Porphyria and genetics
Porphyria is a collection of disorders characterized by an accumulation of porphyrins in the body, which are vital for heme production in red blood cells. This buildup can lead to significant damage, primarily affecting the nervous system and skin. Different types of porphyria, such as acute intermittent porphyria, porphyria cutanea tarda, and erythropoietic protoporphyria, exhibit varied symptoms and onset ages, with some occurring in childhood and others at puberty or adulthood. Genetic factors play a crucial role in porphyria, with mutations in at least eight genes linked to the disorder. These mutations can result in either autosomal dominant or recessive inheritance patterns, affecting the likelihood of passing on the condition. Symptoms can range from skin sensitivity to severe neurological issues, and diagnosis often involves a combination of family history, physical exams, and specific tests for porphyrin levels. While there is no cure for porphyria, management strategies include avoiding known triggers, such as certain medications and dietary factors. Recent advancements, like the FDA-approved drug Givlaari, provide new avenues for reducing the frequency of acute porphyria attacks.
Porphyria and genetics
DEFINITION: Porphyria refers to a group of disorders. All share the same problem: a buildup of porphyrins in the body. Porphyrins help to make heme, a part of the red blood cell. However, a buildup of the porphyrins in the body causes damage. It most often affects the nervous system and skin.
Some porphyria disorders include acute intermittent porphyria, porphyria cutanea tarda, and erythropoietic protoporphyria. Another disorder, congenital erythropoietic protoporphyria, is present from birth. Some types of porphyria start in early childhood, some at puberty, and others during adulthood. Attacks may be separated by long periods of time. The attacks can be triggered by drugs, infections, alcohol consumption, and dieting.
Risk Factors
The most common risk factor for porphyria is having a family member with this disease. Caucasians are at greater risk than African Americans or Asians, and females also have an increased risk related to their menstrual cycles. Most onsets happen between the ages of twenty and forty.
Etiology and Genetics
“Porphyria” is a general term used to describe a group of disorders caused by faulty heme production. Mutations in at least eight different genes are known to be responsible. The protein products of these genes are all enzymes necessary for the biosynthesis of heme, so a mutation which results in a missing or altered form of the enzymes could severely limit the amount of heme produced in various body tissues.
The CPOX gene (found on chromosome 3 at position 3q12) specifies an enzyme known as coproporphyrinogen oxidase; HMBS (at position 11q23.3) encodes the enzyme hydroxymethylbilane synthase; PPOX (at position 1q22) specifies protoporphyrinogen oxidase; and UROD (at position 1p34) encodes uroporphyrinogen decarboxylase. Mutations in any of these four genes can result in an autosomal dominant form of porphyria, meaning that a single copy of the mutation is sufficient to cause full expression of the disease. An affected individual has a 50 percent chance of transmitting the mutation to each of his or her children. Many cases of autosomal dominant porphyria, however, result from a spontaneous new mutation, so in these instances affected individuals will have unaffected parents.
The ALAD gene (at position 9q32) specifies the enzyme aminolevulinate dehydratase, and the UROS gene (at position 10q25.2–q26.3) encodes uroporphyrinogen III synthase. Mutations in either of these two genes cause autosomal recessive forms of porphyria, which means that both copies of the gene must be deficient in order for the individual to be afflicted. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers are 75 percent unaffected and 25 percent affected.
The FECH gene (at position 18q21.2–q21.3), which encodes the enzyme ferrochelatase, is unique in that it is associated with both autosomal dominant and autosomal recessive porphyria, depending on the specific molecular nature of the mutation. Finally, the ALAS2 gene (at position Xp11.21), which specifies the enzyme aminolevulinate, delta-, synthase 2, is associated with an X-linked dominant form of porphyria. A single copy of the mutation is sufficient for disease expression, but while an affected woman will transmit the mutation to one-half of her children, regardless of sex, an affected father will transmit the disease to all of his daughters and none of his sons.
Symptoms
Porphyria can cause skin or nervous system problems. Urine from some types of the disorder may be reddish in color due to the presence of excess porphyrins. The urine may darken after standing in the light. Specific symptoms depend on the type.
In acute intermittent porphyria (AIP), nervous system symptoms occur most often after puberty. Nerves of the intestines can cause gastrointestinal problems. Attacks can last from days to weeks. Symptoms of future attacks resemble the initial episode and may include abdominal pain and cramping; nausea and vomiting; constipation; painful urination or urinary retention; pain in the limbs, head, neck, or chest; muscle weakness; loss of sensation; tremors; sweating; rapid heart rate; high blood pressure; breathing problems; heart arrhythmia; and seizures. Mental symptoms of AIP include hallucinations, restlessness, depression, anxiety, insomnia, confusion, and paranoia.
