Porphyrias are a group of rare genetic disorders caused by deficiencies in enzymes involved in heme synthesis. This results in the accumulation of toxic heme precursors known as porphyrins. There are two main types - cutaneous porphyrias which present with skin symptoms like blistering rashes, and acute hepatic porphyrias which present with severe neurological symptoms. The specific porphyrin accumulated and symptoms depend on which enzyme is deficient. Diagnosis involves biochemical analysis of porphyrins in urine, stool or blood. There is no cure, but acute attacks can be prevented by avoiding triggers.
3. 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
4. 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.
5. • Metal insertion in
porphyrins is
performed by a class
of complexes called
chelatases
Ferrochelatase
Heme Iron Insertion
13. • An Insane Prussian Peek Blue
Die
• Most common
• Latent prior to puberty
• Abdominal pain, neuropsychiatric
symptoms
ACUTE INTERMITTENT PORPHYRIA
14. CONGENITAL ERYTHROPOIETIC PORPHYRIA
•Defect in Uroporphyrinogen III Cosynthetase
•Carrot Eating Prevents Usual Terrible Complications
•Photosensitivity
•Pink coloured urine
15. POPRPHYRIA CUTANEA TARDA
•PORPHYRIA CUTANEA TARDA
•Enzyme def: Uroporphyrinogen Decarboxylase
•Pneumonic: People Can Tell U Drink Constantly
18. Porphyria Cutanea Tarda
People Can Tell U Drink Constantly
Uroporphyrinogen Decarboxylase
Variegate Porphyria
Veld People aPpear Pretty Odd
Protoporphyrinogen Oxidase
19. Hereditary Coproporphyria
Hairy Crazy People Can Pee Orange
Coproporphyrin oxidase
Acute Intermittent Porphyria
An Insane Prussian Peed Blue Dye
PBG Deaminase
20. • 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?
21. • 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
22. • 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
23. Treatment involves administration of hemin,
which provides negative feedback for the
heme biosynthetic pathway, and therefore,
prevents accumulation of heme precursors
24. 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?
25. 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
26. • 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
27. • 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
28. • 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.
29.
30. Porphyria in the British and German Royal Families
The Madness of Inbreeding
31. George III : Severe abdominal pain, mental confusion, dark urine.
32. 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
42. 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
43. • Can be hepatic or erythropoietic, reflecting the
two major locations of heme synthesis
- hepatic can be acute or chronic
44. • 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)
45. Lead poisoning
- inhibition of ferrochelatase and ALA dehydratase
- displaces Zn+2 at enzyme active site
Acquired Porphyrias
48. • 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
49. • 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
57. • 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
58. 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.
59. 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
60. 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.
61. 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.
62. 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).
63. 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
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