8/3/2019 Period 1,2. Group I. ZerinaB, LauraN, GabrielC, HelenL, Porphyria

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Genetic Disorders:

Porphyria

How is porphyria diagnosed?Other than DNA and en-

zyme testing, more commontests can show evidence of thedisorder. Because porphyria isso rare, general hospital labstypically have not had experi-ence with the disease before, making it more difficultto diagnose. The disorder's signs and symptoms arenot distinctive, and require laboratory tests to make adefinite diagnosis. In general, urine, blood, and stoolsample tests are performed. In either of these cases,an elevated level of porphyrins can be detected. Inacute porphyria patients, samples should be takenonly during an attack, otherwise a false negative re-sult may occur.What is the connection between porphyria and

vampires?In 1985, David Dolphin suggested that those con-sidered "vampires" in folklores, may have stemmedfrom the conditions of those suffering with porphy-ria. He made the case by emphasizing the symptomsof those with the disease:

Sensitivity to sunlight – Porphyria sufferers areexceedingly sensitive to light, which disfigures anddarkens the skin of victims.

Fangs – Exposure to light may cause the withering

of lips and gums, furthering projecting teeth and pro- jecting them as fangs.

Drinking of blood and avoidance of garlic- In his-tory, it is throughout that those with the disease mayhave tried to alleviate they symptoms by drinkinganimal blood, and seeking garlic as an herbal remedy.The chemicals contained in garlic however, can ag-gravate a victim's symptoms, causing them to experi-ence severe pain.

Thus porphyria, may have contributed to theorigin of vampire legends.

Are there any organizations associated with the health andprevention of porphyrias?

The primary foundation associated with the healthand prevention of porphyria is The American Porphyria Foun-dation (APF.) It was formed in 1982, when Executive Director,Desiree Lyon joined with a family affected by the diseases, toform a patient-run organization that would educate doctors andthe general public about porphyria, raise funds for research, and

advocate for better patient care.One of the APF’s earliest efforts was join-ing with other rare disease advocates to form the National Or-ganization for Rare Disorders (NORD) in 1983, and testifying

before Congress in the same year in support of the OrphanDrug Act, which encourages pharmaceutical companies to de-velop drugs for diseases that have a small market. Panhematin,which remains the only specific treatment for acute porphyriaavailable in the United States, was the first drug to be approvedunder the ODA.

Since then, the APF has published informa-tional, easily understandable, material on all the porphyrias for

patients, has developed an educational DVD and website con-cerning the diseases, educated doctors through seminars, helpedthousands of patients worldwide find their way to treatment,and continually sought funds to improve research, training,diagnosis, and care for the various porphyrias.

Sources:

Zerina Balic, Laura Nekrasov, Gabe Cohen,

Helen LamGoup I/ Periods 1+2

8/3/2019 Period 1,2. Group I. ZerinaB, LauraN, GabrielC, HelenL, Porphyria

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What is porphyria?Porphyrias are a group of inherited di sorders which affect

the nervous system and/or skin. Each type of porphyria is due tothe deficiency of one of the enzymes needed to make a sub-stance in the body, heme. The body makes heme mainly in the

bone marrow and the liver. The process of making heme iscalled the heme biosynthetic pathway. Each step of the processis controlled by one of eight enzymes. If any one of the enzymesis deficient, the process is disrupted. As a result, porphyrin, a

precursor of heme, may build up in body tissues and cause ill-ness.What is heme?

Heme is a red pigment composed of iron linked to a chemi-cal called protoporphyrin. Heme has important functions in the

body. The largest amounts of heme are in the blood and bonemarrow, in the form of hemoglobin within red blood cells. In theliver, heme is a component of proteins that breaks down hor-mones, drugs, and energy-generating compounds. What are the types of porphyrias?

Porphyrias can be broadly classified into two types, as acute

porphyrias and cutaneous porphyries . They are distinguished by their genetic cause, which in turn affect their symptoms.Acute types of porphyria primarily affect t he nervous systemwhereas cutaneous types mainly affect the skin and are far morecommon worldwide.

What is the history of the disease?The term "porphyria" derives from the Greek "porphyry"

which means "purple pigment." This refers to the production of purple feces and urine in victims during an attack. Hippocrates

has been cited for recognizing and describing the disease, whileit was first explained biochemically, and named by Felix Hoppe-Seyler in 1874. Dutch physician B.J. Stokvis described the acute

porphyrias in 1889.

