific enzymatic defect involved, but the expressions overlap in some porphyrias. The neurovisceral porphyrias correspond with the hepatic porphyrias (ie, acute intermittent porphyria [AIP], variegate porphyria [VP], hereditary coproporphyria [HCP], and ALA deficiency porphyria [ADP]); and the photosensitive porphyrias correspond with the erythropoietic porphyrias (i.e., porphyria cutanea tarda [PCT], hepatoerythropoietic porphyria [HEP], erythropoietic protoporphyria [EPP], and congenital erythropoietic porphyria [CEP]). This chapter covers the classification and pathophysiology of porphyrias and the epidemiology, molecular defects and pathophysiology, diagnosis, and treatment of each of the clinical presentations of porphyria. A table lists the drugs that are safe and unsafe for patients with AIP, VP, HCP, and ADP. Figures illustrate the classification and major symptoms of the porphyrias and the corresponding defect in the biosynthesis of heme that causes the disease; the steps in the biosynthesis of heme; and the mechanisms that precipitate symptoms in AIP. This chapter contains 99 references.

Amounts of Faecal Porphyrin-Peptide Conjugates in the Porphyrias

Clinical Science ◽

10.1042/cs0430299 ◽

1972 ◽

Vol 43 (2) ◽

pp. 299-302 ◽

Cited By ~ 10

Author(s):

M. R. Moore ◽

G. G. Thompson ◽

A. Goldberg

Keyword(s):

Porphyria Cutanea Tarda ◽

Normal Subjects ◽

Peptide Conjugates ◽

Peptide Complex ◽

Variegate Porphyria ◽

Hereditary Coproporphyria ◽

Different Types

1. The levels of ‘X-porphyrin’, a porphyrin-peptide complex, have been studied in the faeces of patients with different types of porphyria, as well as in fifty normal subjects. 2. These levels have been shown to be significantly elevated in untreated porphyria cutanea tarda and in variegate porphyria. 3. Lesser elevations were seen in acute intermittent porphyria and hereditary coproporphyria. There was no elevation in erythropoietic protoporphyria.

Acute Intermittent Porphyria: A Report of 3 Cases with Neuropathy

Case Reports in Neurology ◽

10.1159/000496420 ◽

2019 ◽

Vol 11 (1) ◽

pp. 32-36

Author(s):

Mohammed Alqwaifly ◽

Vera Bril ◽

Dubravka Dodig

Keyword(s):

Biosynthetic Pathway ◽

Metabolic Disorders ◽

Case Series ◽

Genetic Mutation ◽

Nerve Conduction Studies ◽

Porphobilinogen Deaminase ◽

Motor Neuropathy ◽

Clinical Presentations ◽

Associated Symptoms

The porphyrias are metabolic disorders due to a defect in the heme biosynthetic pathway. Patients have diverse clinical presentations with neuropathy being frequent in acute intermittent porphyria (AIP). Associated symptoms are abdominal pain and seizures. Three patients presenting with neuropathy were later diagnosed with AIP on the basis of clinical features, erythrocyte porphobilinogen deaminase activity, neuropathic patterns, and nerve conduction studies. Testing for the HMBS genetic mutation confirmed the diagnosis of AIP in 1 patient. The findings from this case series confirm that porphyric neuropathy in AIP is a predominantly motor neuropathy with differing neuropathic presentations ranging from focal motor neuropathy to quadriplegia and respiratory failure.

δ-Aminolevulinic Acid Synthetase Activity in Human Plasma: Relation to Erythropoiesis and Evidence of Induction in Erythropoietic Porphyria

Blood ◽

10.1182/blood.v39.1.13.13 ◽

1972 ◽

Vol 39 (1) ◽

pp. 13-22 ◽

Cited By ~ 4

Author(s):

KEN MIYAGI ◽

C. J. WATSON

Keyword(s):

Human Plasma ◽

Peripheral Blood ◽

Aminolevulinic Acid ◽

Porphyria Cutanea Tarda ◽

Synthetase Activity ◽

Significant Activity ◽

Large Numbers ◽

Normal Individuals ◽

Method Of Measurement

Abstract Measurement of δ-aminolevulinic acid synthetase (ALA-S) activity in human plasma has been carried out with samples from normal individuals, cases of erythropoietic porphyria (EP) and erythropoietic protoporphyria (EPP), and of the three principal forms of hepatic porphyria—acute intermittent porphyria, variegate porphyria, and porphyria cutanea tarda. The method of measurement depends on formation of 14C-ALA when the plasma is incubated with 14C-succinic acid, succinyl-Co A synthetase, glycine, and other essential substances. The normal samples, as well as those from the hepatic porphyria cases, had small but significant activity of the same extent; those from the erythropoietic group showed consistently higher values, especially in the two cases of congenital type. A remarkably high value in one of these cases in which there was outspoken erythropoiesis was believed to be related to the presence of many fluorescing normoblasts in the peripheral blood. Following multiple transfusions these disappeared concomitantly with striking reduction of the porphyria. The plasma ALA-S activity declined to 1.4% of the pretransfusion value. These results are considered in respect to the question of induction of ALA-S in the developing red cells of the disease, special attention being given to the minor increase of ALA-S activity in the plasma of a nonporphyric individual whose peripheral blood contained large numbers of circulating normoblasts.

