MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

nemoci-sympt/PLICNI/alfa-1-antitrypsinova-deficience/genetika-typy-prognoza

Dědičnost

  • Autosomal co-dominant transmission
    • One defective allele tends to result in milder disease than two defective alleles [2]
  • Affected individuals have inherited an abnormal AAT gene from each parent [1]

SERPINA 1

  • Gene that encodes AAT is called SERPINA1
  • Located on the long arm of chromosome 14
  • The production of alpha1-antiprotease is controlled by a pair of genes at the protease inhibitor (Pi) locus
    • The SERPINA1 (formerly known as Pi) gene
  • Highly pleomorphic
  • More than 100 allelic variants (denoted by letters) [4]

Alely

  • At least 150 alleles of AAT (SERPINA1) have been identified
    • Each has a letter code
      • Based upon electrophoretic mobility of the protein produced [1]
  • Over 75 mutations of the SERPINA1 gene have been identified [2]
    • Many with clinically significant effects
  • Most common cause of severe deficiency
    • Single base-pair substitution leading to a glutamate to lysine mutation at position 342 (dbSNP: rs28929474)
    • PiS is caused by a glutamate to valine mutation at position 264 (dbSNP: rs17580)

AAT phenotypes

  • Based on the electrophoretic mobility of the proteins produced by the various abnormal AAT alleles [1]

Pittsburgh mutation


Dysfunctional alleles

  • Produce a normal quantity of AAT protein
    • protein does not function properly [1]
  • Some mutant forms fail to fold properly
    • Targeted for destruction in the proteasome [2]
  • Some have a tendency to polymerize
    • Retained in the endoplasmic reticulum [2]
  • PiMM
    • Pi = protease inhibitor
    • "MM" = banding pattern of that person in isoelectric focusing [2]


Life expectancy

  • Those who smoke is 50 years
  • Those who do not smoke it is almost normal [2]

MM

  • Normal allele = “M” = most common version (allele) of the SERPINA1 gene
    • Most people in the general population have MM in each cell
  • Normal = normal levels of AAT + normal function = normal genotype is MM
  • PiMM: 100% (normal) [2]
  • Other versions of the SERPINA1 gene
    • Lead to reduced levels of alpha-1 antitrypsin [1]
  • Most common (90%) allele is M (PiM)
    • Homozygous individuals (MM) produce normal amounts of alpha1-antiprotease
      • Serum levels of 20-53 µmol/L or 150-350 mg/dL [4]

M/Null

  • Levels approximately 35% of normal levels [4]
  • They do not develop disease [4]

MS (or SS) combination

  • Usually produce enough alpha-1 antitrypsin to protect their lungs
  • Slightly increased risk of impaired lung or liver function [1]
  • PiMS: 80% of normal serum level of A1AT [2]
  • Levels approximately 35% of normal levels [4]
  • They do not develop disease [4]

PiMZ genotypes

  • Blood levels of A1AT are reduced to 40 - 60% of normal levels
  • Usually sufficient to protect the lungs in people who do not smoke [2]
  • PiMZ: 60% of normal serum level of A1AT [2]
  • Slightly increased risk of impaired lung or liver function [3]
  • Levels approximately 35% of normal levels [4]
  • They do not develop disease [4]





Null alleles

  • Null gene for alpha1-antitrypsin
  • Lead to no detectable AAT protein in the plasma
  • Null genotype are the least common
  • Associated with severe alpha1-antitrypsin deficiency [4]
  • Are at risk for the most severe form of associated lung disease but not liver disease but not liver disease [1]
  • Severe deficiency of AAT
    • Strong risk factor for early-onset emphysema
      • But not every severely deficient individual would develop emphysema [1]
  • Least common [3]
  • High risk for emphysema (100% by the age of 30 years) [4]
  • None with the null gene develop liver disease [4]




S allele

  • Produces moderately low levels of this protein
  • More frequent among individuals of Spanish or Portuguese descent [4]





PiSS genotypes

  • Blood levels of A1AT are reduced to 40 - 60% of normal levels
  • Usually sufficient to protect the lungs in people who do not smoke [2]
  • PiSS: 60% of normal serum level of A1AT [2]






SZ combination

  • Have a higher risk of developing lung diseases (such as emphysema)
    • Particularly if they smoke
  • Blood levels of A1AT are reduced to 40 - 60% of normal levels
  • Usually sufficient to protect the lungs in people who do not smoke [2]
  • PiSZ: 40% of normal serum level of A1AT [2]
  • 20-50% increased likelihood of developing emphysema compared with MM homozygotes [4]
  • Serum levels are 75-120 mg/dL [4]



Z allele

  • Produces very little AAT
  • Two copies of the Z allele (ZZ) in each cell
    • Are likely to have AAT deficiency
  • Deficient phenotype
    • Associated with plasma AAT levels less than 35% of the average normal level [1]
  • Most common deficient allele associated with emphysema [1]
  • Carried by about 2-3% of the Caucasian population in the United States [1]
  • PiZ allele
    • Between 1 in 625 and 1 in 2000 are homozygous [2]
  • Of 1 in 1550 individuals [2]
  • Gene frequency of 0.026 [2]
  • Alpha1-antitrypsin produced has a lysine substituted for glutamate
  • Results in spontaneous polymerization within the endoplasmic reticulum of the hepatocyte
    • Leads to decreased serum levels
  • Accumulation of intrahepatic alpha1-antitrypsin
    • Apoptosis of hepatocytes [4]
  • 1. laboratory abnormalities
  • 2. hepatitis
  • 3. fibrosis and cirrhosis [4]
  • Highest in patients of Northern or Western European descent [4]


PiZ/Null

  • Associated with severe alpha1-antitrypsin deficiency [4]

PiZZ genotype

  • A1AT levels are less than 15% of normal
  • Likely to develop panacinar emphysema at a young age
  • 10 to 15% of these people will develop liver fibrosis or liver cirrhosis
    • A1AT is not secreted properly and accumulates in the liver
  • Liver biopsy in such cases will reveal
    • PAS-positive diastase-resistant granules
      • Unlike glycogen and other mucins which are diastase sensitive
        • Diastase treatment disables PAS staining
    • Hepatocytes with A1AT
      • Will stain with PAS even after diastase treatment
        • Referred to as diastase resistant [2]
  • Highest prevalence of the PiZZ variant
    • In the northern and western European countries
    • Mean gene frequency of 0.0140 [2]
  • Serum levels cca 3.4-7 µmol/L
    • 10-15% of normal serum levels [4] [2] (severe alpha-1 antitrypsin deficiency) [2]
  • PiZZ individuals had a 16% likelihood of surviving to age 60 years
    • In contrast to an 85% likelihood for the general US population [4]
  • Emphysema was the most common cause of death (72%)
  • Chronic liver disease was second (10%) [4]
  • NIH registry
    • Of 1129 affected individuals
      • Mortality rate was approximately 3% per year
      • Excess mortality was ascribable entirely to lung and liver disease [4]
  • Danish registry
    • Better, especially for nonindex cases involving nonsmokers
      • Survival closely approximated that of the healthy Danish population
      • Poor outlook for index cases and the additional mortality risk among patients who smoked [4]
  • Specific features that portend a poor prognosis include:
    • FEV1 >50%
      • 5-y mortality rate is 4% [4]
    • FEV1 35-49% [4]
      • 5-y mortality rate is 12% [4]
    • FEV1<35 [4]
      • 5-y mortality rate is 50% [4]
    • Significant bronchodilator response (>12% and >200 mL) [4]
    • Smoking [4]
    • Male sex [4]
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Poslední aktualizace: 18. 12. 2022 3:12:03