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

Marina Aiello,Alfredo Chetta,Alberto Fantin,Giuseppina Bertorelli,Ilaria Ferrarotti,Chiara Longo

doi:10.1002/rcr2.528

Marina Aiello, Alfredo Chetta + Show 4 more

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https://doi.org/10.1002/rcr2.528

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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.

Highlights

Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant genetic disorder characterized by a decreased serum concentration of alpha-1 antitrypsin (AAT)
The aim of this study was to analyse the genetic variants associated with AATD in 117 patients admitted to our outpatient clinic and characterized by a serum concentration of AAT lower than 113 mg/dL
Our study revealed the frequency of rare genetic variants in a wide cohort of subjects affected by AATD, where the patients with PI*MMMalton and PI*MMWurzburg genotypes were respectively 5.8% and 3.8% of all patients with a pathological genotype

Summary

Introduction

Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant genetic disorder characterized by a decreased serum concentration of alpha-1 antitrypsin (AAT). AAT, a small glycoprotein encoded by a gene located on chromosome 14, belongs to the serine protease family (Serpin) and is synthesized and released mainly by hepatocytes. The Z variant is the most common, clinically significant, deficient variant, characterized by the replacement of amino acid Glu342 to Lys342. Among other rare pathological variants, the so called “M-like” variants (e.g. MMalton, MWurzburg, MProcida, etc.) play an interesting role. These mutations produce an isoelectrophoretic pattern similar to the normal M variants; a phenotypic analysis can misdiagnose these variants as normal and only the gene sequencing allows their univocal identification [2]

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