
==== Front
Respir Med Case Rep
Respir Med Case Rep
Respiratory Medicine Case Reports
2213-0071
Elsevier

S2213-0071(24)00120-5
10.1016/j.rmcr.2024.102097
102097
Case Report
Alpha-1 antitrypsin deficiency associated with rare SERPINA1 alleles p.(Phe76del) and p.(Asp280Val): A family study
Lepiorz Marc marc.lepiorz@barmherzige-regensburg.de
a⁎
Baier Julius a
Veith Martina b
Greulich Timm b
Pfeifer Michael a
a Department of Pneumology, Krankenhaus Barmherzige Brüder, Regensburg, Germany
b University Medical Center Giessen and Marburg, Philipps University, Department of Medicine, Pulmonary and Critical Care Medicine, Member of the German Center for Lung Research, (DZL), Marburg, Germany
⁎ Corresponding author. Department of Pneumology, Krankenhaus Barmherzige Brüder, Prüfeninger Str. 86, 93049 Regensburg, Germany. marc.lepiorz@barmherzige-regensburg.de
28 8 2024
2024
28 8 2024
51 10209720 3 2024
21 3 2024
25 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
This report describes family members with alpha-1 antitrypsin (AAT) deficiency arising from two rare alleles of SERPINA1 – p.(Phe76del) and p.(Asp280Val) along with the more common deficiency allele, Pi*Z. The index case, a 51-year-old female presented with cough, bloody sputum, fever, weight loss and night sweats. In addition to a respiratory infection, scans revealed bronchiectasis and bronchiolitis without emphysema. Her AAT level was 30 mg/dL and genetic testing revealed a Pi*Z/p.(Phe76del) genotype. Follow up testing of her relatives revealed the rare p.(Asp280Val) variant as well. AAT deficiency remains underdiagnosed. Early detection and intervention could improve quality of life and outcomes.

Handling editor: AC Amit Chopra
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pmc1 Introduction/background

Alpha-1 antitrypsin (AAT) is a glycoprotein (52 KDa) that is primarily synthesized in the liver and is transported to the lungs via the cardiovascular system. In lung tissue, AAT serves as a modulator of elastase activity and, in particular, neutrophil elastase (NE). When the homeostasis between AAT and NE is disrupted, as in AAT deficiency (AATD), elastase activity predominates resulting in lung tissue damage and dysfunction.

AAT is coded for by the SERPINA1 gene. The most common allele of SERPINA1 is the M-allele which is associated with normal serum levels of AAT. The most common alleles associated with decreased AAT levels are the S- and Z-alleles which are associated with 40 % and 90 % reductions in serum AAT, respectively [1]. In addition to these two common pathogenic alleles, over 500 additional genetic variants of SERPINA1 have been identified [2].

Depending on the genetic background, the mutation p.(Phe76del) leads to one of the following rare variants: Pi*MMalton (M2), Pi*MPalermo (M1Val), Pi*MNichinan (V) or Pi*Q0LaPalma (S) [1] Clinical reports on patients with a p.(Phe76del) variant in combination with the Pi*Z generally showed serious lung dysfunction while reports on patients that showed this mutation in combination with Pi*M showed mixed lung and liver dysfunction [3,4].

The p.(Asp280Val) mutation, which is associated with Pi*PLowell (M1Val); Pi*PDuarte (M4), Pi*YBarcelona (p.Pro39His) [1], has not been associated with significantly reduced AAT levels except when heterozygous with a severe deficiency allele. The p.(Asp280Val) variant when expressed with another deficiency variant, was associated with increased risk of pulmonary disease [5]. Interestingly, although p.(Asp280Val) was linked to lower levels of serum AAT, the enzyme present was functioning normally [6].

Bronchiectasis has been reported to be a frequent manifestation of AATD especially in individuals with Pi*ZZ genotype [7]. However, the nature and prevalence of bronchiectasis in AATD has not been extensively studied [8]. A recent study of 505 patients with the Pi*ZZ genotype found that 9.1 % of these patients had bronchiectasis alone and that bronchiectasis was present in 27 % of the emphysema patients [8].

In this article, we describe the clinical characteristics of a family in which three AAT variants were identified: the more common Pi*Z-variant, and the rare variants p.(Phe76del) - and p.(Asp280Val). The index case has the genotype Pi*Z/p.(Phe76del) and was found to have bronchiectasis without emphysema.

2 Clinical case presentation

Written informed consent was obtained from all participants in this study to allow their de-identified information to be used in this article. Approval from the University of Regensburg Ethics Committee was not requested since the university does not require ethics committee approval for the reporting of individual patient cases. This study was completed in compliance with the Helsinki Declaration (2013 Revision) and all applicable local and national regulations.