What are the genetic causes of the various types of porphyria?Each form of porphyria results from mutation in either the

ALAD, ALAS2, CPOX, FECH, HMBS, PPOX, UROD or UROsgenes. (Located on chromosomes 9, X, 3, 18, 11, 1, 1, 10, respec-tively)

Mutations in the ALADgene, CPOX gene, HMBSgene, PPOX gene, or UROSgene can cause ALAD defi-ciency porphyria, hereditarycoproporphyria, acute inter-mittent porphyria, variegate

porphyria, and congenitalerythropoietic porphyria respectively. These mutations are pointmutations, specifically missense mutations , in which a singlenucleotide is exchanged during DNA replication, changing thecode of a single amino acid. This causes the reduced activity of adehydratase, oxidase, or synthase enzyme which regulate the lev-els of porphyrins in the body. The accumulation of these porphy-rins to toxic levels will result in a porphyria attack. They are inher-ited in an autosomal dominant pattern, in which one copy of the

gene in each cell is mutated.Mutations in the FECH gene or UROD gene can cause eryth-

ropoietic protoporphyria and porphyria cutanea tarda, respectively.These are also missense-point mutations. A mutation in one codeof the gene reduces each cell's production of a ferrochelatase or decarboxylase enzyme by half. This is not enough however tocause the symptoms of porphyria, and therefore another mutationin the FECH gene or UROD gene must be inherited to cause thedisorder. These mutations reduce the function of the associatedenzyme allowing porphyrins to build up in developing red bloodcells to toxic levels. Depending on the areas in which these por-

phyrins accumulate, they can have varying negative affects on the body. They are inherited in an autosomal recessive pattern , inwhich both copies of the gene in each cell have mutations. The

parents of an individual with the condition each carry one copy of the mutated gene, but do not show symptoms of the disorder.

Mutations in the ALAS2 gene can cause erythropoietic proto- porphyria. These mutations are deletions in which a small amountof nucleotides towards the end of the ALA2 gene are removed.This change results in an overactive synthase enzyme, which caus-es an increased production of ALA in red blood cells. This excessALA is converted to porphyrin compounds, thus causing an over-sensitivity of light which characterizes this condition. This type of

porphyria has an X-lined dominant pattern of inheritance, where the gene responsible for the disorder is located on the Xchromosome, and only one copy of the gene in each cell is mutat-ed.

What are the symptoms of acute porphyrias?The acute porphyrias affect the nervous system and can lead to

abdominal pain, vomiting, acute neuropathy (damage of the nerves),muscle weakness, seizures, and mental disturbances, such as hallucina-tions, depression, anxiety, and paranoia. Cardiac arrhythmias (abnormalheartbeat) and tachycardia (faster heartbeat) may also result. Pain isoften severe, but only lasts for a short amount of time, one to twoweeks. Acute porphyria attacks are rare before puberty and after meno-

pause.What are the symptoms of cutaneous porphyrias?

The cutaneous porphyrias affect the skin, causing photodermatitis(abnormal skin reaction to sunlight) , blisters, necrosis of the skin(premature death of living tissue), itching, swelling, and increased hair growth on areas such as the forehead. Cutaneous porphyrias begin toshow signs and symptoms during infancy or childhood and are oftenchronic conditions.

* In both forms of porphyrias, accumulated porphyrins excretedin the urine and feces can causes various changes in color when ex-

posed to sunlight, to a red, brown, or even purple color. What are the triggers of acute porphyrias?

Porphyrias can be triggered by drugs, chemicals, fasting, smok-ing, drinking alcohol, infections, emotional and physical stress, men-strual hormones, and exposure to the sun.What are the treatments for acute porphyrias?

Acute porphyria is an incurable disease, but can be made tolerablethrough the usage of certain medications, and by avoiding known trig-gers. Hermatin and heme arginate are drugs that can be used to treatacute porphyria in the United States and Britain. To ensure effective-ness, they must be given very early in an attack. Although they can notcure the disease, they can suppress the attack by reducing intensity andshortening it. They are forms of heme, which can reduce the burden

placed on the body to produce heme, thus lowering porphyrin levels.Intravenous sugar and glucose may also be included in treatment

to maintain an adequate intake of carbohydrates and combat dehydra-tion. It is recommended that patients who have previously experience

acute porphyria attacks, or genetic carriers, to wear an alert bracelet atall times.What are the treatments for cutaneous porphyrias?

Treatment of cutaneous porphyrias focuses on reducing theamount of porphyrins in your body to help eliminate symptoms. Phle-

botomy involves drawing a certain amount of blood from one of moreveins, which reduces the amount of iron in the body, thus decreasing

porphyrins. This must be undergone several times before the diseasegoes into remission. Activated charcoal, a form of extremely porouscarbon, and cholestyramine, which binds bile in the intestinal tract to

prevent reabsorption, can absorb excess porphyrins in the body, allow-ing the accumulated toxic levels to dramatically decrease. Beta caroteneis a long-term treatment of cutaneous porphyrias, which includes dailydoses of beta carotene. Beta carotene, which is converted by the bodyto vitamin A, can increase the skin's tolerance to sunlight. Occasionally,

blood transaction is used to suppress heme production.