Leukocyte Adhesion Deficiency (LAD) is a rare, life-threatening genetic immunodeficiency where white blood cells (leukocytes) cannot migrate from the bloodstream into infected tissues.
LAD-1 is an inherited immune disorder that occurs in about 1 in 1 million people worldwide.
The FDA has granted accelerated approval to the gene therapy marnetegragene autotemcel (Kresladi) for the treatment of pediatric patients with severe leukocyte adhesion deficiency type 1 (LAD-1).
The approval is specifically for children with LAD-1 caused by biallelic variants in the ITGB2 gene who lack a matched sibling donor for hematopoietic stem cell transplant (HSCT).
It marks the first gene therapy for the ultrarare disease.
Mutations in the ITGB2 gene leave white blood cells without functional CD18, a protein necessary for the cells to adhere to blood vessel walls and migrate
This occurs because the cells lack specific surface proteins required to “stick” to and exit blood vessels, leaving them trapped in the blood while the infection spreads unchecked.
LAD typically presents in infancy with several distinctive clinical findings.
Delayed Umbilical Cord Separation: The cord often remains attached for 3 weeks or longer (normal is 1–2 weeks).
Absence of Pus: Infections do not form pus because neutrophils cannot reach the area to die and accumulate there.
Recurrent Infections: Frequent bacterial and fungal infections of the skin, gums, and respiratory tract.
Impaired Wound Healing: Wounds heal slowly or not at all, often leading to necrotic ulcers.
Persistent Leukocytosis: Blood tests show a consistently high white blood cell count (sometimes over 100,000/µL) even when no active infection is visible.
The Three Types of LAD
LAD-I Mutations in the ITGB2 gene leading to a deficiency of CD18.
The most common form; involves severe, life-threatening infections from birth.
LAD-II-Defect in fucose metabolism (SLC35C1 gene), impairing leukocyte rolling.
Rare; includes intellectual disability, short stature, and the Bombay blood group.
LAD-III-Mutation in the FERMT3 gene (kindlin-3), affecting integrin activation. Combines LAD-I symptoms with a severe bleeding disorder similar to Glanzmann thrombasthenia.
Diagnosis and Treatment Diagnosis is typically confirmed via flow cytometry, which checks for the absence of specific surface proteins like CD18 (for LAD-I), and genetic testing.
Curative Treatment: Hematopoietic stem cell transplantation is currently the only cure for LAD-I and LAD-III.
Management: For LAD-II, fucose supplementation may improve symptoms in some patients.
Supportive care includes lifelong prophylactic antibiotics.