Principal Investigator: Dr Amy Dickey
Massachusetts General Hospital,Boston , USATags: 47222, acute-intermittent-porphyria, pathogenic-mutations, penetrance, porphyria, Risk, subclinical-disease
The porphyrias are group of eight disorders resulting from inherited defects in heme production. Heme is the molecule that carries oxygen on red blood cells. Each porphyria arises from a genetic mutation in a different enzyme important for making heme. The “acute” forms of porphyria result in intermittent episodes of severe abdominal pain, along with neurologic and psychiatric symptoms. The “cutaneous” forms of porphyria result in either painful or blistering/scaring sensitivity to sunlight. Each of the porphyrias is rare, but they are all though to be significantly under-diagnosed. For most patients, there is a significant delay in diagnosis, with delays lasting years or even decades. The mutations that cause porphyria are much more common than the disease itself. For instance, the mutation that causes acute intermittent porphyria (AIP) is found in about 1 in 1700 individuals, but the disease is found in about 1 in 100,000. In families where AIP diagnosis has been confirmed, approximately 1-2 out of every 10 people with the mutation will have symptoms of the disease. These patients are more likely to be tested because of their family history. Even those without typical symptoms of AIP are at increased risk of liver cancer from the mutation itself. It is not known whether the diagnosis is simply missed in a large number of people with the disease or if there are unknown genetic or environmental factors that explain why so few individuals with disease-causing mutations are diagnosed with porphyria.
Many known disease-causing mutations for porphyria have been tested in the UK Biobank. This study plans to investigate if those with porphyria disease-causing mutations have an increased likelihood of symptoms and diagnoses that may actually be caused by porphyria itself. Subsequently, genetic and environmental data will also be analyzed to search for factors that explain why some have symptoms and others do not. Recently, new therapies have been developed for both the acute and the cutaneous porphyrias, so it is even more important now to be able to identify patients with porphyria. Understanding the consequences of porphyria disease-causing mutations in those without a diagnosis could provide a rationale for increased physician education efforts or screening strategies that would increase the likelihood of diagnosis and would subsequently increase the ability to provide patients with appropriate therapies.