43 results match your criteria ALA Dehydratase Deficiency Porphyria

Spotlight on Givosiran as a Treatment Option for Adults with Acute Hepatic Porphyria: Design, Development, and Place in Therapy.

Drug Des Devel Ther 2022 16;16:1827-1845. Epub 2022 Jun 16.

Department of Internal Medicine, Section on Gastroenterology and Hepatology, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Small interfering ribonucleic acids [siRNAs] are short ribonucleic acid (RNA) fragments cleaved from double-stranded RNA molecules that target and bind to specific sequences on messenger RNA (mRNA), leading to their destruction. Therefore, the siRNA down-regulates the formation of selected mRNAs and their protein products. Givosiran is one such siRNA that uses this mechanism to treat acute hepatic porphyrias. Read More

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Neurological Manifestations of Acute Porphyrias.

Curr Neurol Neurosci Rep 2022 Jun 4. Epub 2022 Jun 4.

Department of Neurology and Rehabilitation, University of Illinois at Chicago College of Medicine, 912 S Wood St, Chicago, IL, 60612, USA.

Purpose Of Review: Porphyrias constitute a group of rare metabolic disorders that result in a deficiency of the heme biosynthetic pathway and lead to the accumulation of metabolic intermediaries. Patients with porphyria can experience recurrent neurovisceral attacks which are characterized by neuropathic abdominal pain and acute gastrointestinal symptoms, including nausea, vomiting, and constipation. Depending on the type of porphyria, patients can present with cutaneous manifestations, such as severe skin photosensitivity, chronic hemolysis, or evidence of neurologic dysfunction, including alterations in consciousness, neurovascular involvement, seizures, transient sensor-motor symptoms, polyneuropathy, and behavioral abnormalities. Read More

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Assessment of porphyrogenicity of drugs and chemicals in selected hepatic cell culture models through a fluorescence-based screening assay.

Pharmacol Res Perspect 2022 06;10(3):e00951

Department of Internal Medicine, Section on Gastroenterology and Hepatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

Compounds that induce 5-aminolevulinic acid [ALA] synthase-1 and/or cytochromes P-450 may induce acute porphyric attacks in patients with the acute hepatic porphyrias [AHPs]. Currently, there is no simple, robust model used to assess and predict the porphyrogenicity of drugs and chemicals. Our aim was to develop a fluorescence-based in vitro assay for this purpose. Read More

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RNAi therapy with givosiran significantly reduces attack rates in acute intermittent porphyria.

J Intern Med 2022 05 23;291(5):593-610. Epub 2022 Jan 23.

Department of Medical Biochemistry and Biophysics, Centre for inherited Metabolic Diseases, Porphyria Centre Sweden., Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Acute hepatic porphyria (AHP) is a group of inherited metabolic disorders that affect hepatic heme biosynthesis. They are associated with attacks of neurovisceral manifestations that can be life threatening and constitute what is considered an acute porphyria attack. Until recently, the sole specific treatment for acute porphyria attacks consisted of the intravenous administration of hemin. Read More

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Expert consensus statement on acute hepatic porphyria in Belgium.

Acta Clin Belg 2021 Aug 7:1-7. Epub 2021 Aug 7.

Dienst Maag-Darm-Leverziekten en Metabool Centrum, UZ Leuven, Belgium.

Acute hepatic porphyrias (AHP) are a group of four different rare to ultra-rare, severely debilitating, and sometimes fatal diseases that significantly impact patients' lives: 5-aminolevulinic acid (ALA) dehydratase deficiency porphyria (ADP), acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). Based on literature estimates, a conservative estimate of the number of AHP patients in Belgium requiring treatment, defined as patients experiencing recurrent attacks and/or chronic debilitating symptoms, is likely limited to 11-34 patients. These patients face a considerable unmet need, as there is currently no pharmaceutical treatment available that effectively prevents attacks and has an impact on other chronic symptoms of the disease. Read More

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5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin.

Mol Genet Metab 2020 12 26;131(4):418-423. Epub 2020 Oct 26.

Departments of Preventive Medicine and Population Health, and Internal Medicine (Division of Gastroenterology and Hepatology), University of Texas Medical Branch, Galveston, Texas, USA.

