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.
The porphyrias are group of eight disorders resulting from genetic defects in heme biosynthesis, most with extremely low penetrance. My hypothesis is that many individuals with porphyria-causing mutations may have subclinical disease, with increased prevalence of symptoms or diseases that are associated with porphyria. My plan is to investigate the clinical consequences of porphyria-causing mutations in individuals with no diagnosis of porphyria. I would also like to investigate whether or not specific porphyria-causing mutations result in differences in disease penetrance.
Expansion of Scope:
I would like to expand the scope of this project to include defects of ALAS and defects in genes related to iron metabolism.
My project proposed to study porphyria in the UK Biobank. Porphyrias are defects of heme synthesis that result in the accumulation of porphyrin molecules. Loss of function mutations in ALAS2, the first enzyme of heme synthesis, results in X-linked sideroblastic anemia, which is not technically considered a porphyria, though it is a defect of the same pathway. Gain-of-function mutations of ALAS2 cause X-linked protoporphyria, which is a porphyria. I would like to study defects in ALAS, both isoforms 1 and 2, in addition to the study of the classical porphyria genes, which are defects of the same pathway.
Heme consists of a protoporphyrin IX molecule with iron inserted in the middle. Defects in iron metabolism influence porphyria, as aberrations in iron availability can be a cause or effect of porphyria. Iron overload can cause porphyria cutanea tarda (PCT) even in the absence of mutations in genes related to heme biosynthesis. In fact, mutations in hemochromatosis genes are actually more common than UROD (5th enzyme in heme synthesis) mutations in PCT. This is because iron overload in the liver causes a function inhibition of UROD. Conversely, other types of porphyria like erythropoietic protoporphyria and X-linked protoporphyria can cause iron deficiency for unclear reasons. Iron availability can also modulate the expression of genes related to heme synthesis. Because of how inter-related heme biosynthesis is to iron metabolism, I would like to analyze genes related to iron metabolism alongside porphyria genes in my analysis of the UK Biobank. These studies require no additional data, as I already have all of the data that would be required to perform this analysis.
Last updated Jul 22, 2019