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Porphyria

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  • Succinate (activated as a CoA ester) and glycine starts things off. The final product, heme, has a predecessor called protoporphyrin IX. Why isn’t this III? When this work was first begun and they realized that the heme group had three substituents, they didn’t know how they were arranged. A chemist drew out all possibilities and the ninth one he drew was the right one. Thus the IX. At right are the rare, inborn errors of metabolism that can happen at each of these steps.
    Here: the final product is a feedback inhibitor for the first step in the process. If final product is not produced, the process keeps pumping along. But in these porphyrias, the wrong stuff is produced and builds up. Nastiness follow. Could be behavioural, too. Color urine, skin lesions.
    Most common: porphyria cutanea tarda. They get blisters, may be sensitive to UV light, have prolific hair growth. Werewolf legend: may be a person who had porphyria.
  • reddish color (purple) due to extra porphyrins
    Porpphyria afflict fewer than 200,000 people in the U.S
    PCT 1 in 1in 10,000
    AIP 1in 20,000
    Derived from the greek word porphyrus meaning purple
  • Begins with minor    behavioral changes (e.g. anxiety, restlessness, insomnia)
    -Some forms of acute porphyria develop photosensitivity
    -skin blisters upon sun exposure
  • The other forms of porphyria build up in the liver
  • Blisters
  • Newborn  B after transplant C two years after transplant

Transcript

  • 1. Porphyria By DR MUHAMMAD MUSTANSAR
  • 2. Uroporphyrinogen I Coproporphyrinogen I Overview of Heme Synthesis Succinyl CoA + Glycine δ-aminolevulinic acid δ-aminolevulinic acid Porphobilinogen Uroporphyrinogen III Coproporphyrinogen III Coproporphyrinogen III Protoporphyrinogen IX Protoporphyrin IX Heme ALA synthase cytoplasmmitochondrial matrix
  • 3. Heme synthesis occurs in all cells due to the requirement for heme as a prosthetic group on enzymes and electron transport chain. By weight, the major locations of heme synthesis are the liver and the erythroid progenitor cells of the bone marrow.
  • 4. • Metal insertion in porphyrins is performed by a class of complexes called chelatases Ferrochelatase Heme Iron Insertion
  • 5. PORPHYRIA - Definition
  • 6. PORPHYRIA – Classification Genetic Acquired
  • 7. PORPHYRIA - Classification
  • 8. PORPHYRIA Clinical Features Acute abdominal pain Acute psychiatric disturbances Peripheral neuropathy Photosensitivity and skin lesions
  • 9. • An Insane Prussian Peek Blue Die • Most common • Latent prior to puberty • Abdominal pain, neuropsychiatric symptoms ACUTE INTERMITTENT PORPHYRIA
  • 10. CONGENITAL ERYTHROPOIETIC PORPHYRIA •Defect in Uroporphyrinogen III Cosynthetase •Carrot Eating Prevents Usual Terrible Complications •Photosensitivity •Pink coloured urine
  • 11. POPRPHYRIA CUTANEA TARDA •PORPHYRIA CUTANEA TARDA •Enzyme def: Uroporphyrinogen Decarboxylase •Pneumonic: People Can Tell U Drink Constantly
  • 12. Congenital Erythropoietic Porphyria Carrot Eating Prevent Usual Terrible Complications Uroporphyrinogen III Cosythetase Erythropoietic Protoporphyria Easily Produces Pebbly Fingers Ferrochelatase
  • 13. Porphyria Cutanea Tarda People Can Tell U Drink Constantly Uroporphyrinogen Decarboxylase Variegate Porphyria Veld People aPpear Pretty Odd Protoporphyrinogen Oxidase
  • 14. Hereditary Coproporphyria Hairy Crazy People Can Pee Orange Coproporphyrin oxidase Acute Intermittent Porphyria An Insane Prussian Peed Blue Dye PBG Deaminase
  • 15. • Porphyrin rings are biological molecules used in a variety of essential chemical processes •The two most well- known porphyrins are heme and chlorophyll What are they?
