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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2015

Open Access 01-12-2015 | Research

Clinical heterogeneity and potential high pathogenicity of the Mmalton Alpha 1 antitrypsin allele at the homozygous, compound heterozygous and heterozygous states

Authors: Philippe Joly, Olivier Guillaud, Valérie Hervieu, Alain Francina, Jean-François Mornex, Colette Chapuis-Cellier

Published in: Orphanet Journal of Rare Diseases | Issue 1/2015

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Abstract

Background

Alpha 1 antitrypsin (A1AT) deficiency (A1ATD) is potentially associated with a high degree of liver and/or lung disease. Apart from the most frequent deficiency alleles, Pi S and Pi Z, some A1AT alleles of clinical significance may be easily misdiagnosed. This is typically the case of the Pi Mmalton variant which shares the same ‘gain-of-function’ liver toxicity than Pi Z and the same ‘loss of function’ lung disease as well.

Methods

The biological diagnosis of A1ATD typically relies on a low serum concentration associated with an abnormal isoelectric focusing (IEF) pattern of migration. However, Sanger direct DNA sequencing may be required for deficiency alleles without biochemical expression (Null alleles) or for A1AT variants whose IEF profiles resemble the wild-type and sub-types M allele but with a low concentration.

Results

We report four cases of A1ATD involving the deficient Pi Mmalton allele with very different clinical expressions: (i) one Mmalton/Mmalton with liver fibrosis and cirrhosis, (ii) two Mmalton/Z with chronic pulmonary obstructive disease in one case and (iii) one M/Mmalton without liver or lung disease. In both cases, the correct diagnosis has necessitated a genetic analysis.

Conclusions

Our study provides another example of Pi Mmalton homozygosity associated with a severe liver disease that emphasizes the necessity of a not delayed diagnosis. The great clinical heterogeneity of the other genotypes (which is in agreement with the literature data) questions about the role of environmental and other modifier genes in the pathogenicity of A1ATD.
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Metadata
Title
Clinical heterogeneity and potential high pathogenicity of the Mmalton Alpha 1 antitrypsin allele at the homozygous, compound heterozygous and heterozygous states
Authors
Philippe Joly
Olivier Guillaud
Valérie Hervieu
Alain Francina
Jean-François Mornex
Colette Chapuis-Cellier
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2015
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-015-0350-6

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