Background: 5-Aminolevulinic acid dehydratase (ALAD) porphyria (ADP) is an ultrarare autosomal recessive disease, with only eight documented cases, all of whom were males. Although classified as an acute hepatic porphyria (AHP), induction of the rate limiting hepatic enzyme 5-aminolevulinic acid synthase-1 (ALAS1) has not been demonstrated, and the marrow may also contribute excess 5-aminolevulinic acid (ALA). Two patients have died and reported follow up for the others is limited, so the natural history of this disease is poorly understood and treatment experience limited. Read More

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December 2020

Hyperhomocysteinemia in patients with acute porphyrias: A potentially dangerous metabolic crossroad?

Eur J Intern Med 2020 09 31;79:101-107. Epub 2020 May 31.

Unit of Internal Medicine, Department of Medical and Surgical Science for Children and Adults, University of Modena and Reggio Emilia, Italy.

Background: Acute porphyrias (AP) are characterized by heme deficiency and induction of hepatic 5-aminolevulinate synthase (ALAS1). Hyperhomocysteinemia (HHcy) is associated with endothelial damage, neurotoxicity and increased risk for vascular diseases. Interestingly, both heme biosynthesis and sulphur amino acid metabolism require vitamin B6, (Pyridoxal-phosphate, PLP) an important cofactor of ALAS1 and of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CGL) enzymes that catabolize homocysteine (Hcy). Read More

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September 2020

Heme biosynthesis and the porphyrias.

John D Phillips

Mol Genet Metab 2019 11 22;128(3):164-177. Epub 2019 Apr 22.

Division of Hematology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States of America. Electronic address:

Porphyrias, is a general term for a group of metabolic diseases that are genetic in nature. In each specific porphyria the activity of specific enzymes in the heme biosynthetic pathway is defective and leads to accumulation of pathway intermediates. Phenotypically, each disease leads to either neurologic and/or photocutaneous symptoms based on the metabolic intermediate that accumulates. Read More

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November 2019

Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs).

Mol Genet Metab 2019 11 6;128(3):213-218. Epub 2019 Mar 6.

Section on Gastroenterology & Hepatology, Wake Forest University School of Medicine/NC Baptist Hospital, Winston-Salem, NC 27157, United States of America.

The acute hepatic porphyrias include four disorders: acute intermittent porphyria [AIP], hereditary coproporphyria [HCP], variegate porphyria [VP], and the rare porphyria due to severe deficiency of ALA dehydratase [ADP]. In the USA, AIP is the most severe and most often symptomatic. AIP, HCP, and VP are due to autosomal dominant genetic abnormalities, in which missense, nonsense, or other mutations of genes of normal hepatic heme biosynthesis, in concert with other environmental, nutritional, hormonal and genetic factors, may lead to a critical deficiency of heme, the end-product of the pathway, in a small but critical 'regulatory pool' within hepatocytes. Read More

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November 2019

Acute Hepatic Porphyrias: Review and Recent Progress.

Hepatol Commun 2019 Feb 20;3(2):193-206. Epub 2018 Dec 20.

Section of Gastroenterology and Hepatology, Department of Internal Medicine Wake Forest University School of Medicine Winston-Salem NC.

The acute hepatic porphyrias (AHPs) are a group of four inherited diseases of heme biosynthesis that present with episodic, acute neurovisceral symptoms. The four types are 5-aminolevulinic acid (ALA) dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria. Their diagnoses are often missed or delayed because the clinical symptoms mimic other more common disorders. Read More

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February 2019

Hepatocellular carcinoma in acute hepatic porphyrias: A Damocles Sword.

Mol Genet Metab 2019 11 9;128(3):236-241. Epub 2018 Oct 9.

UMRs 1149, Centre de Recherche sur l'Inflammation, Institut National de la Santé et de la Recherche Médicale, F-75018 Paris, France; Assistance Publique-Hôpitaux de Paris, HUPNVS Centre Français des Porphyries, Hôpital Louis Mourier, 178 Rue des Renouillers, F-92701 Colombes, France; Laboratory of Excellence Gr-Ex, France; Université Paris Diderot, UFR de Médecine Xavier Bichat, F-75018 Paris, France.