  • 16. • A group of rare disorders caused by deficiencies of enzymes of the heme biosynthetic pathway • The majority of the porphyrias are inherited in a autosomal dominant fashion - thus, affected individuals have 50% normal levels of the enzymes, and can still synthesize some heme PORPHYRIAS
  • 17. • Affected individuals have an accumulation of heme precursors (porphyrins), which are toxic at high concentrations • Attacks of the disease are triggered by certain drugs, chemicals, and foods, and also by exposure to sun
  • 18. Treatment involves administration of hemin, which provides negative feedback for the heme biosynthetic pathway, and therefore, prevents accumulation of heme precursors
  • 19. Group of rare genetic disorders caused by improper synthesis of heme Caused by an abnormal function of an enzymatic step, resulting in accumulation of heme precursors, specifically porphyrins and porphyrin precursors There are two types of porphyria: cutaneous and acute What is it?
  • 20. The most common type of cutaneous is: porphyria cutanea tarda (PCT) Most common type of acute: acute intermittent porphyria (AIP) Symptoms are not always present Triggered by environmental factors
  • 21. • Cruelly referred to as a Vampire’s disease. Thought to be a cause of the madness of King George III. • Can be caused by lead poisoning: The fall of the Roman Empire! Heme Biosynthesis: Porphyrias
  • 22. • Some symptoms of porphyrias have lead people to believe that these diseases provide some basis for vampire legends: • Extreme sensitivity to sunlight • Anemia Not a ‘vampire’s’ disease
  • 23. • This idea has been discarded both for scientific reasons: • Porphyrias do not cause a craving for blood. • Drinking blood would not help a victim of porphyria And for compasionate reasons:Porphyria is a rare, but frightening condition: hard to diagnose and there is no cure.
  • 24. Porphyria in the British and German Royal Families The Madness of Inbreeding
  • 25. George III : Severe abdominal pain, mental confusion, dark urine.
  • 26. PORPHYRIAS GLYCINE + SuccinylCoA δ-aminolevulinic acid(ALA) Porphobilinogen(PBG) hydroxymethylbilane uroporphyrinogen III coprophyrinogene III Protoporphyrinogene IX protoporphyrin IX Heme ALA synthase ALA dehydratase PBG deaminase Uroporphyrinogen III cosynthase Uroporphyrinogen decarboxylase Coproporphyrinogen oxidase Protoporphyrinogen oxidase Ferrochelatase ALA-dehydratase Deficiency porphyria Acute intermittent porphyria Congenital erythropoietic porphyria Prophyria cutanea tarda Herediatary coproporphyria Variegate porphyria Erythropoietic protoporphyria Mitochondria 9q34 11q23 10q26 1q34 9 1q14 18q21.3 3p21/Xp11.21 Agent Orange
  • 27. Formation of porphobilinogen: Lead Poisoning
  • 28. • Severe abdominal pain, nausea, vomiting and constipation • Muscle pain, weakness • Urinary retention • Heart palpitations • Confusion, hallucinations, seizures • Tachycardia, excess sweating, hypertension Acute Porphyria Attacks of Porphyria
  • 29. • Extreme photosensitivity – Deterioration of facial features, fingers • Increased hair growth • Impairment of liver function • Gall stones Cutaneous Porphyria
  • 30. • Acute Intermittent Porphyria (AIP) – Autosomal dominant – Porphobilinogen deaminase • Variegate Porphyria (VP) – Autosomal dominant – Protoporphyrinogen oxidase Types of Acute Porphyria
  • 31. • Hereditary Coproporphyria (HCP) – Autosomal dominant – Coproporphyrinogen oxidase • ALAD-Deficiency Porphyria (ADP) – Autosomal recessive – Delta-aminolevullinic acid dehydratase (ALAD)
  • 32. • Porphyria Cutanea Tarda (PCT) – Familial or Nonfamilial – Uroporphyrinogen decarboxylase • Erythropoietic Protoporphyria (EPP) – Autosomal dominant – Ferrochelatase Types of Cutaneous Porphyria
  • 33. • Congenital Erythropoietic Porphyria – Autosomal recessive – Uroporphyrinogen III cosynthase • Hepatoerythropoietic Porphyria (HEP) – Autosomal recessive – Uroporphyrinogen decarboxylase
  • 34. SUMMARY OF PORPHYRIAS
  • 35. Caused by hereditary or acquired defects in heme synthesis - Accumulation and increased excretion of metabolic precursors (each unique) - Most porphyrias show a prevalent autosomal dominant pattern, except congenital eythropoietic porphyria, which is recessive Porphyrias