The initial patient (index case) was a 51-year-old, Caucasian female of Turkish descent that was initially seen at Krankenhaus Barmherzige Brüder in Regensburg, Germany in August 2022 with the following symptoms: cough, bloody sputum, fever, weight loss and night sweats. The patient has never been a smoker. Initial lung function tests and arterial blood gases were within normal limits: forced expiratory volume in 1 s (FEV1) 78 %, FEV1/forced vital capacity (FVC) 77 %, total lung capacity (TLC) 114 % and diffusing capacity of the lungs for carbon monoxide (DLCO) 104 % (Table 1).Table 1 Spirometry results for the index patient at diagnosis.

Table 1	Target	Result	% Target	
Body Plethysmography	
 TLC (L)	4.97	5.67	114	
 VC In (L)	3.12	1.77	57	
 TGV (L)	2.70	4.00	148	
 RV (L)	1.75	2.92	167	
 RV/TLC (%)	35.96	51.44	143	
 Raw eff (kPa*s/L)	0.30	0.21	70	
 sRaw eff (kPa*s)	0.96	0.84	87	
 FVC (L)	3.47	2.75	79	
 FEV1 (L)	2.78	2.16	78	
 FEV1/FVC (%)	80.52	78.45	97	
 PEF (L/s)	6.35	4.87	77	
 MEF 75 (L/s)	5.60	4.63	83	
 MEF 50 (L/s)	3.90	2.68	69	
 MEF 25 (L/s)	0.92	0.71	78	
 FIV 1 (L)	–	1.51	–	
Helium/Carbon monoxide (Single Breath)			
 DLCO (mmol/min/kPa)	7.09	7.35	104	
 KCO (mmol/min/kPa/L))	1.46	1.60	110	
 VI (L)	3.12	2.03	65	
 TLC (L)	4.97	4.78	96	
 FRC (L)	2.70	3.47	128	
 RV (L)	1.78	2.26	129	
TLC = total lung capacity; VC = vital capacity; TGV = thoracic gas volume; RV = residual volume; Raw = airway resistance; sRaw = specific airway resistance; FVC = forced vital capacity; FEV1 = forced expiratory volume in 1 second; PEF = peak expiratory flow; MEF 75 = maximal expiratory flow at 75 % of FVC; FIV = forced inspiratory volume; DLCO = diffusing capacity of the lungs for carbon monoxide; KCO = transfer factor for carbon monoxide; VI = volume of inhaled gas; FRC = functional residual capacity.

After the patient had a bronchopulmonary infection that was resistant to a macrolide antibiotic, further tests (including computed tomography) revealed that the patient had bronchiectasis and bronchiolitis especially in the lower right lobe without emphysema (Fig. 1). The patient was negative for eosinophils, exhaled nitric oxide, anti-neutrophil cytoplasmic antibodies (ANCA) and tuberculosis. Levels of immunoglobulin subclasses (A, E, M and G) were within normal limits.Fig. 1 Transverse CT-scans of the index patient. Scans showing areas of bronchiectasis (*), emphysema (>) in image A and bronchiolitis with tree and bud opacity (^) in image B.

Fig. 1

Bronchoalveolar lavage revealed granulocytosis and evidence of a Haemophilus influenzae infection which was treated with amoxicillin/sulbactam. Eight months later there were further exacerbations of the patient's pulmonary symptoms with evidence of a Pseudomonas aeruginosa infection. This infection was successfully treated with 14 days of piperacillin/tazobactam and ciprofloxacin.

The AAT level in this patient was 30 mg/dL, well below the protective threshold of 50 mg/dL [9]. Genetic testing (Alpha ID, Grifols, Barcelona, Spain) of the index patient revealed that the patient was compound heterozygous for the SERPINA1 gene: Pi* Z/p.(Phe76del). Genotyping was performed at the German AAT Laboratory at the University of Marburg using the Progenika AAT Genotyping Kit (Progenika Biopharma, SA, Derio, Spain) which can simultaneously identify 14 deficiency variants of the SERPINA1 gene based on Luminex xMAP technology (Luminex Corporation, Austin, TX, USA). The laboratory methods are described in detail elsewhere [10].

As a follow-up to the patient's AATD diagnosis, several family members were screened for SERPINA1 mutations (Fig. 2). In addition to the Pi*Z variant, the two rare variants p.(Phe76del), and p.(Asp280Val) were also found. The patient's mother (84 years old) was found to have the Pi*MZ genotype and has had a persistent cough for years and suffers from dyspnea on exertion. Both of the mother's husbands are deceased and one died at the age of 30 years. Based on available information, the other husband did not have any pulmonary symptoms.Fig. 2 Genetic screening of family members of the index case (III.3) for SERPINA1 variants. Circles indicate female family members and squares indicate males.

