What is Alpha-1 Antitrypsin Deficiency?

Defining Alpha-1 Antitrypsin Deficiency has historically been challenging due to the complexity of genetic variations and their diverse clinical presentations. Traditional medical definitions focus primarily on specific allele combinations, which has led to overly restrictive diagnostic criteria and widespread underdiagnosis. This narrow approach has left countless patients without answers, treatment, or hope.

Through extensive research and lived experience, Mark Egly—himself a person living with Alpha-1 Antitrypsin Deficiency—has pioneered a transformative understanding of this condition. The world recognizes AATD as a rare disease. Mark teaches us that Alpha-1 Antitrypsin Deficiency is not rare—it is rarely diagnosed.

This critical distinction drives the Mark Egly Foundation's mission. Current diagnostic standards are insufficient. Many individuals suffering from AATD go unidentified for decades, if they are identified at all. We are advocating for an expanded standard of care with broader, more inclusive definitions that prioritize patient awareness, early detection, and comprehensive treatment.

While the traditional medical definition has been limited, we can establish clear fundamental characteristics of AATD:

1. SERPINA1 Gene Mutation AATD is a genetic disorder involving mutations in the SERPINA1 gene, which provides instructions for producing Alpha-1 Antitrypsin protein.

2. Insufficient Protein Production The mutated SERPINA1 gene prevents the body from producing adequate quantities of Alpha-1 Antitrypsin to protect tissues from damage caused by excess neutrophil activity and other inflammatory processes.

3. Protein Misfolding In some genetic variations, the liver produces improperly folded Alpha-1 Antitrypsin protein. This misfolding serves a dual threat:

• The malformed protein cannot effectively protect body tissues
• The misfolded proteins accumulate in the liver, potentially causing liver damage
• Less functional AAT reaches the bloodstream, leaving tissues vulnerable

Alpha-1 Antitrypsin Deficiency is inherited through allele combinations from both parents. The M allele is considered the normal variant and provides optimal levels of functional AAT protein. However, numerous deficient variants exist, each associated with varying degrees of protein deficiency or dysfunction.

The severity of AATD depends on which combination of alleles you inherit:

• MM (Normal): Two normal alleles provide full AAT protection
• MZ or MS: One normal and one deficient allele (carrier status)
• ZZ, SZ, or other combinations: Two deficient alleles result in significant AATD

The complexity of Alpha-1 Antitrypsin Deficiency is reflected in the extensive number of identified genetic variants. The comprehensive list below represents known alleles documented at the time of Mark Egly's groundbreaking patent submission. This genetic diversity underscores why a one-size-fits-all diagnostic approach is inadequate.

Understanding the Table:

• Allele: The variant name of the SERPINA1 gene
• Pathogenic Mutation: The specific genetic change
• Consequence: The clinical impact with SIFT and PolyPhen predictive scores

SIFT and PolyPhen scores predict the likelihood that a genetic change will affect protein function. Lower SIFT scores and higher PolyPhen scores indicate greater predicted damage.

Known Alleles of the SERPINA1 Gene

This extensive genetic variation demonstrates why Alpha-1 Antitrypsin Deficiency cannot be defined by a simple checklist. Each variant represents a unique genetic story, and many individuals suffer from AATD without fitting traditional diagnostic criteria.

The Mark Egly Foundation is dedicated to:

• Expanding diagnostic criteria beyond restrictive allele-based definitions
• Educating healthcare providers about the full spectrum of AATD presentations
• Advocating for universal newborn screening to identify AATD before symptoms emerge
• Supporting research that explores the broader impact of AAT deficiency on human health
• Empowering patients with knowledge, resources, and community support

If you or a family member has received genetic testing results and have questions about specific alleles or Alpha-1 risk, we encourage you to:

• Consult with a genetic counselor or Alpha-1 specialist
• Contact the Mark Egly Foundation for educational resources
• Join our community support network
• Consider participating in Alpha-1 research studies

The Mark Egly Foundation honors Mark's pioneering research and his vision of a world where Alpha-1 Antitrypsin Deficiency is recognized, diagnosed early, and treated comprehensively.