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

Regulatory description of the disease

“Ataxia-telangiectasia is a rare, inherited neurodegenerative disorder caused by mutations in the ATM gene. It primarily affects the nervous system, causing progressive loss of muscle control and coordination (ataxia) that typically begins in early childhood. The disease also causes small dilated blood vessels (telangiectasias), immune deficiencies, and an elevated risk of cancer.” (opens the source at this quote in a new tab)

Clinical definition

“Ataxia telangiectasia (A-T) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. A-T is often referred to as a genome instability or DNA damage response syndrome.” (opens the source at this quote in a new tab)
“A-T is a complex disorder with substantial variability in the severity of features between affected individuals, and at different ages.” (opens the source at this quote in a new tab)

ATM gene and protein

“The mode of inheritance for A-T is autosomal recessive. A-T is caused by mutations in the ATM (ataxia telangiectasia, mutated) gene which was cloned by Savitsky et al. in 1995” (opens the source at this quote in a new tab)
“ATM is located on human chromosome 11q22-q23” (opens the source at this quote in a new tab)
“The ATM gene encodes a large 3056 amino acid protein of the same name whose best known, and arguably most well understood, role is coordinating the cellular response to DNA DSBs.” (opens the source at this quote in a new tab)

Autosomal recessive inheritance and recurrence risk

“A-T is caused by biallelic pathogenic variants in ATM and inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ATM pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and having A-T, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial ATM pathogenic variants.” (opens the source at this quote in a new tab)

Classic and variant forms

“The phenotypic spectrum of ataxia-telangiectasia (A-T), a multisystem disorder, is a continuum ranging from classic A-T at the severe end and variant A-T at the milder end. Nonetheless, distinguishing between classic A-T and variant A-T on this spectrum helps understand differences in disease course, rate of progression, and life expectancy.” (opens the source at this quote in a new tab)

“People with mild A-T present with less severe, later onset manifestations associated with longer survival” (opens the source at this quote in a new tab)

Genotype and residual ATM kinase activity

“To study genotype-phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A-T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype.” (opens the source at this quote in a new tab)
“Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan.” (opens the source at this quote in a new tab)
“The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity.” (opens the source at this quote in a new tab)

“In general, nonsense and/or frameshift variants lead to the classic A-T phenotype, whereas missense and splice site variants are more typically associated with variant A-T.” (opens the source at this quote in a new tab)

Proportion of cases with a variant form

“It appears that approximately one case in three of A-T in the UK is of a mild-variant form (compared to an estimated one in five in other parts of the world).” (opens the source at this quote in a new tab)

Heterozygous carriers

“Although individuals heterozygous for an ATM pathogenic variant are not at risk for A-T, their risk of developing cancer is increased compared to that of the general population (in particular, heterozygous females have an increased risk of developing breast cancer).” (opens the source at this quote in a new tab)