Fig. 2

A half-brother (designated III.2 in Fig. 2) is an ex-smoker with a history of a severe, persistent cough, elevated liver enzymes and pancreatitis. One sister (III.4) has the same genotype as the patient (Pi*Z/p.(Phe76del)) and has been diagnosed with ANCA-positive vasculitis. A younger sister (III.6) has the genotype (Pi*M/p.(Phe76del)) has occasional respiratory distress and is extremely sensitive to cigarette smoke. The younger sister's husband (III.7), who is from the same village, has the genotype Pi*M/p.(Asp280Val) and was diagnosed two years ago with chronic obstructive pulmonary disease (COPD). His father has COPD as well.

The patient's children and nieces (IV.4-IV.7) are currently living in Germany and have not been tested for insurance reasons. They are aware of the hereditable nature of AATD and all are non-smokers.

3 Discussion

AATD is an underdiagnosed, and, consequently, an undertreated disease. Screening of patient populations that are potentially AAT deficient is important so that patients with AATD could reap the potential benefits of early therapeutic intervention (e.g., smoking cessation and AAT augmentation therapy). These benefits could include slowing of disease progression. A recent longitudinal study demonstrated that AAT replacement therapy decreased the deterioration of lung function in patients with less severe disease (GOLD Stage 2) and decreased overall mortality in the AATD population studied [11].

The case reported here is remarkable for its phenotypic presentation. This patient had pulmonary infectious symptomology with bronchiectasis but without significant emphysema. Greulich et al. reported that the presence of bronchiectasis was a strong predictor of the Pi*ZZ genotype and advocated AATD testing in patients with bronchiectasis in the absence of emphysema or COPD, i.e., in patients with a similar phenotype to the patient in this case [12].

A recent analysis of the European Bronchiectasis registry (EMBARC) found that AATD was uncommon in the patients included in this network [13]. However, other studies have found a much higher incidence of AATD variants in patients with bronchiectasis not due to cystic fibrosis [14,15]. Conversely, as previously noted, when patients with known AATD in the European Alpha1 Research Collaboration (EARCO) registry were surveyed for bronchiectasis, 9.1 % were found to have bronchiectasis alone and 27 % were found to have bronchiectasis in the presence of emphysema [8]. Based on these studies, current European Respiratory Society guidelines recommend AATD testing in patients that have bronchiectasis without evident etiology [16].

Buck et al. reported beneficial effects of AAT augmentation therapy (decreased exacerbations) in a patient with bronchiectasis and frequent exacerbations [17]. However, at present, there are no prospective, controlled studies supporting this possible method of treatment.

In addition to this case report, only a few other studies report patients with bronchiectasis who were tested and found to have rare AAT variants [[18], [19], [20], [21]]. Clearly additional research on the clinical characterization of rare AAT variants is needed. Based on currently available data it is advisable to test patients with COPD for AATD and to consider testing patients with bronchiectasis of unknown etiology. Patients with rare SERPINA1 variants should be evaluated and treated individually based on their serum AAT levels and clinical symptoms. Patient education on AATD and possibly referral to a center with AATD expertise may help in making treatment decisions. Genetic testing of family members could help identify relatives with early stage disease who might benefit from therapeutic intervention and young individuals who have not developed symptoms and who could benefit from lifestyle interventions (e.g., smoking prevention or cessation).

4 Conclusion

• The patient identified in this case was compound heterozygous for a rare SERPINA1 variant p.(Phe76del)and the common deficiency variant Pi*Z and presented with bronchiectasis in the absence of COPD.

• Genetic analysis of her family members revealed several other affected individuals including some with a different rare variant, p.(Asp280Val).

• More widespread testing of selected pulmonary patients could lead to earlier diagnosis of AATD and earlier intervention potentially improving quality of life and outcomes.

Funding

The publication of this case study was supported by 10.13039/501100016387 Grifols . The funder had no role in study design, the collection, analysis and interpretation of data, or in the decision to submit the article for publication.

CRediT authorship contribution statement

Marc Lepiorz: Conceptualization, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. Julius Baier: Conceptualization, Formal analysis, Investigation, Methodology, Writing – review & editing. Martina Veith: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – review & editing. Timm Greulich: Conceptualization, Formal analysis, Investigation, Methodology, Writing – review & editing. Michael Pfeifer: Conceptualization, Formal analysis, Investigation, Methodology, Writing – review & editing.