Porphyrias are inherited diseases with low penetrance affecting the heme biosynthesis pathway. Acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP) together constitute the acute hepatic porphyrias (AHP). These diseases have been identified as risk factors for primary liver cancers (PLC), mainly hepatocellular carcinoma (HCC: range 87-100%) but also cholangiocarcinoma, alone or combination with HCC. Read More

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November 2019

Acute hepatic and erythropoietic porphyrias: from ALA synthases 1 and 2 to new molecular bases and treatments.

Curr Opin Hematol 2017 May;24(3):198-207

aINSERM U1149 CNRS ERL 8252, Centre de Recherche sur l'inflammation, Université Paris Diderot, site Bichat, Sorbonne Paris Cité bLaboratory of excellence, GR-Ex, Paris cAP-HP, Centre Français des Porphyries, Hôpital Louis Mourier, Colombes dAP-HP, Hôpital Beaujon, Service de Biochimie Clinique, Clichy, France.

Purpose Of Review: Many studies over the past decade have together identified new genes including modifier genes and new regulation and pathophysiological mechanisms in inherited inborn diseases of the heme biosynthetic pathway. A new porphyria has been characterized: X-linked protoporphyria and the perspective to have innovative treatment at very short-term became a reality. We will summarize how recent data on both ALAS1 and ALAS2 have informed our understanding of disease pathogenesis with an emphasis on how this information may contribute to new therapeutic strategies. Read More

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Acute Porphyrias.

J Emerg Med 2015 Sep 7;49(3):305-12. Epub 2015 Jul 7.

Department of Medicine, University of Connecticut, Farmington, Connecticut; Department of Medicine, University of North Carolina, Chapel Hill, North Carolina.

Background: Porphyrias are a group of eight metabolic disorders characterized by defects in heme biosynthesis. Porphyrias are classified into two major categories: 1) the acute or inducible porphyrias and 2) the chronic cutaneous porphyrias. The acute hepatic porphyrias are further classified into acute intermittent porphyria (AIP), hereditary coproporphyria, variegate porphyria, and porphyria due to severe deficiency of delta-aminolevulinic acid (ALA) dehydratase (ALADP). Read More

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September 2015

Clinically important features of porphyrin and heme metabolism and the porphyrias.

Metabolites 2014 Nov 3;4(4):977-1006. Epub 2014 Nov 3.

Department of Medicine, Universities of CT, Farmington, CT 06030 and North Carolina, Chapel Hill, NC 27599, USA.

Heme, like chlorophyll, is a primordial molecule and is one of the fundamental pigments of life. Disorders of normal heme synthesis may cause human diseases, including certain anemias (X-linked sideroblastic anemias) and porphyrias. Porphyrias are classified as hepatic and erythropoietic porphyrias based on the organ system in which heme precursors (5-aminolevulinic acid (ALA), porphobilinogen and porphyrins) are chiefly overproduced. Read More

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November 2014

Direct assay of delta-aminolevulinic acid dehydratase in heme biosynthesis for the detection of porphyrias by tandem mass spectrometry.

Anal Chem 2010 Aug;82(15):6730-6

Department of Chemistry, University of Washington, Seattle, Washington 98195-1700, USA.

We report a new assay of human delta-aminolevulinic acid dehydratase (ALAD), an enzyme converting delta-aminolevulinic acid (ALA) into porphobilinogen. The assay is developed for use in the clinical diagnosis of delta-aminolevulinic acid dehydratase-deficient porphyria, a rare enzymatic deficiency of the heme biosynthetic pathway. The assay involves the incubation of erythrocyte lysate with the natural substrate, ALA, followed by quantitative in situ conversion of porphobilinogen to its butyramide, and liquid-liquid extraction into a mass spectrometer-friendly solvent. Read More

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Porphyria syndrome associated with diabetic nephrosclerosis and erythropoietin.

Compr Ther 2006 ;32(3):163-71

Department of Medicine, Northwestern University Medical School, Chicago, IL, USA.

The porphyrias are inherited or acquired metabolic disorders caused by a partial deficiency in one of the enzymes of the heme biosynthetic pathway. Eight enzymes are utilized in the synthesis of heme. An enzyme defect in one of the last seven enzymes will result in one of the seven different forms of porphyria, some of which have similar signs and symptoms. Read More

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Dual gene defects involving delta-aminolaevulinate dehydratase and coproporphyrinogen oxidase in a porphyria patient.

