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Introduction
What is Porphyria?
Also called Vampire Syndrome, is a group of rare disorders passed down through families, in which an important part of Hemoglobin, called heme, is not made properly.
What is Heme?
A prosthetic group that consists of an iron atom contained in the center
body.
During production of Heme, different intermediate compounds or precursors are created and modified. If one of the eight essential enzymes in Heme production is deficient due to mutation in the gene coding for it, certain precursors may accumulate in bone marrow or liver, appear in excess in the blood, and get excreted in the urine or stool. This may lead to various physical symptoms or even damage of the nervous system. Mutation causing the reduction in enzyme activity also limits the amount of heme being produced. This may result in degenerative changes in the central nervous system. It also results in a decrease of the amount of Oxygen being sent to the heart for pumping and subsequently leads to reduction in the amount of oxygen being supplied to various parts of the body.
II.
Protoporphyrin IX
Heme
including Africans, Asians, Australian aborigines, Caucasians, Peruvian, Mexican, Native Americans.
Links between porphyrias and mental illness have been noted for
decades. In the early 1950s patients with porphyrias and severe symptoms of depression were treated with electroshock.
suggested as an explanation for the origin of vampire and werewolf legends, based upon certain perceived similarities between the condition and the folklore.
2.
Neurologic symptoms caused by the Porphyrias (acute porphyrias). For example : Hereditary coproporphyria, Acute intermittent porphyria
3.
4.
whether the excess precursors originate primarily in the liver (hepatic porphyrias) or primarily in the bone marrow (erythropoietic porphyrias).
nervous system.
Increased ALA concentrations in the brain may inhibit gammaaminobutyric acid release(GABA).
Clinical symptoms
1.
2.
Problems with the nervous system and muscles, seizures, mental disturbances, nerve damage (Acute Porphyria)
3.
Light sensitivity causing rashes, blistering, and scarring of the skin (Porphyria Cutanea tarda)
Numbness or tingling
Pain in the arms or legs Pain in the back Personality changes Low blood pressure
people with a genetic mutation associated with the disease never experience signs or symptoms.
northern European countries, such as Sweden, in the United Kingdom and in India.
North America.
South Africa; about 3 in 1,000 people in this population have the genetic change that causes this form of the disorder.
India
In India, AIP has been reported from various parts of the country and
Maheshwari community surveyed in Sri-Dungargarh municipal area of Bikaner. The fifteen patients belonged to 11 families and the female to male ratio was 9:6. Most of them were encountered in the age group 11 -20 years.
(Rajashekar Reddi, Nitin K Sethi, Ish Anand, PK Sethi., 2002, Acute Intermittent Porphyria : Management Aspects., JIACM, J Assoc Physicians India)
Genetic Basis
Each form of porphyria results from mutations in one of these
1.
These genes are necessary for coding for the enzymes needed to produce heme.
2.
The mutations reduce enzyme activity, which limits the amount of heme produced.
3.
porphyrins and porphyrin precursors, formed during the process of heme production, accumulate in liver and other organs. On accumulation in the skin, the precursors interact with sunlight and cause the cutaneous forms of porphyria.
4.
The acute forms of the disease occur when porphyrins and porphyrin precursors build up in and damage the nervous system.
Type
ALA-Dehydratase Porphyria (ADP) Acute Intermittent Porphyria (AIP) Congenital Erythropoietic Porphyria (CEP)
Inheritance
Gene
Gene Locus
9q33.1
Enzyme
ALA dehydratase
11q23.3 10q25.2-q26.3
1p34
Hepatoerythropoietic Autosomal recessive UROD Porphyria (HEP) Hereditary Autosomal dominant CPOX Coproporphyria (HCP) Variegate Porphyria Autosomal dominant PPOX (VP) Erythropoietic Autosomal recessive FECH Protoporphyria (EPP)
X-linked Protoporphyria (XLP) X-linked ALAS2
1p34 3q12
Note : One type of porphyria, porphyria cutanea tarda, results from both
genetic and nongenetic factors. About 20 percent of cases are related to mutations in the UROD gene. The remaining cases are not associated with UROD gene mutations and are classified as sporadic. Factors contributing to the development of porphyria cutanea tarda are :
1.
