Role of genetic testing in the management of patients with inherited porphyria and their families

Abstract

The porphyrias are a group of mainly inherited metabolic conditions that result from partial deficiency of individual enzymes in the haem biosynthesis pathway. Clinical presentation is either with acute neurovisceral attacks, skin photosensitivity or both, and is due to overproduction of pathway intermediates. The primary diagnosis in the proband is based on biochemical testing of appropriate samples, preferably during or soon after onset of symptoms. The role of genetic testing in the autosomal dominant acute porphyrias (acute intermittent porphyria, hereditary coproporphyria and variegate porphyria) is to identify presymptomatic carriers of the family specific pathogenic mutation so that they can be counselled on how to minimize their risk of suffering an acute attack. At present the additional genetic factors that influence penetrance are not known, and all patients are treated as equally at risk. Genetic testing in the erythropoietic porphyrias (erythropoietic protoporphyria, congenital erythropoietic porphyria and X-linked dominant protoporphyria) is focused on predictive and preconceptual counselling, prenatal testing and genotype-phenotype correlation. Recent advances in analytical technology have resulted in increased sensitivity of mutation detection with success rates of greater than 90% for most of the genes. The ethical and consent issues are discussed. Current research into genetic factors that affect penetrance is likely to lead to a more refined approach to counselling for presymptomatic gene carriers.

Porphyria: often discussed but too often missed

“…The challenges posed in the biochemical analysis of a patient in remission highlight the necessity for genetic testing in those at risk (see below). Usually an acute attack leads to identification of the proband case, with asymptomatic carriers of the genetic mutation in their families identified through screening 25. Low clinical penetrance is a recognised feature of the autosomal dominant acute porphyrias 2…”

“…Once the acute attack has remitted, the key aim is to prevent further episodes and to identify any other at-risk family members, who are typically asymptomatic, through genetic testing 25. Prevention is largely through education on avoiding potential precipitating factors.…”

Clinical, Biochemical and Molecular Characteristics of the Main Types of Porphyria

“…Enzyme activity measurement and genetic testing confirm the type of porphyria and help to identify the asymptomatic -but at-risk-family members of the index patient. DNA analysis which identifies a family specific, causative mutation is now the method of choice for family studies, especially in non-erythroid variant of AIP and in cases when low-normal and high-reduced values of enzyme activity overlap or hematological diseases responsible for abnormal blood cells distribution coexist to present a false normal or abnormal enzyme activity [1,9,[35][36][37].…”

“…For detection of large intragenic deletions/duplications the multiplex ligation-dependent probe amplification (MLPA) or gene dosage analysis by fluorescent PCR are recommended [36,38]. Sensitivity for mutation detection in HMBS, CPOX and PPOX genes is 97-100%.…”

Novel A219P Mutation of Hydroxymethylbilane Synthase Identified in a Chinese Woman with Acute Intermittent Porphyria and Syndrome of Inappropriate Antidiuretic Hormone

“…The diagnosis of AIP is based on both clinical manifestations and conventional biochemical methods. Given the uncertainty of whether traditional biomedical methods can be used effectively to diagnose clinically latent cases, gene investigation is considered essential for managing families with presumed acute intermittent porphyria (Whatley & Badminton, 2013). Currently, approximately 390 mutations in the HMBS gene have been identified as being responsible for AIP (www.hgmd.cf.ac.uk), some of which have been studied in the Chinese population (Liu et al, 2011;Kong et al, 2013).…”