Histological Features
Histologically, AT is marked by degeneration of the
cerebellar Purkinje cells, which leads to the progressive ataxia observed in patients. The cerebellum often shows loss of Purkinje cells, and there may be a decrease in the density of the granular layer. Additionally, the thymus may exhibit hypoplasia or even complete absence, contributing to the immunodeficiency seen in AT.
What Causes Ataxia Telangiectasia?
The condition is caused by mutations in the
ATM gene (Ataxia Telangiectasia Mutated), which plays a crucial role in the detection and repair of DNA damage. The inability to repair DNA effectively leads to the various systemic manifestations of the disease, including increased cancer risk and neurological symptoms.
Clinical Manifestations
Patients with AT typically present with progressive difficulty in coordination (ataxia), dilated blood vessels (telangiectasias) primarily in the eyes and skin, and recurrent infections due to immunodeficiency. Histological examination of the skin may show dilated capillaries, particularly in sun-exposed areas.
Pathophysiological Mechanisms
The pathophysiological mechanisms underlying AT involve defective DNA repair and cell cycle regulation, primarily due to the malfunctioning ATM protein. This leads to cellular apoptosis, particularly in neurons, and contributes to the neurodegenerative aspects of the disease. Additionally, the impaired immune response is a result of defective V(D)J recombination, crucial for antibody diversity.
Diagnosis
Diagnosis of AT is often clinical but can be confirmed with genetic testing for mutations in the ATM gene. Histologically, a brain biopsy might reveal cerebellar atrophy, mainly involving the Purkinje and granular cells. Immunohistochemical staining may show decreased ATM protein levels in affected tissues.
Management and Treatment
Currently, there is no cure for AT. Management is generally symptomatic and supportive, including physical therapy for ataxia, antibiotics for infections, and regular screenings for cancer. Experimental treatments, such as gene therapy and targeted molecular drugs, are under investigation. Research Directions
Current research is exploring the potential of gene editing technologies, such as
CRISPR-Cas9, to correct ATM gene mutations. Additionally, studies are investigating the role of antioxidants and other neuroprotective agents in slowing disease progression.
