Genetic testing is vital to confirming the diagnosis of acute hepatic porphyria (AHP) in symptomatic patients, and identifying family members who carry mutations but have no symptoms, a study by Mount Sinai researchers — that found family mutations in 50 percent of the asymptomatic people tested — reports.
The study, based on diagnostic lab work done at that site from January 2007 through December 2017, also reported 77 new mutations linked to AHP.
“Acute hepatic porphyrias: Identification of 46 hydroxymethylbilane synthase, 11 coproporphyrinogen oxidase, and 20 protoporphyrinogen oxidase novel mutations” was published in the journal Molecular Genetics and Metabolism.
AHP is a term that includes four disease types — acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and a rare disease form called gamma-aminolevulinic acid dehydratase deficiency porphyria (ADP).
Each type results from mutations in disease-causing genes. These genes are, respective to disease types above: hydroxymethylbilane synthase (HMBS), coproporphyrinogen oxidase (CPOX), protoporphyrinogen oxidase (PPOX), and gamma-aminolevulinic acid dehydratase (ALAD).
All the genes are related to the heme biosynthesis pathway that, when mutated, lead to impaired production of heme, a vital molecule with responsibilities that include oxygen transport in the blood.
Genetic testing for mutations is important to confirming a diagnosis of AHP. It also identifies asymptomatic family members, allowing them to receive counseling on risk factors — drugs, fasting, stress, etc. — that are known to promote disease development.
The gold standard in diagnosing AHP in people without disease symptoms is measuring the blood and urine levels of aminolevulinic acid (ALA) and porphobilinogen (PBG), key factors in heme production.
The Mount Sinai Porphyrias Diagnostic Laboratory specializes in molecular testing for all the porphyrias. Since the three main types of AHPs present similar symptoms, it offers a Triple Test Panel that can sequence the HMBS, CPOX, and PPOX genes together. The lab can also test each gene individually for mutations.
During the 11-year period, the Mount Sinai laboratory received 2,342 physician referrals for molecular diagnostic testing for AHP; most — 1,692 — involved people with no relation to anyone else being referred, and 650 were members of an AHP-affected family.
Among unrelated referrals, 398 people (23.5 percent of total group) were diagnosed with AHP – 315 of them with AIP due to mutations in the HMBS gene. Forty-six of these mutations found had not previously been reported.
Another 29 people in this unrelated group were diagnosed with HCP during this period, and 11 novel mutations in the COPX gene were found. VP was diagnosed in 54 people due to PPOX mutations, 20 of which had never previously been reported.
Of the 650 family members of mutation-positive individuals, 304 (46.8 percent) carried the same mutation found in their family.
Overall, these results show the variable nature of AHPs and support “the usefulness of molecular testing to confirm the positive biochemical findings in symptomatic patients and identify at-risk asymptomatic family members,” the study concluded.