title: Clinical heterogeneity and potential high pathogenicity of the Mmalton Alpha 1 antitrypsin allele at the homozygous, compound heterozygous and heterozygous states.
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.
authors.affiliation: Unité de Pathologie Moléculaire du Globule Rouge, Laboratoire de Biochimie et de Biologie Moléculaire, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France. philippe.joly@chu-lyon.fr.|Centre de Recherche et d'Innovation sur le Sport (CRIS)-EA 647, Université Claude-Bernard Lyon 1, Villeurbanne, France. philippe.joly@chu-lyon.fr.|Labex GR-Ex, Institut Universitaire de France, Paris, France. philippe.joly@chu-lyon.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Joly
authors.affiliation: Service d'hépato-gastroentérologie, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France. olivier.guillaud@chu-lyon.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Guillaud
authors.affiliation: Service d'anatomie pathologique, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France. valerie.hervieu@chu-lyon.fr.
authors.forename: Valérie
authors.initials: V
authors.lastname: Hervieu
authors.affiliation: Unité de Pathologie Moléculaire du Globule Rouge, Laboratoire de Biochimie et de Biologie Moléculaire, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France. alain.francina@wanadoo.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Francina
authors.affiliation: Service de pneumologie, Groupement Hospitalier Est, Hospices Civils & Université Claude Bernard-Lyon 1, Bron, France. jean-francois.mornex@chu-lyon.fr.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Mornex
authors.affiliation: Laboratoire d'Immunologie, Centre de Biologie Sud, Centre hospitalier Lyon-Sud, Hospices Civils & Université Claude Bernard-Lyon 1, Lyon, France. colette.cellier@chu-lyon.fr.
authors.forename: Colette
authors.initials: C
authors.lastname: Chapuis-Cellier
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000483:Alleles; D001483:Base Sequence; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D000515:alpha 1-Antitrypsin / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D000515:alpha 1-Antitrypsin