Alpha₁-antitrypsin deficiency: a clinical-genetic overview

Figures & data

Table 1 Summary of studies evaluating AAT augmentation in severe antitrypsin deficiency

Study	Comparisons	Results treated by AAT augmentation versus untreated	Evidence level
Seersholm et al^Citation40	FEV1 decline in German patients treated with AAT and Danish untreated patients	FEV1 decline in treated Germans was 56 mL/year, less than the 75 mL/year in Danes (P = 0.02)	C
Alpha-1-antitrypsin deficiency registry study group^Citation41	Nonrandomized comparison of patients receiving AAT augmentation with untreated patients	Decreased mortality (risk ratio 0.64), (P = 0.02) in patients with FEV1 35%–49% predicted decline in FEV1 was less with augmentation: 66 versus 93 mL/year, (P = 0.03)	C
Dirksen et al^Citation43	Randomized placebo controlled trial in 56 patients over 3 years	CT scan progression of emphysema less in treated patients, (P = 0.07); no difference in FEV1	B
Wencker et al^Citation44	Retrospective comparison of decline in FEV1 before and after treatment	Decline in FEV1 34 mL/year less after therapy than the 49 mL/year before therapy (P = 0.019)	C
Chapman et al^Citation45	Meta-analysis of the above studies and patients on AAT treatment with matched controls from the Canadian AAT registry (total n = 1509)	Positive effect of AAT augmentation with reduction in FEV1 decline by 26% (17.9 mL/year). Effect due to subjects with FEV1 30%–65% of predicted	C
Dirksen et al^Citation46	Randomized weekly AAT augmentation versus placebo for 2.0–2.5 years (total n = 77)	Trend suggestive of reduction in progression of emphysema by CT densitometry (P = 0.049–0.084)	B
Gotzsche and Johansen^Citation47	Cochrane meta-analysis of Dirksen’s two placebo controlled randomized trials	Lung density deteriorated less in treated group (P = 0.03)	B
Stockley et al^Citation48	Integrated analysis of Dirksen’s two placebo controlled randomized trials	Yearly loss in lung density in treated group significantly less than placebo 1.73 g/L versus 2.74 g/L, (P = 0.006)	B

Abbreviations: AAT, α₁-antitrypsin; CT, computerized tomography; FEV₁, forced expiratory volume in one second.

Table 2 Common laboratory tests available for the investigation of AAT deficiency

Test type	Test method	Patient type
		Symptomatic patient	1^st degree relative of proband OR preconceptual counseling
Initial investigation	Serum AAT level	AAT level determines need to proceed to diagnostic test	Proceed to diagnostic test regardless of the serum AAT level
Preliminary diagnostic	Targeted DNA analysis for the presence of the SERPINA1 S and Z mutations iso-electric focusing	Stop here if the preliminary diagnostic test result agrees with the serum AAT level	Use a method sensitive to the mutation type present in the proband Stop here if the preliminary diagnostic test result agrees with the serum AAT level
Definitive diagnostic	Gene sequencing	Utilize: i. As an alternative to the preliminary diagnostic test, or ii. To further investigate cases in which the preliminary diagnostic test does not explain a relatively low serum AAT level

Abbreviation: AAT, α₁-antitrypsin.

Table 3 Sample mutations of the SERPINA1 gene described with standardized and legacy nomenclature

Nucleotide nomenclaturea	Protein nomenclature (Unprocessed)	Protein nomenclature (legacy)	Synonyms
17 kb deletion of all coding exons			Nullisoladi procida; Nullprocida
c.17C>T	p.Ser6Leu	p.Ser-19Leu	Zwrexham
c.194T>C	p.Leu65Pro	p.Leu41Pro	Mprocida
c.227_229delTCT	p.Phe76del	p.Phe52del	Mmalton; Mpalermo
c.230C>T	p.Ser77Phe	p.Ser53Phe	Siiyama
c.272G>A	p.Gly91Glu	p.Gly67Glu	Mmineral springs
c.275C>T	p.Thr92ile	p.Thr68ile	Nulllisbon
c.347T>A	p.lle116Asn	p.lle92Asn	Nullludwigshafen
c.415G>A	p.Gly139Ser	p.Gly115Ser	Nulldevon; NullNewport
c.552delC	p.Tyr184X	p.Tyr160Ter	Nullgranite falls
c.646+1G>T			Nullwest
c.721A>T	p.Lys241X	p.Lys217Ter	Nullbellingham
c.739C>T	p.Arg247Cys	p.Arg223Cys	F
c.839A>T	p.Asp280val	p.Asp256val	Pduarte; Plowell; Nullcardiff
c.863A>Tb	p.Glu288val	p.Glu264val	S
c.1027_1028delTC	p.Ser343ArgfsX16	p.Ser319ArgfsX16	Nullhong kong 1
c.1078G>A	p.Ala360Thr	p.Ala336Thr	wbethesda
c.1096G>Ab	p.Glu366Lys	p.Glu342Lys	Z
1130dupT	p.Leu377PhefsX24	p.Leu353PhefsX24	Nullmattawa
c.1158delC	p.Glu387ArgfsX11	p.Glu363ArgfsX11	Nullbolton
c.1158dupC	p.Glu387ArgfsX14	p.Glu363ArgfsX14	Nullsaarbruecken
c.1178C>T	p.Pro393Leu	p.Pro369Leu	Mheerlen

Notes:

a Nucleotide changes are described relative to NM_001127705.1:

b The most common SERPINA1 mutations: i) c.863 A>T (or “S”) is most common in individuals of Southern European origin, the allele frequency in white subjects in North America is about 6%; ii) c.1096G>A (or “Z”) is most common in individuals of Northern European origin, the allele frequency is about 2% in white subjects in North America.

SeersholmNWenckerMBanikNDoes alpha1-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary alpha1-antitrypsin deficiency?Eur Respir J19971010226022639387950

 PubMed Web of Science ®Google Scholar

The Alpha-1-Antitrypsin Deficiency Registry Study GroupSurvival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsinAm J Respir Crit Care Med1998158149599655706

 PubMed Web of Science ®Google Scholar

DirksenADijkmanJHMadsenFA randomized clinical trial of alpha(1)-antitrypsin augmentation therapyAm J Respir Crit Care Med19991605 Pt 11468147210556107

 PubMed Web of Science ®Google Scholar

WenckerMFuhrmannBBanikNKonietzkoNLongitudinal follow-up of patients with alpha(1)-protease inhibitor deficiency before and during therapy with IV alpha(1)-protease inhibitorChest2001119373774411243951

 PubMed Web of Science ®Google Scholar

ChapmanKRStockleyRADawkinsCWilkesMMNavickisRJAugmentation therapy for alpha1 antitrypsin deficiency: a meta-analysisCOPD20096317718419811373

 PubMedGoogle Scholar

DirksenAPiitulainenEParrDGExploring the role of CT densitometry: a randomised study of augmentation therapy in alpha 1-antitrypsin deficiencyEur Respir J20093361345135319196813

 PubMed Web of Science ®Google Scholar

GotzschePCJohansenHKIntravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung diseaseCochrane Database Syst Rev201077CD00785120614465

 PubMed Web of Science ®Google Scholar

StockleyRAParrDGPiitulainenEStolkJStoelBCDirksenATherapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometryRespir Res20101113620920370

 PubMed Web of Science ®Google Scholar