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TESTING INFO Dr. Robert Desnick , head Mount Sinai Med School Genetics and Dana Doheny


TESTING INFO Dr. Robert Desnick , head Mount Sinai Med School Genetics and Dana Doheny
Porphyria Biochemical and DNA Testing
There are two types of testing that are used in the diagnosis of Porphyria: (1) biochemical testing on urine, blood, and stool to measure the amounts specific porphyrins and porphyrin precursors and (2) DNA analysis to identify the causative mutation (or change) in a specific Porphyria gene. When an acute porphyria is suspected, the first-line of testing that is recommended is porphobilinogen (PBG) and d-aminolevulinic acid (ALA) measurements on a urine sample that has been protected from the light by wrapping in tin foil. Measurement of total porphyrins in urine can also be done to help differentiate a specific acute porphyria. The urine can be either a random sample or a 24-hour collection, with the urine collected at the time of an attack prior to any treatment, including carbohydrate loading, glucose infusions, or hemin, and analyzed at an experienced lab. When a cutaneous porphyria is suspected, the first-line of testing is fluorometric measurement of total plasma (blood) porphyrins and the red cell porphyrins. Experience is also important in interpretation of the results. Misdiagnosis has become a common problem in patients who do not have a Porphyria, but present with suggestive symptoms and have clinically insignificant small or nonspecific elevations in the biochemical tests.

DNA analysis is considered the “gold standard” for the diagnosis of Porphyria. It is recommended that biochemical testing be done prior to DNA analysis to determine whether a diagnosis of porphyria is likely and to suggest the specific type of porphyria. However, DNA analysis can be done without biochemical testing and can be done when a person is not symptomatic. The Mount Sinai Genetic Testing Laboratory in New York City performs DNA analysis for Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria (HCP), Variegate Porphyria (VP), Porphyria Cutanea Tarda (PCT) and its autosomal recessive form, Hepatoerythropoietic Porphyria (HEP), Congenital Erythropoietic Porphyria (CEP), Erythropoietic Protoporphyria (EPP), and X-Linked Protoporphyria (XLP). The Lab does not perform DNA analysis for the very rare Aminolevulinic Acid Dehydratase Deficiency Porphyria (ADP), but will perform this analysis on a research basis if results of biochemical testing are consistant with ADP. For DNA analysis of each of the porphyrias the lab does gene sequencing which means that studies are preformed to identify any change (or mutation) in the gene where disease-causing mutations occur. By sequencing genomic DNA, >97% of the known gene mutations listed in the Human Gene Mutation Database can be detected as well as most previously un-recognized mutations. In the event that a mutation is not found, it is recommended that further biochemical testing be performed if the patient becomes symptomatic and/or additional DNA analyses be considered depending on the patient’s symptoms, previous genetic testing, and/or results of previous biochemical tests. If a mutation is identified, it is recommended that the patient be clinically evaluated by a Porphyria specialist and that other family members be tested to determine if they have the mutation.

All porphyrias, except some forms of PCT, are genetic, meaning that they are caused by a mutation (or change) in a specific Porphyria gene. Each type of porphyria involves the deficiency of a specific enzyme in the pathway of heme formation. The exception is ‘sporadic’ PCT, in which the enzyme deficiency develops during life from a combination of environmental factors (for example, iron accumulation, acquired liver disease, alcohol, and some medications including estrogen). Each of the eight enzymes in the heme pathway has its own gene, located on one of the human chromosomes. In the acute porphyrias, all people with symptoms have a mutation in one of the acute Porphyria genes, but most people who have a mutation never develop symptoms; this is referred to as “latent” acute porphyria. Acute attacks are often provoked by drugs such as barbiturates, sulfonamide antibiotics, anti-seizure drugs, rifampin, metoclopramide, and alcohol, reduced food intake, often in an effort to lose weight, infections, surgery, stressful situations, and, in some women, after ovulation and during the last part of the menstrual cycle when progesterone levels are high.

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