Porphyria cutanea tarda (PCT) is the most common porphyria. Most are not inherited; they are acquired at some point. Symptoms of PCT may include sun sensitivity, and sun-exposed skin may be fragile. Minor injury may damage the skin. Additional symptoms may include blisters on the face, hands, arms, feet, and legs; skin that heals slowly; skin susceptible to infection; skin that thickens and scars; skin color changes; excess hair growth; and reddish urine in infancy or childhood.
Symptoms of erythropoietic protoporphyria may include sun sensitivity; redness or swelling, but usually no blisters; an itching or burning sensation; long-term skin and nail changes; and gallstones.
Congenital erythropoietic protoporphyria (CEP) is extremely rare. Symptoms may include reddish urine in infancy; sun sensitivity, beginning in early infancy; fragile sun-exposed skin; blisters on sun-exposed skin; blisters that are open and are prone to infection; and changes in skin color. Additional symptoms may include skin thickening, excess hair growth, scarring, reddish-brown teeth, an enlarged spleen, and hemolytic anemia.
Screening and Diagnosis
The doctor will ask a patient about any symptoms and will take a medical and family history. A physical exam will also be done. The symptoms can be very vague. As a result, the diagnosis is often delayed.
Tests differ for the various types of porphyria and may include blood, urine, and/or stool tests. These tests check for excess porphyrin or a specific enzyme deficiency. In some cases, specific genetic testing may also be available.
Treatment and Therapy
For all types of porphyria, treatment includes avoiding known triggers and drugs that can precipitate an attack and eating a high-carbohydrate diet. Porphyria that affects the skin requires special attention to protect the skin from injury and/or infection.
Specific treatment depends on the type of porphyria. Patients with acute intermittent porphyria may need to be hospitalized during an attack. In the hospital, they may be given heme by vein (intravenous) in the form of hematin, heme albumin, or heme arginate; glucose by vein; and drugs to control symptoms, such as pain, nausea, anxiety, and insomnia.
Porphyria cutanea tarda treatment may include blood removal weekly to monthly; low doses of antimalarial drugs, such as chloroquine (Aralen Phosphate) or hydroxychloroquine (Plaquenil); and radiological imaging to monitor for increased risk of liver cancer.
Erythropoietic protoporphyria treatment may include oral beta-carotene; maintaining normal iron levels with food or supplements; medication to aid excretion of porphyrins in the stool, such as activated charcoal, cholestyramine, blood transfusions, and heme by vein in the form of hematin, heme albumin, or heme arginate; and splenectomy, the removal of the spleen.
Treatment for congenital erythropoietic protoporphyria may include oral beta-carotene; oral charcoal, to aid excretion of porphyrins in the stool; blood transfusions; splenectomy; and bone marrow transplantation.
In 2019, the FDA granted approval to Givlaari (givosiran) for the treatment of adult patients with acute hepatic porphyria. The drug, which is the first FDA approved treatment for the disease, reduced the occurrence of porphyria attacks by roughly 70 percent. For this reason, Givlaari was granted "Breakthrough Therapy" status and slated for priority review.
Prevention and Outcomes
Genetic testing may identify individuals at risk for porphyria. An individual who has a family member with the diagnosis of porphyria may be eligible for testing. An individual whose family member has had a test that showed DNA changes can also be tested for these changes.
Family history can be reviewed during genetic counseling. The genetic counselor will help find the risks for this disorder in an individual and in his or her offspring. The counselor will also discuss appropriate testing.
Genetic mutation cannot be corrected. However, attacks can be anticipated, prevented, or controlled. Steps to avoid porphyria attacks and complications include protecting skin from injury or infection and avoiding drugs and other triggers.
Triggers for acute intermittent porphyria include drugs, such as barbiturates; sulfa drugs; seizure drugs; and steroid hormones, such as estrogen and progesterone. Other triggers include hormonal changes related to the menstrual cycle, weight-loss diets or fasting, infections, alcohol, stress, surgery, and cigarette smoke.
Triggers for porphyria cutanea tarda include alcohol, estrogens, hydrocarbons, and certain pesticides or chemicals. Sunlight and weight-loss diets or fasting can trigger erythropoietic protoporphyria. Sunlight can trigger congenital erythropoietic protoporphyria.
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