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Clinical manifestations in patients with PI*MMMalton genotypes. A matter still unsolved in alpha-1 antitrypsin deficiency.

ABSTRACT: We report the genetic variants associated with alpha-1 antitrypsin deficiency (AATD) in 117 patients admitted to our outpatient clinic and characterized by a serum concentration of AAT lower than 113?mg/dL. We focused on the M-like heterozygous variant of the SERPINA1 gene called PI*MMMalton, and describe three patients with this variant. While the role of homozygous AATD in liver and pulmonary disease is well established, the association between heterozygous AATD and chronic liver and pulmonary disease is still under investigation. The PI*MMMalton genotype was found in 5.8% of patients with a pathological genotype of AATD and in 14.3% of the subjects when considering only those with intermediate AATD. There were no liver or renal abnormalities in patients with the PI*MMMalton genotype. The PI*MMMalton patients included here showed a normal liver function, and none had renal function abnormalities or abdominal aortic aneurysm. Only a prevalence of lung disease was detected.

SUBMITTER: Aiello M

PROVIDER: S-EPMC7029433 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Clinical manifestations in patients with PI*MMMalton genotypes. A matter still unsolved in alpha-1 antitrypsin deficiency.

Aiello Marina M Fantin Alberto A Longo Chiara C Ferrarotti Ilaria I Bertorelli Giuseppina G Chetta Alfredo A

Respirology case reports 20200219 3

We report the genetic variants associated with alpha-1 antitrypsin deficiency (AATD) in 117 patients admitted to our outpatient clinic and characterized by a serum concentration of AAT lower than 113 mg/dL. We focused on the M-like heterozygous variant of the SERPINA1 gene called PI*MMMalton, and describe three patients with this variant. While the role of homozygous AATD in liver and pulmonary disease is well established, the association between heterozygous AATD and chronic l ...[more]

PMID: 32076552

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Project description:BACKGROUND:Alpha-1-antitrypsin (AAT) deficiency (AATD) of Z, Mmalton, Siiyama type is associated with liver storage of the mutant proteins and liver disease. The Z variant can be diagnosed on isoelectric focusing (IEF) while Mmalton and Siiyama may be missed or misdiagnosed with this technique. Therefore, molecular analysis is mandatory for their characterization. In particular, that holds true for the Mmalton variant as on IEF profile it resembles the wild M2 subtype. METHODS:This is a retrospective analysis involving review of medical records and of liver biopsy specimens from a series of Mmalton, Z and Siiyama Alpha-1-antitrypsin deficiency patients. The review has been implemented by additional histological stains, electron microscopic observations and 3-D modeling studies of the sites of the mutations. RESULTS:Z, Mmalton and Siiyama liver specimen contained characteristic intrahepatocytic PAS-D globules. The globules differed in the three variants as only Mmalton cases showed dark basophilic precipitates within the AAT inclusions. The precipitates were visualized in haematoxylin-eosin (H.E.) stained preparations and corresponded to calcium precipitates as demonstrated by von Kossa staining. On immunohistochemistry, ZAAT inclusions were stained by polyclonal as well as monoclonal noncommercial anti-AAT antibody (AZT11), whilst Mmalton and Siiyama inclusion bodies remained negative with the monoclonal anti-Z antibody. 3-D protein analysis allowed to predict more severe misfolding of the Mmalton molecule as compared to Z and Siiyama that could trigger anomalous interaction with endoplasmic reticulum chaperon proteins, namely calcium binding proteins. CONCLUSIONS:Mmalton AAT inclusion bodies contain calcium precipitates inside them that allow the differential diagnosis with Siiyama and ZAAT inclusions in routine histological sections. The study has confirmed the specificity of the monoclonal AZT11 for the Z mutant. Thus, the combination of these two features is crucial for the distinction between the three variants and for predicting the genotype, whose confirmation would definitely require molecular analysis. Our study provides new data on the pathomorphogenesis of Mmalton inclusion bodies whose mineralization could play a central role in disease pathogenesis of Mmalton that is distinct from the Z and Siiyama variants. Calcium is known to be a major effector of cell death either via the increased intracellular concentration or the alteration of homeostasis.

Project description:BackgroundAlpha-1 antitrypsin deficiency (AATD) can result in severe liver and respiratory disorders. The uninhibited elastase activity on the elastic tissue of arterial walls suggests that AATD may also impact vascular health. Thus, we performed a meta-analysis of the studies evaluating cardiovascular risk in individuals with AATD and non-AATD controls.MethodsA systematic literature search was conducted in the main scientific databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Differences between cases and controls were expressed as odds ratios (OR) with 95% confidence intervals (95%CI). The protocol was registered on PROSPERO under the identification number CRD42023429756.ResultsThe analysis of eight studies showed that, with a prevented fraction of disease of 15.0% and a corresponding OR of 0.779 (95%CI: 0.665-0.912; p = 0.002), a total of 24,428 individuals with AATD exhibited a significantly lower risk of ischemic heart disease compared to 534,654 non-AATD controls. Accordingly, given a prevented fraction of disease of 19.5%, a lower risk of acute myocardial infarction was documented when analyzing four studies on 21,741 cases and 513,733 controls (OR: 0.774; 95%CI: 0.599-0.999; p = 0.049). Sensitivity and subgroup analyses substantially confirmed results. Meta-regression models suggested that these findings were not influenced by AATD genotypes or prevalence of chronic obstructive pulmonary disease (COPD) among cases and controls, while higher differences in the prevalence of male sex (Z-score: 3.40; p < 0.001), hypertension (Z-score: 2.31; p = 0.021), and diabetes (Z-score: 4.25; p < 0.001) were associated with a lower effect size.ConclusionsIndividuals with AATD may exhibit a reduced risk of ischemic heart disease, even in the presence of mild deficiency of the serine protease inhibitor. Although caution is warranted due to the observational nature of the data, future pharmacological and rehabilitation strategies should also take this controversial relationship into account.

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Clinical manifestations in patients with PI*MMMalton genotypes. A matter still unsolved in alpha-1 antitrypsin deficiency.

Publications

Clinical manifestations in patients with PI*MM<sub>Malton</sub> genotypes. A matter still unsolved in alpha-1 antitrypsin deficiency.

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