The Z mutation is a deficiency allele that reduces the quantity of alpha-1 antitrypsin (AATalpha-1 antitrypsin More) in the blood, and causes AATD in people with two mutations (e.g. ZZ, SZ). The MZ genotype is not associated with an increased risk for lung disease in nonsmokers. Higher risk is seen in MZ individuals who smoke. A slightly increased risk for liver disease has been seen in MZ populations. Because Alpha-1 is a genetic condition, your result means that your relatives are at increased risk to have AATD or carry abnormal alpha-1 genes. We encourage you to make your family members and any reproductive partner aware of the condition in your family and the availability of testing.
Alpha-1 Alleles - AlphaNet
Z:
• the most common clinically significant allele
• causes misfolding of antitrypsin in the liver – making normal quantities of the protein but it misfolds, gets stuck to others and forms polymers which get stuck in the liver.
• 85% trapped in the liver
• originated in Scandinavia
• estimated that 2-3% of people in North America have one copy of the Z alleleWhat is Your Phenotype and What Does it Mean? – Kimberly Foil, MS, CGC, Genetic Counseling Program, Alpha-1 Foundation; Division of Pulmonary Medical term referring to the lungs. and Critical Care Medicine, Medical University of South Carolina (MUSC)
It is very common to have inherited one copy of the normal Alpha-1 gene (referred to as "M") along with an abnormal version of that gene (referred to as "Z", "S", or another variant) that contain the instructions for making alpha-1 antitrypsin, or AAT. Individuals with one normal and one abnormal copy of the AAT gene (referred to as "MZs”) are also called "heterozygotes." AAT is normally produced in the liver and travels through the blood to protect the lungs and liver from inflammation. Historically, it has been assumed that heterozygotes, sometimes also termed "carriers", are symptom free or not predisposed to the clinical symptoms s of Alpha-1. That is, having one normal allele was presumed to be protective. However, over time the Alpha-1 patient community has raised questions about the potential risk for lung and/or liver disease among individuals in this group. There is scientific basis for that concern as a growing body of evidence shows that some small fraction of MZS develop either lung or liver injury characteristic of Alpha-1. The challenges lie in identifying those who might be at higher risk among the large number of MZS who will never develop disease, determining whether treatments that are applied for ZZ Alpha-1 patients might be beneficial, and, if detected early, can measures be taken to prevent disease before it occurs?
The lack of sufficient evidence to clearly define risk for MZS has resulted in uncertainty for both patients and practitioners and variation in treatment approaches. This has not served the Alpha-1 community well. Because of the implications for the enormous number of individuals around the world who harbor a single Z gene, it is important to identify the relative risk of disease for this subpopulation and determine whether treatments being considered for ZZ individuals in upcoming clinical trials, if proven effective, might benefit MZs as well.
In sum, the workshop underlined the need to reject the assumption that inheritance of a single Z gene does not increase disease risk among all MZs. Every day, more is being learned about the relative risks of lung and liver disease among this population but there is a lag in understanding viable treatment options because of an insufficient evidence base. Innovation is needed in study design, recruitment and enrollment strategies, and in facilitating the entire clinical trial process.
In 2017, the Alpha-1 Foundation and its partners convened a workshop to assess what was known about the MZ state and identify future lines of research into disease mechanisms and clinical features in MZ heterozygotes. That workshop concluded with the development of a series of research questions to pursue regarding the clinical implications of MZ status, and possible approaches for answering them. Over the past 6 years, more data have become available from studies around the world. The Foundation thought it was important to take another look at these issues and convened the workshop and included stakeholders from the research, pharmaceutical, and patient communities.
Scientific presentations highlighted that population-based and family studies of MZs reveal that when exposed to an environmental injury such as cigarette smoking, a proportion of these individuals have relatively higher risk for lung disease than do individuals with no Z variant. A similar situation exists for risk of liver injury. Evidence collected from human cells involved in inflammation in the lung and liver, mouse models of Alpha-1, and tissue from the livers of Alpha-1 patients who received a transplant provide clues to the disease mechanisms associated with Z heterozygosity. Early-stage research is focused on whether treatment strategies for ZZ patients are appropriate and beneficial for MZ individuals. Participants discussed clinical trials design and infrastructure needs to identify and study the MZ population.
Z Variant Heterozygosity: Disease Risk and Treatment Implications - Alpha-1-to-One, Winter 2023
The management of individuals with the PI*MZ genotype, characterized by mild or moderate AATalpha-1 antitrypsin More deficiency, is less clear than of those with the most common severe deficiency genotype (PI*ZZ). Recent genetic data suggest that the PI*MZ genotype may be significantly more prevalent than currently thought. The only specific treatment for lung disease associated with severe AATD is the intravenous infusion of AATalpha-1 antitrypsin More augmentation therapy, which has been shown to slow disease progression in PI*ZZ individuals. There is no specific evidence for the clinical benefit of AATalpha-1 antitrypsin More therapy in PI*MZ individuals, and the risk of emphysemaObstructive airway disease in which the walls of the alveoli (air sacs) are damaged or destroyed. More development in this group remains controversial. As such, current guidelines do not support the use of AATalpha-1 antitrypsin More augmentation in PI*MZ individuals.
Alpha-1 antitrypsin (AAT) augmentation therapy in individuals with the PI*MZ genotype: a pro/con debate on a working hypothesis – BMC PulmonaryMedical term referring to the lungs. More Medicine