SNP Shot: Genomic Insights

Porphyria refers to a group of genetic disorders stemming from defects in the biochemical pathway responsible for producing heme. Heme is a crucial molecule present in all bodily organs, with the highest concentrations found in blood, bone marrow, and the liver. It is a vital component of hemoproteins, a class of iron-containing proteins, most notably hemoglobin, which transports oxygen throughout the body.

Researchers have identified various types of porphyria, each characterized by its unique genetic origin and the resulting signs and symptoms. Cutaneous porphyrias primarily affect the skin. These porphyrias cause the skin to become exceptionally sensitive to sunlight, leading to blistering, fragility, and potential complications like infections, scarring, changes in skin pigmentation, and increased hair growth. Examples of cutaneous porphyrias include congenital erythropoietic porphyria, erythropoietic protoporphyria, hepatoerythropoietic porphyria, and porphyria cutanea tarda.

Acute porphyrias primarily impact the nervous system. The term "acute" signifies the rapid onset and relatively short duration of their symptoms. These symptoms can include severe abdominal pain, vomiting, constipation, and diarrhea. Additionally, individuals experiencing an acute porphyria episode may suffer from muscle weakness, seizures, fever, and mental disturbances such as anxiety and hallucinations. These signs can be life-threatening, especially if the respiratory muscles become paralyzed. Acute porphyrias include acute intermittent porphyria and ALAD deficiency porphyria. Hereditary coproporphyria and variegate porphyria can manifest with both acute and cutaneous symptoms.

Porphyrias can also be classified as erythropoietic or hepatic, based on where porphyrins and their precursors, the harmful compounds implicated in these disorders, initially accumulate. In erythropoietic porphyrias, these substances originate in the bone marrow. Examples include erythropoietic protoporphyria and congenital erythropoietic porphyria. These types of porphyria can lead to anemia (low red blood cell count) and splenomegaly (enlarged spleen). Conversely, hepatic porphyrias involve the production of porphyrins and their precursors primarily in the liver. This can result in abnormal liver function and elevate the risk of liver cancer.

Environmental factors play a significant role in influencing the occurrence and severity of porphyria symptoms. Triggers such as alcohol consumption, smoking, certain medications, hormonal changes, other illnesses, stress, and dietary changes (including fasting) can provoke symptoms in susceptible individuals. Furthermore, sun exposure exacerbates skin damage in those with cutaneous porphyrias.

Inheritance:

Some porphyrias follow an autosomal dominant inheritance pattern, meaning that a single mutated copy of the responsible gene in each cell is sufficient to cause the disorder. This mutation reduces the activity of an enzyme crucial for heme production, thus increasing the likelihood of developing porphyria. Examples of autosomal dominant porphyrias include acute intermittent porphyria, most cases of erythropoietic protoporphyria, hereditary coproporphyria, and variegate porphyria. While some cases of porphyria cutanea tarda are linked to genes inherited in an autosomal dominant pattern, most affected individuals do not inherit a gene mutation. Other porphyrias are inherited in an autosomal recessive pattern, requiring two mutated copies of the gene in each cell to manifest the condition. Typically, both parents of an individual with an autosomal recessive porphyria carry one copy of the mutated gene but do not exhibit any symptoms. Examples of autosomal recessive porphyrias include ALAD deficiency porphyria, congenital erythropoietic porphyria, and some cases of erythropoietic protoporphyria. Erythropoietic protoporphyria, when caused by mutations in the ALAS2 gene, displays an X-linked dominant inheritance pattern. The ALAS2 gene resides on the X chromosome, one of the two sex chromosomes. In females (who possess two X chromosomes), a mutation in one copy of the gene may be enough to cause the disorder. In males (who have only one X chromosome), a mutation in their single copy of the gene will lead to the condition. Males might experience more severe symptoms than females. A hallmark of X-linked inheritance is that fathers cannot transmit X-linked traits to their sons. Mutations in the UROD gene are associated with both porphyria cutanea tarda and hepatoerythropoietic porphyria. Individuals who inherit one altered copy of the UROD gene face an increased risk of developing porphyria cutanea tarda, influenced by multiple genetic and non-genetic factors. Those who inherit two altered copies of the UROD gene in each cell will develop hepatoerythropoietic porphyria.