An increased amount of Iron in the liver. Mutations in the HFE gene (which cause an iron overload disorder) are also associated with porphyria cutanea tarda.
2.
3.
Other, as-yet-unidentified genetic factors may also play a role in this form of porphyria.
Molecular Basis
Acute Intermittent Porphyria
It is a hepatic porphyria.
small insertions and deletions, missense mutations, as well as mutations in the PBGD promoter region
HMBS/PBGD gene
comprises 8,673 bases. 15 exons. There are 2 types of transcripts : Housekeeping and Erythroid-specific :
Type I mutations
Patients exhibit reduced enzymatic activity as well as reduced PBGD protein content, both at approximately 50 percent of normal. Single base substitutions or deletions leading to a single amino acid change, resulting in the loss of expression of the enzyme protein.
Type II mutations
They are characterized by decreased PBGD activity in nonerythroid cells (eg liver) at approximately 50 percent of normal, but with normal erythroid PBGD activity. single base substitutions which occur in the exon/intron boundary of exon 1
Occurs in exons 10 and 12, which are regions thought to be essential for catalytic activity of the enzyme
Diagnosis
Biochemical Diagnosis
Urinalysis
Urinalysis
Urinalysis is the physical, chemical, and microscopic examination of
urine. It involves a number of tests to detect and measure various compounds that pass through the urine.
A special stick ("dipstick") tests for various substances in the urine. The
stick contains little pads of chemicals that change color when they come in contact with the substances of interest. It is used to detect presence of porphyrin precursors.
Upon further chemcical analysis and quantification, it has been found that : Aminolevulinic acid Normal urinary excretion of ALA is <7 mg. It increases to 25 to 100 mg. Porphobilinogen Normal urinary excretion of PBG has been variously given as <2 mg. It increases to 50 to 200 mg.
Protoporphyrin is normally found in the highest amount. More tests are needed to show the levels of specific porphyrins.
values (a range of values seen in a group of healthy people) for the individual components are also included:
Total porphyrin levels: 16 to 60 mcg/dL
Molecular Diagnosis
Acute intermittent porphyria (AIP) is an autosomal dominant disorder
caused by a porphobilinogen (PBG) deaminase deficiency. A denaturing gradient gel electrophoresis (PCR-DGGE) analysis followed by direct sequencing of the DNA fragments can be performed to investigate molecular defect.
to 100%.
acrylamide gel; initially the fragments move according to molecular weight, but as they progress into higher denaturing conditions, each (depending on its sequence composition) reaches a point where the DNA begins to melt and forces DNA molecules to unwind
The melting severely retards the progress of the molecule in the gel,
(depending on the sequence, as little as a single bp change can cause a mobility shift). Alleles are detected by differences in mobility. This can also be used to differentiate diseased condition from normal using known genes responsible for a particular disease.
Treatment
Note : Porphyria does not kill usually. It affects the quality of life.
Some of the medicines used to treat porphyria may include:
Heme therapy Panhematin (US), Heme-arginate.
{Hematin administered intravenously while Panhematin is consumed; form of alkaline heme; corrects heme deficiency in liver, represses production of precursors e.g., decreases level of PBG in urine (important in AIP)}.
Propranolol to control the heartbeat as the heartbeat may get affected
Other treatments may include: Chloroquine - famous for use in malaria treatment, has also been
observed to regulate ALA Synthase activity, causes reduction in precursor formation and accumulation.
Fluids and glucose to boost carbohydrate levels, which helps limit the
production of porphyrins.
Depending on the type of porphyria, the doctor may suggest to take the
hematopoietic stem cells (HSCs) from Uros(mut248) mice was done. complete and long-term enzymatic, metabolic, and phenotypic correction of the disease, favoured by a survival advantage of corrected red blood cells.
Genetic counselling may benefit people who want to have children and who have a family history of any type of Porphyria as most of them are genetically inherited.
Current Research
led to hepatic heme depletion via induction or suicidal inactivation of cytochrome P450. The process is now sufficiently understood such that prediction of porphyria from structural and functional information of the enzymes in an individual may be possible in the near future.
Porphyria [porphyriafoundation.com]
The British Porphyria Association [porphyria.org.uk]
Thank You