Clinical Diagnosis of Acute Porphyria

Study Overview
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Brief Summary
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The purpose of this study is to test whether a focused questionnaire and laboratory tests can better define risk factors associated with possible genetic porphyria. The investigators hypothesize that the genetic carrier state of acute porphyria is distinctive enough that the Genetic Carrier Profile the investigators devise through this study will be useful in identifying carriers of genetic porphyria among the large population with undiagnosed abdominal pain.

Detailed Description
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The porphyrias are a group of genetic diseases caused by disturbances in the formation of heme, an essential component of hemoglobin and other proteins, leading to either acute (neurologic) and/or chronic (cutaneous) symptoms. Acute porphyria is often difficult to diagnose because symptoms may not be specific and, unless the patient is in an active attack, laboratory values typically may not be useful for diagnosing porphyria. The purpose of this study is to test whether a focused questionnaire and laboratory evaluation tool can better define risk factors associated with possible genetic porphyria. The goals of this study are: To determine the presence and number of abnormal lab tests and porphyria-like symptoms in adult family members of the first person in a family who has been diagnosed with a disease of acute porphyria, 50% of whom are expected to carry the same genetic defect of the index case. To devise a Genetic Carrie Profile that could be used to screen people in whom the diagnosis of porphyria is being considered. To test the Profile in patients with symptoms suggestive of HCP and/or urine tests showing some elevation of porphyrins. To explain other possible causes of minor increases in porphyrin levels in patients with recurrent abdominal pain who have not been diagnosed with porphyria

Official Title
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Clinical Diagnosis of Acute Porphyria

Conditions
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Hereditary Coproporphyria (HCP), Acute Intermittent Porphyria (AIP), Variegate Porphyria (VP)

Participation Criteria
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Eligibility Criteria
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Group 1 Inclusion Criteria: Be 15 years of age or older Be a first-degree relative (child, sibling, parent, or grandparent) of an individual with genetically proven acute porphyria (AIP, HCP or VP) Not have had any previous genetic testing for acute porphyria Group 2 Inclusion Criteria: Be 15 years of age or older Have a history of suggestive clinical features, such as abdominal, back or limb pain, recurrent nausea lasting days, reaction to medications, psychiatric history, or sun sensitivity. An increase in urinary, fecal or serum porphobilinogen (PBG) and/or porphyrins Groups 1 and 2 Exclusion Criteria: Have previously had genetic testing for acute porphyria Have a history of alarm symptoms, such as anemia, unintentional weight loss, signs of GI (gastrointestinal) bleeding, or dysphagia (difficulty in swallowing). Follow Up Sub-Study (Group 3) Inclusion Criteria: Have been seen by one of the Porphyria Consortium physicians/investigators 10 or more years prior to study initiation Had a slight increase in porphyrins during the initial visit Not given a diagnosis of porphyria at the time of the visit Follow Up Sub-Study (Group 3) Exclusion Criteria: You have been seen by the Porphyria Consortium physician/investigator less than 10 years prior to study initiation.

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1<br>Group 1 will include subjects 15 years of age or older who are a first-degree relative (child, sibling, parent, or grandparent) of an individual with genetically proven acute porphyria (AIP, HCP or VP), and have not had any previous genetic testing for porphyria themselves. | |
| Group 2 (Not Yet Enrolling)<br>Group 2 will consist of subjects 15 years of age or older who have a history of clinical features suggestive of acute porphyria, such as such as abdominal, back or limb pain, recurrent nausea lasting days, reaction to medications, psychiatric history, or sun sensitivity, and an increase in urinary, fecal or serum porphobilinogen (PBG) and/or porphyrins. | |
| Group 3<br>Subjects in Group 3 will participate in the Follow Up Sub-Study. This group will include individuals who have been seen by one of the Porphyria Consortium physicians/investigators for suspicion of porphyria 10 or more years prior to study initiation, but were not given a diagnosis of porphyria at the time of their initial visit. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence of positive biochemical features by first-line testing in subjects suspected of being a genetic carrier of acute porphyria | All subjects will be assessed for any elevation of quantitative urine porphobilinogen (PBG). | Assessed once at baseline visit for all subjects | 
| Presence of positive biochemical features by second-line testing in subjects suspected of being a genetic carrier of acute porphyria | All subjects will be assessed for any elevations of fractionated quantitative urine porphyrins. | Assessed once at baseline visit for all subjects | 
| Presence of positive biochemical features by second-line testing in subjects suspected of being a genetic carrier of acute porphyria | All subjects will be assessed for any elevations and levels of fractionated quantitative fecal porphyrins. | Assessed once at baseline visit for all subjects | 
| Clinical features suggestive of the acute porphyria carrier state | Through a focused questionnaire, we will determine the typical duration of pain attacks. | Assessed once at baseline visit for all subjects | 
| Acute porphyria genetic carrier state | All subjects will undergo DNA analysis to detect a mutation in the HMBS, CPOX, or PPOX genes, respectively. | Assessed once at baseline visit for all subjects | 
| Other possible causes of mildly elevated porphyrins and recurrent pain | Participants in the Follow-up Sub-study section of this protocol will be interviewed concerning other possible causes of mildly elevated porphyins and recurrent pain. These will be patients previously seen by the investigator who were deemed not to have porphyria. | Assessed once during a one-time telephone or in-person interview | 
| Presence of heavy metals | All subjects will undergo a blood test to screen for the presence of heavy metals as a cause for minor elevations of porphyrin levels. | Assessed once at baseline visit for all subjects | 
| Validity of Genetic Carrier Profile | The biochemical and clinical features of genetically proven but asymptomatic HCP will be tabulated and compared to subjects who are not genetic carriers. Its accuracy in predicting risk factors for HCP will be tested in subjects in Group 2. | The profile will be tested once during the baseline visit for subjects in Group 2. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of disease manifestations in genetically confirmed AIP and HCP | Subjects who are confirmed to have AIP and HCP will be assessed at annual follow up visits for the presence and frequency of porphyria symptoms. | Assessed annually for 5 years | 
| Prevalence of HCP in a population with elevation of urine coproporphyrin and pain symptoms. | Based on the number of subjects in Group 2 determined by DNA analysis to have HCP, we will approximate the prevalence of HCP in a population with elevations in coproporphyrin and pain symptoms that are undiagnosed. | Assessed once enrollment and genetic testing of subjects in Group 2 are complete - after a 1-year recruitment and enrollment period. |