Updates on the diagnosis and management of the most common hereditary porphyrias: AIP and EPP

Hematology ◽

10.1182/hematology.2020000124 ◽

2020 ◽

Vol 2020 (1) ◽

pp. 400-410

Author(s):

Michael Linenberger ◽

Kleber Y. Fertrin

Keyword(s):

Biosynthetic Pathway ◽

Aminolevulinic Acid ◽

Clinical Manifestations ◽

High Plasma ◽

Suppressive Therapy ◽

Gene Encoding ◽

Burning Pain ◽

Recessive Mutations ◽

Systemic Distribution

Abstract The porphyrias are a family of metabolic disorders caused by defects in the activity of one of the enzymes in the heme biosynthetic pathway. Acute intermittent porphyria (AIP), caused by autosomal dominant mutations in the gene encoding hydroxymethylbilane synthase, can lead to hepatocyte overaccumulation and systemic distribution of the proximal porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). ALA and PBG are toxic to neurons and extrahepatic tissue and cause the neurovisceral clinical manifestations of AIP. Management of AIP includes awareness and avoidance of triggering factors, infusions of hemin for severe acute attacks, and, if indicated for chronic suppressive therapy, maintenance treatment with hemin or givosiran, a small interfering RNA molecule that antagonizes ALA synthase 1 transcripts. Erythropoietic protoporphyria (EPP) is most commonly caused by autosomal recessive mutations in the gene encoding ferrochelatase (FECH), the heme pathway terminal enzyme. FECH deficiency leads to erythrocyte overaccumulation and high plasma levels of lipophilic protoporphyrins that photoactivate in the skin, causing burning pain and erythema. Protoporphyrins excreted in the bile can cause gallstones, cholestasis, fibrosis, and ultimately liver failure. Management of EPP includes skin protection and afamelanotide, an α-melanocyte stimulating hormone analog that increases melanin pigment and reduces photoactivation. Liver transplantation may be necessary for severe EPP-induced liver complications. Because AIP and EPP arise from defects in the heme biosynthetic pathway, hematologists are often consulted to evaluate and manage suspected or proven porphyrias. A working knowledge of these disorders increases our confidence and effectiveness as consultants and medical providers.

Metabolic Disease

10.1093/med/9780190276478.003.0011 ◽

2017 ◽

Author(s):

Virginia P. Sybert

Keyword(s):

Metabolic Disorders ◽

Porphyria Cutanea Tarda ◽

Hunter Syndrome ◽

Acrodermatitis Enteropathica ◽

Prolidase Deficiency ◽

Treatment Mode ◽

Hereditary Coproporphyria

Chapter 11 covers Porphyrias (Congenital Erythropoietic Porphyria, Erythropoietic Protoporphyria, Hereditary Coproporphyria, Porphyria Cutanea Tarda, and Variegate Porphyria), Mucopolysaccharidoses (Hunter Syndrome), and Other Metabolic Disorders (Acrodermatitis Enteropathica, Alkaptonuria, Biotinidase Deficiency, Familial Cutaneous Amyloidosis, and Prolidase Deficiency). Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

Metabolic Disease

10.1093/med/9780195397666.003.0011 ◽

2012 ◽

Author(s):

Virginia P. Sybert

Keyword(s):

Metabolic Disease ◽

Metabolic Disorders ◽

Porphyria Cutanea Tarda ◽

Hunter Syndrome ◽

Biotinidase Deficiency ◽

Acrodermatitis Enteropathica ◽

Prolidase Deficiency ◽

Hereditary Coproporphyria

Porphyrias – Congenital Erythropoietic Porphyria – Erythropoietic Protoporphyria – Hereditary Coproporphyria – Porphyria Cutanea Tarda – Variegate Porphyria – Mucopolysaccharidoses – Hunter Syndrome – Other Metabolic Disorders – Acrodermatitis Enteropathica – Alkaptonuria – Biotinidase Deficiency – Familial Cutaneous Amyloidosis – Prolidase Deficiency

Acute Intermittent Porphyria in a Man with Dual Enzyme Deficiencies

Case Reports in Genetics ◽

10.1155/2020/8873219 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

G. N. Cerbino ◽

L. Abou Assali ◽

L. S. Varela ◽

L. Tomassi ◽

A. Batlle ◽

...

Keyword(s):

Biosynthetic Pathway ◽

Metabolic Disorders ◽

De Novo ◽

Porphyria Cutanea Tarda ◽

Uroporphyrinogen Decarboxylase ◽

History Of ◽

Biochemical Testing ◽

De Novo Variant ◽

Deficient Activity

Porphyrias are a heterogeneous group of metabolic disorders that result from the altered activity of specific enzymes of the heme biosynthetic pathway and are characterized by accumulation of pathway intermediates. Porphyria cutanea tarda (PCT) is the most common porphyria and is due to deficient activity of uroporphyrinogen decarboxylase (UROD). Acute intermittent porphyria (AIP) is the most common of the acute hepatic porphyrias, caused by decreased activity of hydroxymethylbilane synthase (HMBS). An Argentinean man with a family history of PCT who carried the UROD variant c.10_11insA suffered severe abdominal pain. Biochemical testing was consistent with AIP, and molecular analysis of HMBS revealed a de novo variant: c.344 + 2_ + 5delTAAG. This is one of the few cases of porphyria identified with both UROD and HMBS mutations and the first confirmed case of porphyria with dual enzyme deficiencies in Argentina.

