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Aqneursa (levacetylleucine)

Ataxia-telangiectasia

Also known as IB1001
Manufacturer
IntraBio
Last updated
206 sources

Product information and disease descriptionPlace of product in therapyDisease description

Natural history, survival, and mortality

25 evidence topics · 28 sources

Course of neurological decline in classic A-T

“In the classic presentation of the disease, ataxia first appears during the toddler stage when children begin to sit and walk.” (opens the source at this quote in a new tab)

“In primary school years, walking becomes more difficult, and children will use doorways and walls for support.” (opens the source at this quote in a new tab)

“Most of these neurologic problems stop progressing after the age of about 12–15 years.” (opens the source at this quote in a new tab)

“Neurological deficits are typically observed during the toddler years resulting in wheelchair dependency around the age of 10.” (opens the source at this quote in a new tab)

“After about age ten years most children with classic A-T require use a wheelchair to compensate for the cerebellar ataxia and extrapyramidal and peripheral nervous manifestations.” (opens the source at this quote in a new tab)

Age at symptom onset and at diagnosis

“Referral centers from 9 Latin American countries participated in this retrospective cohort study, and 218 patients were included. Median (IQR) ages at symptom onset and diagnosis were 1.0 (1.0-2.0) and 5.0 (3.0-8.0) years, respectively.” (opens the source at this quote in a new tab)

“The mean age at which the first neurological symptom was noted was 1.8 ± 1.0 years. The mean age at diagnosis of ataxia telangiectasia was 3.95 ± 2.56 years, and the mean age at the time of walking capacity reporting was 7.97 ± 4.60 years.” (opens the source at this quote in a new tab)

Loss of walking capacity: Global A-T Family Data Platform

“Children with ataxia telangiectasia who presented with neurological symptoms at 5 years of age or younger and were 18 years of age or younger at the time of walking capacity reporting were included.” (opens the source at this quote in a new tab)

“Mean walking capacity scores from 372 participants remained stable until age 5, followed by progressive worsening between ages 5 and 14, with persistently high scores thereafter.” (opens the source at this quote in a new tab)

“the majority of patients reported walking independently all or most of the time (225/372, 60.5%); 72/372 (19.3%) reported needing assistance for walking, while 75/372 (20.2%) used a wheelchair.” (opens the source at this quote in a new tab)

“The mean age at which wheelchair dependence developed was 13.5 years.” (opens the source at this quote in a new tab)

“We could not control for disease severity, as genetic confirmation and ATM kinase activity data were not available.” (opens the source at this quote in a new tab)

Mean age by walking capacity category: Global A-T Family Data Platform
Walking capacity categoryMean age and number of participants
Walks independently“5.0 ± 2.7 years (N = 170)”
Walks independently most of the time“6.6 ± 3.5 years (N = 55)”
Needs assistance for long trips“10.3 ± 3.7 years (N = 62)”
Walks with bilateral support“10.1 ± 2.7 years (N = 10)”
Uses wheelchair without assistance“14.2 ± 2.5 (N = 9)”
Uses wheelchair with assistance“13.4 ± 3.2 (N = 66)”
Age at wheelchair use in national and referral cohorts

“The mean age of loss of walking was 10 years and of writing 8 years.” (opens the source at this quote in a new tab)

“Thirty one patients (34.1%) became dependent on wheelchair at a mean age of 12.1±2.8 years. Eleven patients (12.1%) became bedridden by a mean age of 14.7±1.8 years.” (opens the source at this quote in a new tab)

“Most of the patients in this cohort were severely affected by ataxia and wheelchair use started at a median age of 9 years.” (opens the source at this quote in a new tab)

“In keeping with the existing view, we found that the median reported age of wheelchair requirement is 10 years. This requirement comes considerably later, by 26–27 years, in those with variant A-T.” (opens the source at this quote in a new tab)

Rate of change on the Scale for the Assessment and Rating of Ataxia in adults

“We analysed longitudinal Scale for the Assessment and Rating of Ataxia (SARA) data from the largest published adult AT cohort to date (n = 82, age > 16 years).” (opens the source at this quote in a new tab)

“Neurological impairment progressed with a mean SARA increase of 0.38 points/year. Adults with classic AT were more severely affected than those with variant AT, with SARA scores approximately 8-9 points higher at baseline. However, neurological progression in adulthood was similar between classic and variant AT (0.33 vs 0.41 points per year), which includes 15 individuals with the antisense oligonucleotide targetable c.5763-1050A>G variant.” (opens the source at this quote in a new tab)

“SARA remains a useful outcome measure but may underestimate progression in advanced disease and non-cerebellar domains.” (opens the source at this quote in a new tab)

SARA scores by disease form

“Ataxia was present in all patients except one (p13) and with increased severity in those with classical A-T as shown by a median SARA score of 30 for these 12 patients compared to a median score of nine for the two with vA-T.” (opens the source at this quote in a new tab)