  • 36. • Can be hepatic or erythropoietic, reflecting the two major locations of heme synthesis - hepatic can be acute or chronic
  • 37. • Those with tetrapyrrole intermediates show photosensitivity due to extended conjugated double bonds • - Formation of superoxide radicals • - Skin blisters, itches (pruritis) • - Skin may darken, grow hair (hypertrichosis)
  • 38. Lead poisoning - inhibition of ferrochelatase and ALA dehydratase - displaces Zn+2 at enzyme active site Acquired Porphyrias
  • 39. Children - developmental defects - drop in IQ - hyperactivity - insomnia - many other health problems
  • 40. Adults - severe abdominal pain - mental confusion - many other symptoms
  • 41. • Each type of porphyria is caused by a different enzyme deficiency involved in the production of heme • Photosensitivity is caused by the light absorbing properties of the porphyrin ring Biochemistry
  • 42. • The causes of neurological symptoms present in acute porphyria are still unknown – One Study suggests: Overproduction + accumulation of ALA and PBG in nervous tissue lead to toxic effects, neurological symptoms (Kochar et al.2007) • Erythropoietic porphyrias (EPP, CPP)cause build up of porphyrins in bone marrow
  • 43. Images of Cutaneous Porphyria
  • 44. Images of Cutaneous Porphyria
  • 45. Skin eruptions in a patient with porphyria cutanea tarda
  • 46. Urine from a patient with porphyria cutanea tarda (right) and from a patient with normal porphyrin excretion (left)
  • 47. Results of bone marrow transplant in CEP Patient
  • 48. SUMMARY OF PORPHYRIAS
  • 49. • The porphyrins are the main precursors of haem, and essential constituents of haemoglobin, myoglobin, the respiratory and P450 liver cytochromes, and of other enzymes (catalases and peroxidases). Disorders of porphyrin metabolism
  • 50. Deficiency in porphyrin pathway leads to accumulation of precursors, which are toxic to tissues in high concentration. The chemical properties of these precursors determines the site of tissue accumulation, and whether they induce photosensitivity.
  • 51. The porphyrias may be inherited or acquired. They are broadly classified as hepatic porphyrias or erythropoietic porphyrias, based on the site of the overproduction and main accumulation of the porphyrins. They manifest with either skin problems or with neurological complications (or occasionally both) and present either acutely or non acutely. a
  • 52. Hepatic porphyrias: are characterized by acute neurological attacks manifesting as seizures, neuropathy, behaviour problems/pyschosis, and hallucinations. Muscle (back) pain, vomiting, and abdominal pain are also common.
  • 53. Acute episodes may be triggered by exposure to certain drugs (e.g. alcohol, oral contraceptive agents, and certain antibiotics) and by other chemicals and certain foods. Fasting can also trigger attacks.
  • 54. Erythropoietic porphyrias: present with skin problems, including lights-sensitive blistering rash and increased hair growth. Spectroscopic and biochemical analysis for abnormalities in porphrin metabolite profile in urine and stools is required for diagnosis. In nearly all cases of actue porphyria syndromes, urinary porphobilinogen is markedly elevated (except in ALA dehydratase deficiency).
  • 55. Types of porphyria Porphyria type Inheritance/site Enzyme System involved Acute porphyrias Acute AR/hep. ALA-dehydratase Neurovisceral Acute/intermittent AD/hep. Porphobilinogen deaminase Neurovisceral Hereditary coproporphyria AD?hep. Coproporphyrinog en oxidase Neurovisceral+ cutaneous Variegate porphyria AD/mixed Protoporphyrinoge n oxidase Neurovisceral+ Cutaneous
  • 56. Types of porphyria Porphyria type Inheritance/site Enzyme System involved Non-acute porphyrias Congenital erythropoietic porphyria AR/ erythro. Uroporphyrinogen III cosynthase Cutaneous Porphyria cutanea tarda AD/ erythro. Uroporphyrinogen decarboxylase Cutaneous Hepatoery thropoietic porphyria AR/erythro. Uroporphyrinogen decarboxylase Cutaneous Erythropoietic protoporphyria AD/erythro Ferrochetalase Cutaneous AR. Autosomal recessive; AD, autosomal dominanc hep., hepatic; erythro., erythropoietic
  • 57. Sickled Red Blood Cells