HPE Alpha 1 Antitrypsin Deficiency | Page 10

EPIDEMIOLOGY Searching for a needle in a haystack Because Alpha 1 Antitrypsin Deficiency (AATD) is still largely underdiagnosed (<10% of what would be expected from epidemiological data), early detection of AATD subjects remains a primary concern and must be conducted in reference centres that can provide the best diagnostic tools Stefania Ottaviani PhD Angelo Guido Corsico MD PhD Ilaria Ferrarotti PhD Center for Diagnosis of Inherited Alpha1- antitrypsin Deficiency Dept of Internal Medicine and Therapeutics, Pneumology Unit IRCCS San Matteo Hospital Foundation University of Pavia, Italy Alpha 1 Antitrypsin Deficiency (AATD) is a relatively common genetic condition, which is often undiagnosed or misdiagnosed. Severe deficiency is usually associated with the homozygous PI*ZZ allele combination, but the clinical expression of other deficient allele combinations is less well characterised, with PI*SZ being the most frequent among these combinations. 1 In an attempt to estimate the number of AATD patients worldwide, Blanco and colleagues studied cohorts selected from 65 of the 193 countries globally. 2 They estimated a total of 253,404 Pi*ZZ worldwide, in the following distribution: Europe, 47.2%; USA, 36.1%; Asia,12.7%; Africa, 1.5%; Australia 1.6%; and, New Zealand 0.9%. Of the almost 120,000 subjects identified as carrying the Pi*ZZ genotype in Europe, most were found in Germany (20,611), France (17,191), the Iberian Peninsula (14,522 in Spain and 4944 in Portugal), the UK (13,044), Italy (10,652), Poland (6791), The Netherlands (5353), Denmark (4090), Latvia (4005), Belgium (3193), and lower numbers were observed in other European countries. 2 Prevalence of S and Z mutations Europe A total of 262 cohorts from 71 countries were included in the analysis to estimate the prevalence and the number of SZ subjects worldwide. With the data provided by these cohorts, a total of 1,490,816 Pi*SZ were estimated: 47.5% in Europe, 39.1% in America and the Caribbean, 5.8% in Africa, 5.2% in Asia, and 2.4% in Australia and New Zealand. By individual countries, the highest numbers were found in Spain (174,822), followed by France (161,680), UK (73,973), Italy (64,137), Germany (60,396), and Portugal (52,836). SZ numbers in the other countries were very variable, but always much lower than those mentioned above. 3 Throughout Europe, the frequency of the Z and S mutations varies widely between countries, geographic regions, and ethnic groups. The frequency of the Z variant is highest in Northern and Western European countries, with a mean gene frequency of 0.014, peaking in southern Scandinavia with a gene frequency of >0.02. The prevalence of PI*Z gradually decreases throughout European countries in a north–west to south–east direction, the lowest figures being recorded in eastern Europe (0.0092). The highest frequency of the S allele is found in the Iberian Peninsula, with a mean gene frequency of 0.0564, suggesting the mutation is likely to have arisen in that region. The prevalence of PI*S gradually decreases along a south–west to north–east gradient (0.0176). 4 It has been calculated that the frequency of the PI*S gene in Spain is 104/1000 inhabitants and that of the PI*Z gene is 17/1000 inhabitants, with a total of 145,000 PI*SZ and 12,000 PI*ZZ individuals having been estimated. 5 Based on the number of patients with AATD (repeatedly coded in 2012 and 2013) and on the German population data from the Federal Statistical Office (80,767,500 inhabitants in 2013), the estimated number of individuals with AATD in Germany, independent of genotype or health status, TABLE 1 Allele frequencies in different populations of Exome aggregation Consortium (ExAC) for the major Population Sample size Z c.1096 G>A S c.860 A>T I c.187 C>T Europe 73,284 0.0183 0.0284 0.0004 Asian 25,142 0.00 0.00 0.00 American 11,578 0.0031 0.0219 0.0002 African 10,406 0.0034 0.0078 0.00 Other 978 0.001 0.002 0.00 Global 121,316 0.01170 0.02007 0.00027 Z: name of the allele based on the position in the IEF gel; c.1096: site of the mutation in the cDNA; G>A: base change from guanine to adenine at position; A>T: base change from adenine to thymine; 10 | 2019 | hospitalpharmacyeurope.com