Br J Haematol 2006 Jan;132(2):237-43

Okayama Prefectural University, Japan.

Summary A Caucasian male had symptoms of acute porphyria, with increases in urinary delta-aminolaevulinic acid (ALA), porphobilinogen (PBG) and coproporphyrin that were consistent with hereditary coproporphyria (HCP). However, a greater than expected increase in ALA, compared with PBG, and a substantial increase in erythrocyte zinc protoporphyrin, suggested additional ALA dehydratase (ALAD) deficiency. Nucleotide sequence analysis of coproporphyrinogen oxidase (CPO) cDNA of the patient, but not of the parents, revealed a novel nucleotide transition G835-->C, resulting in an amino acid change, G279R. Read More

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January 2006

Neurovisceral porphyrias: what a hematologist needs to know.

Hematology Am Soc Hematol Educ Program 2005 :24-30

The Liver-Biliary-Pancreatic Center, University of Connecticut, MC-1111, 263 Farmington Avenue, Farmington, CT 06030, USA.

The acute or inducible hepatic porphyrias comprise four inherited disorders of heme biosynthesis. They usually remain asymptomatic for most of the lifespan of individuals who inherit the specific enzyme deficiencies but may cause life-threatening attacks of neurovisceral symptoms. Failure to consider the diagnosis frequently delays effective treatment, and inappropriate diagnostic tests and/or mistaken interpretation of results may lead to misdiagnosis and inappropriate treatment. Read More

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November 2009

The third case of Doss porphyria (delta-amino-levulinic acid dehydratase deficiency) in Germany.

J Inherit Metab Dis 2004 ;27(4):529-36

Clinical Biochemistry--Consultation Porphyria, Postfach 12 20, D-35002 Marburg an der Lahn, Germany.

Delta-aminolevulinic acid dehydratase (ALAD) deficiency porphyria, or Doss porphyria, was first reported in Germany in 1979. Only four bona fide cases of Doss porphyria have been reported to date that were confirmed by immunological and molecular analyses of their ALAD mutations. Here we describe the fifth case of Doss porphyria. Read More

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January 2005

Late-onset porphyrias: what are they?

Cell Mol Biol (Noisy-le-grand) 2002 Feb;48(1):97-101

Laboratory of Biochemical Hematology, The Rockefeller University, New York, NY 10021, USA.

Porphyrias are inherited disorders of heme biosynthesis. ALA dehydratase porphyria (ADP) and congenital erythropoietic porphyria (CEP) are autosomal recessive porphyrias, and are typically expressed at birth or in childhood. However, a few cases of late-onset recessive porphyrias have been reported. Read More

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February 2002

Genetic rescue of Leishmania deficiency in porphyrin biosynthesis creates mutants suitable for analysis of cellular events in uroporphyria and for photodynamic therapy.

J Biol Chem 2002 Apr 8;277(17):14902-9. Epub 2002 Feb 8.

Department of Microbiology, University of Health Sciences, Chicago Medical School, North Chicago, Illinois 60064, USA.

Leishmania was found deficient in at least five and most likely seven of the eight enzymes in the heme biosynthesis pathway, accounting for their growth requirement for heme compounds. The xenotransfection of this trypanosomatid protozoan led to their expression of the mammalian genes encoding delta-aminolevulinate (ALA) dehydratase and porphobilinogen deaminase, the second and the third enzymes of the pathway, respectively. These transfectants still require hemin or protoporphyrin IX for growth but produce porphyrin when ALA was supplied exogenously. Read More

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Porphyrin biosynthesis intermediates are not regulating delta-aminolevulinic acid transport in Saccharomyces cerevisiae.

Biochem Biophys Res Commun 2000 Jun;272(3):946-50

Centro de Investigaciones sobre Porfirinas y Porfirias, CIPYP (CONICET, FCEyN, UBA), Ciudad Universitaria, Buenos Aires, Argentina.

In Saccharomyces cerevisiae, as in all eukaryotic organisms, delta-aminolevulinic acid (ALA) is a precursor of porphyrin biosynthesis, a very finely regulated pathway. ALA enters yeast cells through the gamma-aminobutyric acid (GABA) permease Uga4. The incorporation of a metabolite into the cells may be a limiting step for its intracellular metabolization. Read More

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Investigations on the formation of urinary coproporphyrin isomers I-IV in 5-aminolevulinic acid dehydratase deficiency porphyria, acute lead intoxication and after oral 5-aminolevulinic acid loading.

