PIP - 42

ALPHA-1 ANTITRYPSIN PHENOTYPES

Nomenclature and gene frequency

Alpha-1 antitrypsin (a1AT) exhibits considerable polymorphism and over 90 genetically determined variants of a1AT have been identified, most of which are associated with normal amounts and activity. The predominant normal variant is designated M and the most common variants associated with varying degrees of a1AT deficiency are the Z and S variants. The Z mutation is the most common cause of disease associated with a1AT deficiency.

Allele

Approx. Frequency

Disease susceptibility

M1

0.60 - 0.72

Normal phenotype

M2

0.14 - 0.19

Normal phenotype

M3

Rare

Normal phenotype

F, X, Psaint albans

Rare

Normal phenotype

Pittsburgh

Rare

Haematological Disease

S

0.02 -0.04

Emphysema

Z

0.01 - 0.02

Emphysema, Liver Disease

Mmalton

Rare

Liver Disease

Mprocida, Mheerlen

Rare

Emphysema

Null

Rare

Emphysema

Clinical Aspects

Patients who are homozygous for one of the deficiency alleles or heterozygous for any two deficiency alleles will have a reduction in a 1AT levels, but not all are associated with disease.

The Z variants are the most clinically significant. a1AT levels in ZZ homozygotes are about 15% of normal and 10% develop juvenile cirrhosis due to hepatocellular damage. Men over 50 who are ZZ are at particular risk of cirrhosis and hepatoma

 

Version 1.0 / April 2014                                                                                                                    Approved by: Consultant Biochemist