DOUBLE PORPHYRIA: LITERATURE REVIEW AND ANALYSIS OF CLINICAL OBSERVATION

Russian Journal of Skin and Venereal Diseases ◽

10.18821/1560-9588-2018-21-2-120-124 ◽

2018 ◽

Vol 21 (2) ◽

pp. 120-124

Author(s):

Alexander B. Krivosheev ◽

L. Ya Kupriyanova ◽

M. A Kondratova

Keyword(s):

Aminolevulinic Acid ◽

Clinical Symptoms ◽

Dorsal Surface ◽

Total Content ◽

Aminocaproic Acid ◽

Progressive Increase ◽

New Variant ◽

Peripheral Polyneuropathy ◽

Prolonged Observation

A brief review of the literature on the problem of double porphyria and analysis of its own observation is presented. For more than 10 years patient B was observed for more than 10 years with a verified diagnosis of acute intermittent porphyria, which manifested with acute pain abdominal syndrome, neurological disorders in the form of peripheral polyneuropathy and hemiparesis of lower extremities, and hypertension syndrome was also noted. The observed clinical symptoms corresponded to an acute porphyrin crisis in the manifestation and / or relapse of acute intermittent porphyria. The diagnosis was confirmed by a quantitative determination of the excretory profile of porphyrin precursors (δ-aminocaproic acid, porphobilinogen) and porphyrin fractions (uroporphyrin, coproporphyrin). Their concentrations are significantly (especially porphyrin precursors) exceeding the control values, which is the cardinal diagnostic criterion of acute intermittent porphyria. Against the backdrop of persistent clinical and biochemical remission of acute intermittent porphyria, symptoms of photosensitization of the skin (blisters, erosion, pigment spots) on the dorsal surface of the hands began to appear in 4 years. Later, hypertrichosis was formed in the temporo-periorbital region. The constellation type of the excretory profile of porphyrins began to change. Against the backdrop of persistent increased excretion of porphyrin precursors (δ-aminolevulinic acid and porphobilinogen), a progressive increase in the excretion of the fraction of uroporphyrin was observed, which became dominant (up to 58% of the total content of porphyrins). Such a prolonged observation in the dynamics allowed us to state the appearance of a new variant of the porphyrin exchange disturbance, which, taking into account clinical symptoms, corresponded to another form of hepatic porphyria, namely, late cutaneous porphyria. The clinical and biochemical changes in the excretory profile of the parameters of porphyrin metabolism registered in the dynamics of observation may indicate the occurrence of a combined enzymatic defect characteristic of double porphyria. In our case, a manifestation of late cutaneous porphyria was noted against a background of compensated acute intermittent porphyria.

Plasma Porphyrins in the Porphyrias

Clinical Chemistry ◽

10.1093/clinchem/45.7.1070 ◽

1999 ◽

Vol 45 (7) ◽

pp. 1070-1076 ◽

Cited By ~ 33

Author(s):

J Thomas Hindmarsh ◽

Linda Oliveras ◽

Donald C Greenway

Keyword(s):

Renal Failure ◽

Healthy Subjects ◽

Porphyria Cutanea Tarda ◽

Plasma Concentrations ◽

Fluorometric Detection ◽

Clinical Sensitivity ◽

Hereditary Coproporphyria ◽

Coproporphyrin I

Abstract Background: As an aid in the diagnosis and management of porphyria we have developed a method to fractionate and quantify plasma porphyrins and have evaluated its use in various porphyrias. Methods: We used HPLC with fluorometric detection to measure plasma concentrations of uroporphyrin I and III, heptacarboxyl III, hexacarboxyl III, pentacarboxyl III, and coproporphyrin I and III. We studied 245 healthy subjects, 32 patients with classical porphyria cutanea tarda (PCT), 12 patients with PCT of renal failure, 13 patients with renal failure, 8 patients with pseudoporphyria of renal failure, 3 patients with acute intermittent porphyria, 5 patients with variegate porphyria, 5 patients with hereditary coproporphyria, and 4 patients with erythropoietic protoporphyria. Results: Between-run CVs were 5.4–13%. The recoveries of porphyrins added to plasma were 71–114% except for protoporphyrin, which could not be reliably measured with this technique. Plasma porphyrin patterns clearly identified PCT, and its clinical sensitivity equaled that of urine porphyrin fractionation. The patterns also allowed differentiation of PCT of renal failure from pseudoporphyria of renal failure. Conclusions: The assay of plasma porphyrins identifies patients with PCT and appears particularly useful for differentiating PCT of renal failure from pseudoporphyria of renal failure.