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Family evaluations in acute intermittent porphyria using red cell uroporphyrinogen I synthetase
Insights
Acute intermittent porphyria (AIP) diagnosis is improved by assessing uroporphyrinogen I synthetase (uro I syn) enzyme activity. Combining enzyme assays with pedigree analysis significantly enhances the ascertainment of latent AIP cases.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Acute intermittent porphyria (AIP) is a disorder of heme biosynthesis.
- AIP is characterized by elevated urinary porphobilinogen (PBG).
- A partial deficiency in uroporphyrinogen I synthetase (uro I syn) causes a defect in PBG conversion.
Purpose of the Study:
- To examine the ascertainment rate of latent AIP.
- To evaluate diagnostic parameters including red cell uro I syn, urinary PBG, and pedigree analysis.
Main Methods:
- Assessed red cell uro I syn activity in 185 individuals from 12 AIP kindreds.
- Performed quantitative urinary PBG measurements.
- Utilized pedigree analysis to evaluate uro I syn data.
Main Results:
- Red cell uro I syn assay alone assigned 80% of individuals as normal or latent AIP.
- An intermediate range of uro I syn activity left 20% unassigned.
- Integrating pedigree analysis reduced unassigned individuals to 10%.
- Enzyme assay detected latent AIP in 37.5% of relatives, while urinary PBG detected only 15.2%.
Conclusions:
- Uro I syn deficiency in AIP follows Mendelian dominant inheritance.
- Combining uro I syn enzyme assays with pedigree analysis improves latent AIP diagnosis.
- The uro I syn deficiency is likely the fundamental inherited defect in AIP.
Abstract:
Acute intermittent porphyria (AIP) is a primary disorder of haem biosynthesis that is chemically characterised by raised urinary porphobilinogen (PBG). A defect in the biochemical pathway at the step of PBG conversion to uroporphyrinogen has been shown to be a result of a partial deficiency of the enzyme uroporphyrinogen I synthetase (uro I syn). The ascertainment rate of latent AIP (that is, chemically manifest but clinically asymptomatic) was examined in 185 individuals from 12 AIP kindreds using three parameters: red cell uro I syn, quantitative urinary PBG, and pedigree analysis with respect to uro I syn. Approximately 80% of individuals could be assigned as normal or latent AIP on the basis of the uro I syn assay alone. The remaining 20% could not be assigned because of an intermediate range of activity for the red cell assay in which the diagnosis cannot be certain. When the pedigree was used in the evaluation of the uro I syn data, the number of uncertain individuals, with respect to AIP, decreased to 10%. The enzyme method detected latent AIP in 37.5% of blood relatives, whereas quantitative urinary PBG alone detected only 15.2%. The pattern of inheritance for the uro I syn deficiency is consistent with Mendelian dominant inheritance, and it is likely that it is the basic inherited defect in AIP.