Name: Aqneursa (levacetylleucine) in Ataxia-telangiectasia: Pathophysiology
Published: 2026-10-02T18:22:10-04:00

Function of the ATM protein

“A-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene which encodes a protein of the same name. The primary role of the ATM protein is coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and other genotoxic stress.” (opens the source at this quote in a new tab)

“The ATM protein assists cells in recognizing damaged or broken DNA strands and coordinates DNA repair by activating enzymes that fix the broken strands.” (opens the source at this quote in a new tab)
“Variants in the ATM gene reduce or eliminate the function of the ATM protein. Without this protein, cells become unstable and die. Cells in the part of the brain involved in coordinating movements (the cerebellum) are particularly affected by loss of the ATM protein.” (opens the source at this quote in a new tab)

Cerebellar degeneration and Purkinje cell loss

“The neuropathological hallmark of A-T is diffuse degeneration or atrophy of the cerebellar vermis and hemispheres, involving Purkinje cells (PCs) and, to a lesser extent, granule neurons.” (opens the source at this quote in a new tab)
“The cause of this cell death is not known, though many hypotheses have been proposed” (opens the source at this quote in a new tab)
“Much of the evidence in existence to date supports the idea that a defective response to genotoxic and/or oxidative stress contributes to the neuronal cell dysfunction and death in A-T.” (opens the source at this quote in a new tab)

“In parallel, ATM also functions in the maintenance of the cellular redox balance, mitochondrial function and turnover and many other metabolic circuits.” (opens the source at this quote in a new tab)
“This review suggests that it is the absence of a comprehensive role of ATM in responding to ongoing DNA damage induced mainly by endogenous agents. It is the ensuing deterioration and eventual loss of cerebellar Purkinje cells, which are very vulnerable to ATM absence due to a unique combination of physiological features, which kindles the cerebellar decay in A-T.” (opens the source at this quote in a new tab)

Proposed mechanisms of neurodegeneration

Mechanism	Hypothesis as listed
Oxidative stress	“Defective response to oxidative stress characterized by elevated ROS and altered cellular redox status”
Mitochondria	“Mitochondrial dysfunction”
Cell cycle	“Failed cell cycle regulation resulting in the re-entry of post-mitotic (mature) neurons into the cell cycle”
Synaptic function	“Synaptic/vesicular dysregulation”
Vasculature	“Defects in brain vasculature”
Protein homeostasis	“Altered protein turnover”

Neurological involvement outside the cerebellum

“Various neuropathological abnormalities (e.g. neuronal changes, gliosis and vascular changes) have also been observed in the cerebrum, brain stem and spinal cord.” (opens the source at this quote in a new tab)
“Importantly, the loss of cerebellar cells does not explain all of the neurologic abnormalities seen in people with A-T, and the effects of ATM deficiency on the other areas of the brain outside of the cerebellum are being actively investigated.” (opens the source at this quote in a new tab)

“In A-T, neurophysiological assessment revealed neuropathic changes as early as the first year of life.” (opens the source at this quote in a new tab)

Neuroimaging correlates of cerebellar degeneration

“For the majority of people with A-T, neuroimaging studies in the toddler years and early child years are normal” (opens the source at this quote in a new tab)
“As the disease progresses, MRI studies support the pathological finding of variable, progressive and diffuse cerebellar atrophy” (opens the source at this quote in a new tab)

Serum neurofilament light chain as a marker of neurodegeneration

“We found significantly increased levels of NfL in patients with A-T compared to healthy controls (21.5 ± 3.6 pg/mL vs. 9.3 ± 0.49 pg/mL, p ≤ 0.01). There was a significant correlation of NfL with age, AFP, and SARA.” (opens the source at this quote in a new tab)

ATM functions outside the DNA damage response

“The pathogenesis of A-T is not limited to the role of ATM in the DNA damage response (DDR) pathway, and it has other functions mainly in the hematopoietic cells and neurons. ATM adjusts the functions of organelles such as mitochondria and peroxisomes and also regulates angiogenesis and glucose metabolisms.” (opens the source at this quote in a new tab)

Cellular phenotype and radiosensitivity

“Cells derived from patients with A-T demonstrate sensitivity to ionizing irradiation, chromosomal instability, shortened telomeres, premature senescence and a defective response to DNA double strand breaks (DSBs)” (opens the source at this quote in a new tab)

“Due to impairment of repair of DNA double-strand breaks, individuals with A-T have an increased sensitivity to ionizing radiation (x-ray and gamma ray)” (opens the source at this quote in a new tab)

Mechanisms of lung disease

“Immune dysregulation in A-T can lead to recurrent pneumonia, bronchiectasis and ILD. Poor mucociliary clearance from an inadequate cough and chronic aspiration from impaired bulbar function can increase severity of chronic respiratory symptoms.” (opens the source at this quote in a new tab)

Unexplained alpha-fetoprotein elevation and telangiectasia

“Why the majority of individuals with A-T have elevated levels of AFP remains unknown.” (opens the source at this quote in a new tab)
“The cause of telangiectasia or dilated, enlarged blood vessels in the absence of the ATM protein is not yet known.” (opens the source at this quote in a new tab)