Clin Biochem 1999 Mar;32(2):119-23

Institute of Clinical Chemistry, University Hospital Grosshadern, Munich, Germany.

Objectives: Investigation of the metabolism of the four urinary coproporphyrin isomers I-IV in the extremely rare 5-aminolevulinic acid dehydratase (ALAD) deficiency porphyria (syn.: Doss porphyria), in acute lead intoxication, and after oral 5-aminolevulinic acid (ALA) loading.

Design And Methods: We analyzed the excretion of total urinary coproporphyrins and the composition of the respective isomers I-IV with ion-pair HPLC methods in these conditions. Read More

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5-Aminolevulinic acid dehydratase deficiency porphyria: a twenty-year clinical and biochemical follow-up.

Clin Chem 1998 Sep;44(9):1892-6

Division of Clinical Biochemistry, Philipps University Hospital, Marburg, Germany.

5-Aminolevulinic acid dehydratase (ALAD) activity in two patients with compound heterozygous 5-aminolevulinic acid dehydratase deficiency porphyria was studied over the last 20 years. The patients' enzyme activity was <10% from 1977 to 1997. An acute crisis in each patient was successfully treated by infusion of glucose and heme arginate. Read More

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September 1998

ALAD porphyria.

S Sassa

Semin Liver Dis 1998 ;18(1):95-101

Laboratory for Biochemical Hematology, Rockefeller University, New York, N.Y. 10021, USA.

ALAD porphyria is an autosomal recessive disorder resulting from a homozygous aminolevulinic acid dehydratase (ALAD) deficiency. Because of an almost complete lack of ALAD activity, patients excrete a large amount of ALA, but not PBG, into urine. The symptoms in this disease are similar to those seen in AIP, but ALAD porphyria can be differentiated from AIP by its autosomal recessive, rather than dominant, inheritance, by the lack of PBG overproduction, and by markedly decreased ALAD activity. Read More

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Acute porphyrias: pathogenesis of neurological manifestations.

Semin Liver Dis 1998 ;18(1):43-52

University of Basel, Dept. Pharmacology, Switzerland.

Four types of hepatic porphyria (acute intermittent porphyria; hereditary coprophorphyria; variegate porphyria; delta-aminolevulinate dehydratase deficiency porphyria) present clinically with an identical neurological syndrome. Symptoms include severe abdominal pain, vomiting, constipation, hypertension, tachycardia, and bladder dysfunction. These symptoms have been ascribed to autonomic neuropathy. Read More

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Increased delta aminolevulinic acid and decreased pineal melatonin production. A common event in acute porphyria studies in the rat.

J Clin Invest 1996 Jan;97(1):104-10

Centre Français des Porphyries, Institut National de la Santé et de la Recherche Médicale, Hôpital Louis Mourier, Colombes, France.

Tryptophan (TRP) is the precursor of melatonin, the primary secretory product of the pineal gland. Hepatic heme deficiency decreases the activity of liver tryptophan pyrrolase, leading to increased plasma TRP and serotonin. As a paradox, patients with attacks of acute intermittent porphyria (AIP), exhibit low nocturnal plasma melatonin levels. Read More

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January 1996

delta-Aminolevulinic acid dehydratase deficiency porphyria (ADP) with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in a 69-year-old woman.

Kobe J Med Sci 1995 Apr;41(1-2):23-31

Department of Internal Medicine, Suma Red Cross Hospital, Kobe, Japan.

delta-Aminolevulinic acid dehydratase deficiency porphyria (ALAD porphyria, ADP) with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in a 69-year-old woman is reported. The patient was admitted to our hospital complaining of slight cough with low-grade fever, and treated with piperacillin sodium, resulting in complete resolution of the symptoms, following a diagnosis of bronchopneumonia. Thereafter, however, she began to complain of vomiting, abdominal pain, facial numbness and paresis of the extremities with gait disturbance, and became comatose with hyponatremia (serum Na concentration 119 mEq/L) in a few days. Read More

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