Congenital Erythropoietic Porphyria (CEP), or Günther’s disease, is a rare inherited disorder affecting the body’s production of heme, a component of hemoglobin that carries oxygen in the blood. It is one of the least common porphyrias, with a prevalence of one in every two to three million people. The condition arises from a disruption in the multi-step chemical process that produces heme. When an enzyme in this pathway is deficient, molecules called porphyrins accumulate to high concentrations, beginning before birth. This build-up is linked to the condition’s name, with “congenital” indicating its presence from birth and “erythropoietic” referring to its association with red blood cell formation.
Genetic Origins of CEP
CEP is a genetic condition caused by mutations in the UROS gene, which holds the instructions for producing the enzyme uroporphyrinogen III synthase. This enzyme performs a specific function in the complex pathway that creates heme for red blood cells. The disorder follows an autosomal recessive inheritance pattern, meaning an affected individual must inherit a mutated copy of the UROS gene from both parents. Individuals with only one mutated copy are carriers who do not show symptoms but can pass the gene to their children. This inheritance pattern explains why CEP is so rare.
When the uroporphyrinogen III synthase enzyme is deficient, the heme production process is disrupted. This blockage leads to a large accumulation of two specific isomers: uroporphyrin I and coproporphyrin I. These non-functional porphyrins build up in the bone marrow, enter red blood cells, and circulate throughout the body, depositing in various tissues and causing damage.
Recognizing the Signs and Symptoms
The primary feature of CEP is extreme photosensitivity. Exposure to sunlight and some artificial light can cause the skin to become fragile and develop fluid-filled blisters. These lesions often rupture and lead to open sores that heal slowly, leaving behind scarring and potential disfigurement of the face and hands. This reaction is caused by the accumulated porphyrins reacting with light.
Another characteristic is erythrodontia, a reddish-brown discoloration of the teeth from porphyrin deposits in the dentin; this pigmentation can also affect bones. Many individuals also experience hypertrichosis, which is excessive hair growth, particularly on the face and hands.
Internally, CEP leads to hematological problems. The porphyrin-loaded red blood cells are fragile and break down easily in a process known as hemolytic anemia. This anemia causes fatigue and may require medical intervention. The spleen often becomes enlarged (splenomegaly) as it works to remove the defective cells.
One of the earliest signs of CEP in infants is reddish-pink or brown urine, caused by the body excreting large quantities of uroporphyrin I. This can appear as a pink stain in a diaper. Over time, other complications can arise, including skeletal fragility and corneal scarring from porphyrin deposits in the eyes.
Pathways to Diagnosis
The diagnostic process for CEP begins with clinical suspicion based on its hallmark symptoms. Confirmation requires biochemical tests that measure porphyrin levels in the body. The key finding is a high elevation of type I porphyrin isomers, specifically uroporphyrin I and coproporphyrin I. Laboratories perform quantitative analysis on urine, red blood cells, and plasma to identify this pattern. The level of uroporphyrin I is particularly high, which distinguishes CEP from other porphyrias.
A simple test involves using ultraviolet (UV) light, such as a Wood’s lamp. When exposed to UV light, the excess porphyrins in the teeth and urine emit a strong pink or red fluorescence, which can support a preliminary diagnosis. The fluorescence of circulating red blood cells under UV light is another indicator used in laboratory assessments.
The diagnosis is confirmed through molecular genetic testing. This involves sequencing the UROS gene to identify the mutations responsible for the deficient enzyme. Identifying the mutations confirms the diagnosis and is valuable for family genetic counseling. In cases with a known family history, prenatal diagnosis can determine if a fetus is affected.
Current Management Strategies
Management of CEP focuses on easing symptoms and preventing long-term complications, as there is no universal cure. The primary strategy is protection from sunlight and other sources of UV radiation. This involves wearing protective clothing, using broad-spectrum sunscreens, and applying UV-protective films to windows in homes and cars. Strict avoidance of sun exposure is necessary to prevent painful blistering and subsequent scarring.
Supportive care includes careful wound management for skin lesions to prevent secondary bacterial infections and meticulous dental hygiene for affected teeth. The hematological aspects of CEP often require regular blood transfusions. These transfusions alleviate severe anemia and can reduce the body’s production of defective red blood cells, thereby lowering porphyrin levels.
For patients who receive frequent transfusions, a secondary complication of iron overload can occur. This may require iron chelation therapy, a treatment that uses medication to remove excess iron from the body. In severe cases, hematopoietic stem cell transplantation (HSCT) from a compatible donor is considered. HSCT is a potentially curative option that replaces the individual’s blood-forming stem cells with healthy ones.
However, this procedure carries significant risks and is not suitable for every patient. Researchers continue to explore other treatments, including gene therapy aimed at correcting the faulty UROS gene, but these are still in experimental stages.