Declaration of competing interest

ML has received grants from CSL, Grifols and Boehringer Ingelheim. JB reports no competing interests. MV has received grants from Grifols. TG has received grants from Grifols and fees from CSL-Behring, Grifols and Kamada. MP has received grants from Boehringer Ingelheim, Sanofi, Astra Zeneca, and GSK.

Acknowledgments

Michael K. James, PhD CMPP (Grifols) is acknowledged for medical writing assistance and Jordi Bozzo, PhD CMPP (Grifols) for editorial assistance.
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References

1 Papiris S.A. Alpha1-antitrypsin deficiency in Greece: focus on rare variants Pulmonology 30 1 2024 43 52 36797151
2 Wiesemann G.S. Novel SERPINA1 alleles identified through a large alpha-1 antitrypsin deficiency screening program and review of known variants Chronic Obstr Pulm Dis 10 1 2023 7 21 36367950
3 Joly P. Clinical heterogeneity and potential high pathogenicity of the Mmalton Alpha 1 antitrypsin allele at the homozygous, compound heterozygous and heterozygous states Orphanet J. Rare Dis. 10 2015 130 26446624
4 Figueira Goncalves J.M. Clinical manifestations of the Mmalton alpha-1 antitrypsin deficiency variant Pulmonology 24 1 2017 48 52
5 Bornhorst J.A. Genotypes and serum concentrations of human alpha-1-antitrypsin "P" protein variants in a clinical population J. Clin. Pathol. 60 10 2007 1124 1128 17906067
6 Cook L. Alpha-1-antitrypsin PLowell: a normally functioning variant present in low concentration Aust. N. Z. J. Med. 25 6 1995 695 697 8770333
7 Greene C.M. alpha1-Antitrypsin deficiency Nat Rev Dis Primers 2 2016 16051
8 Stockley R.A. The prevalence of bronchiectasis in patients with alpha-1 antitrypsin deficiency: initial report of EARCO Orphanet J. Rare Dis. 18 1 2023 243 37573351
9 American Thoracic Society and European Respiratory Society American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency Am. J. Respir. Crit. Care Med. 168 7 2003 818 900 14522813
10 Veith M. Diagnosing alpha-1-antitrypsin deficiency using A PCR/luminescence-based technology Int J Chron Obstruct Pulmon Dis 14 2019 2535 2542 31819391
11 Fraughen D.D. Augmentation therapy for severe alpha-1 antitrypsin deficiency improves survival and is decoupled from spirometric decline - a multi-national registry analysis Am. J. Respir. Crit. Care Med. 208 9 2023 964 974 37624745
12 Greulich T. Results from a large targeted screening program for alpha-1-antitrypsin deficiency: 2003 - 2015 Orphanet J. Rare Dis. 11 1 2016 75 27282198
13 Chalmers J.D. Bronchiectasis in Europe: data on disease characteristics from the European Bronchiectasis registry (EMBARC) Lancet Respir. Med. 11 7 2023 637 649 37105206
14 Aliberti S. Alpha(1)-Antitrypsin inherited variants in patients with bronchiectasis Arch. Bronconeumol. 59 6 2023 401 402 36710175
15 Izquierdo M. Impact of bronchiectasis on COPD severity and alpha-1 antitrypsin deficiency as a risk factor in individuals with a heavy smoking history Chronic Obstructive Pulmonary Diseases 2023 Journal of the COPD Foundation
16 Miravitlles M. European Respiratory Society statement: diagnosis and treatment of pulmonary disease in alpha1-antitrypsin deficiency Eur. Respir. J. 50 5 2017
17 Buck E. Augmentation therapy with human alpha-1-proteinase inhibitor reduces exacerbations in patient with bronchiectasis and alpha-1-antitrypsin deficiency Respir Med Case Rep 39 2022 101740
18 Mosella M. Description of a new rare alpha-1 antitrypsin mutation in Naples (Italy): PI*M S-Napoli Ann. Thorac. Med. 13 1 2018 59 61 29387258
19 Carpagnano G.E. A new SERPINA-1 missense mutation associated with alpha-1 antitrypsin deficiency and bronchiectasis Lung 195 5 2017 679 682 28668972
20 de Seynes C. Identification of a novel alpha1-antitrypsin variant Respir Med Case Rep 20 2017 64 67 28053854
21 Milger K. Identification of a novel SERPINA-1 mutation causing alpha-1 antitrypsin deficiency in a patient with severe bronchiectasis and pulmonary embolism Int J Chron Obstruct Pulmon Dis 10 2015 891 897 26005342