SARA and A-T NEST score ranges by functional severity in variant A-T
Severity classFunctional definition and score ranges
Mild“Individuals still ambulant with/without a walking aid and could use the upper limbs for most activities without help. A‐T NEST scores within this group were > 55, SARA scores <22.”
Moderate“Individuals used a wheelchair frequently, but were able to transfer, walk a few steps with help, and use the upper limbs for most activities, such as feeding themselves. A‐T NEST scores within the moderate group were 42 to 75, SARA scores 15 to 33.”
Severe“Individuals were permanently wheelchair bound, were unable to transfer unaided, and had significant limitation of upper limb function, requiring assistance with most activities of daily living. A‐T NEST scores within this group were < 46, SARA scores >30.”
Structure of SARA and its limitations in A-T

“It assesses 8 domains: gait, stance, sitting ability, speech disturbance, finger chase, nose-finger test, fast alternating hand movements and heel-shin slide. It carries a maximum score of 40 with higher scores indicating more severe ataxia symptoms” (opens the source at this quote in a new tab)

“However, the SARA score remains unvalidated specifically for use in A-T and is not without its limitations.” (opens the source at this quote in a new tab)

“Many classical A-T patients lose ambulation by their teenage years, and it is unclear how this influences the assessment of disease progression in non-ambulant patients who continue to report clinical deterioration” (opens the source at this quote in a new tab)

“The medical records of 55 individuals (males = 27, females = 28) with genetically confirmed diagnoses of A-T who attended the National Adult A-T Clinic at Royal Papworth Hospital over a 7-year period were retrospectively reviewed in a longitudinal manner.” (opens the source at this quote in a new tab)

“The A-T NEST correlates strongly with the SARA score at the single timepoint level and changes proportionally with the SARA score longitudinally which demonstrates its ability to track the severity of the disease over time.” (opens the source at this quote in a new tab)

“Even in advanced stages of A-T, the scores lose their value, since the course of the disease for patients who are already wheelchair-bound becomes gradually more difficult to quantify by an increase in points.” (opens the source at this quote in a new tab)

“The SARA score was available from 28 A-T patients and correlated significantly with NfL (r = 0.41, p ≤ 0.05)” (opens the source at this quote in a new tab)

A-T Index and A-T NEST: relation to age and individual progression

“The overall index was applied to 52 patients with A-T, 2 to 29 years of age.” (opens the source at this quote in a new tab)

“In a linear regression model of individuals under 19 years of age, controlled for correlation within sibships, age accounted for 87% of the variation in the A-T Index.” (opens the source at this quote in a new tab)

“Neurological assessments were performed using the A-T Index (Crawford Score) and the A-T Neurological Examination Scale Toolkit (A-T NEST).” (opens the source at this quote in a new tab)

“Unlike the per-genotype analysis, the individual progression of neurological scores in the 34 patients that attended on three or more occasions was not smooth and linear (and in some cases improved over time).” (opens the source at this quote in a new tab)

“Residual kinase activity confers a milder phenotype but there is no difference between kinase-dead and protein-null genotypes.” (opens the source at this quote in a new tab)

International Cooperative Ataxia Rating Scale scores in a pediatric cohort

“We recruited 63 patients with ataxia, aged 10.76 ± 3.2 years, followed at 6 international AT centers, 49 of them (77.8%) with classical AT.” (opens the source at this quote in a new tab)

“Mean ICARS score was 44.7 ± 20.52, and it's severity positively correlated with age (Spearman correlation, r = 0.46, p < 0.01).” (opens the source at this quote in a new tab)

Median survival: United States cohorts

“In the prospective ATCC cohort, median survival is calculated to be 25 years (fig 1). In the retrospective ATCP cohort, median survival is 19 years (fig 2).” (opens the source at this quote in a new tab)

“Mortality crossed the 25th and 75th centiles in the prospective ATCC cohort at ages 18 and 28, and at ages 14 and 28 in the retrospective ATCP cohort.” (opens the source at this quote in a new tab)

“The median date of death in the ATCP cohort was 1993, compared with the median date of death in the ATCC cohort of 2001.” (opens the source at this quote in a new tab)

“Life expectancy does not correlate well with severity of neurological impairment.” (opens the source at this quote in a new tab)

Causes of death: Johns Hopkins prospective cohort

“There were 24 deaths through the end of 2004.” (opens the source at this quote in a new tab)

“nine apparently died of complications of chemotherapy or cancer, seven of pneumonia, four had significant acute neurological deterioration associated with multiple CNS telangiectatic vascular abnormalities, two died from sudden unknown causes, and two died from complications of chronic lung disease.” (opens the source at this quote in a new tab)

“Hence most deaths should be considered to be the result of a complication of ataxia telangiectasia rather than an inevitable consequence of severe neurological debilitation.” (opens the source at this quote in a new tab)

Survival and risk factors for death: French national cohort

“We performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzed ATM mutations in 184 patients, along with neurologic manifestations, infections, and cancers.” (opens the source at this quote in a new tab)

“Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954.” (opens the source at this quote in a new tab)

“Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality.” (opens the source at this quote in a new tab)

“Cancer (hazard ratio, 5.8; 95% CI, 2.9-11.6) was a major risk factor for mortality among patients with null mutations, whereas respiratory tract infections (hazard ratio, 4.1; 95% CI, 1.8-9.1) were the leading cause of death among patients with hypomorphic mutations.” (opens the source at this quote in a new tab)

Survival: Latin American multicenter cohort

“Mean survival was 24.2 years, and Kaplan-Meier 20-year-survival rate was 52.6%, with higher mortality associated with female gender and low IgG levels.” (opens the source at this quote in a new tab)

Survival: German single-center cohort

“Our study includes 69 A-T patients between 8 January 2002 and 1 December 2019.” (opens the source at this quote in a new tab)

“The 15-year OS of 82·5% (72-95%) was significantly decreased among A-T patients with malignancies, who had a median OS of 2·11 years, with a two-year-estimated OS of 50·7% (31-82%).” (opens the source at this quote in a new tab)

Survival by phenotype and immunological status: Dutch cohort

“This retrospective cohort study of 61 AT patients shows that classical AT patients had a shorter survival than variant patients (HR 5.9, 95%CI 2.0-17.7), especially once a malignancy was diagnosed (HR 2.5, 95%CI 1.1-5.5, compared to classical AT patients without malignancy).” (opens the source at this quote in a new tab)

“Patients with the hyper IgM phenotype with hypogammaglobulinemia (AT-HIGM) and patients with an IgG2 deficiency showed decreased survival compared to patients with normal IgG (HR 9.2, 95%CI 3.2-26.5) and patients with normal IgG2 levels (HR 7.8, 95%CI 1.7-36.2), respectively.” (opens the source at this quote in a new tab)

Survival, IgA deficiency, and causes of death: European Society for Immunodeficiencies registry

“As shown in Fig. 1, A-T patients with deficient IgA died significantly earlier than patients with no deficient IgA (p < 0.0001). The corresponding hazard ratio (HR) for patients with IgA deficiency compared to those with IgA-levels greater than 0.07 g/L was 1.9 (1.34–2.77).” (opens the source at this quote in a new tab)

“Data about the cause of death was available from 60 A-T patients with available IgA values in the ESID registry and the patients from the Frankfurt cohort (Fig. S2). Of these, 27 died from respiratory failure, 29 died from cancer, and 4 died for other reasons.” (opens the source at this quote in a new tab)

Deaths and causes of death: Italian Primary Immunodeficiency Network cohort

“Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network.” (opens the source at this quote in a new tab)

“At the end of the Fup, 11 patients were dead at a mean age ± SD of 22.4 ± 6.5 years. Causes of death were severe pneumonia (n = 6), pneumonia + malignancy (n = 2), and malignancy (n = 3).” (opens the source at this quote in a new tab)

Age at death and causes of death: systematic review of published cases

“687 cases reported 752 causes of death among which malignancy was the most frequently reported cause. Median (IQR, range) age of death (n = 294) was 14 years 0 months (10 years 0 months to 23 years 3 months, 1 year 3 months to 76 years 0 months).” (opens the source at this quote in a new tab)

“As expected, median age of death was lower in classical cases (14 years 0 months) compared to variant cases (48 years 0 months), likely due to no ATM protein kinase activity resulting in a more severe phenotype in classical cases.” (opens the source at this quote in a new tab)

“Predominance of case reports, and case series demonstrate the lack of robust evidence to determine the natural history of A-T.” (opens the source at this quote in a new tab)

Excess mortality relative to the general population

“The standardized mortality ratio was 24.6 (95% CI, 21.1–28.4) overall and 232.9 (95% CI,178.1–299.2) among individuals with cancer.” (opens the source at this quote in a new tab)

“For white and black A-T patients, respectively, all-cause mortality was 50 and 147 times higher than expected based on U.S. mortality rates.” (opens the source at this quote in a new tab)

Life expectancy and leading causes of death

“The two most common causes of death are chronic lung disease (about one-third of cases) and cancer (about one-third of cases).” (opens the source at this quote in a new tab)

“Life expectancy in classic A-T is significantly reduced due to cancer, pulmonary disease, and infections. Most affected individuals do not live longer than age 30 years” (opens the source at this quote in a new tab)

“Individuals with the hyper IgM phenotype of classic A-T have a poorer prognosis than individuals with classic A-T, and most die before age 15 years due to respiratory failure” (opens the source at this quote in a new tab)

Survival after a cancer diagnosis

“Overall survival was shorter in patients with AT who developed cancer compared with those who did not develop cancer (15 v 24 years, respectively; P < .001).” (opens the source at this quote in a new tab)

Course of variant A-T

“The study includes 57 individuals. Mean age at assessment was 37.5 years. Most had their first symptoms by age 10 (81%).” (opens the source at this quote in a new tab)

“Disease severity was mild in one third of patients, and 43% were still ambulant 20 years after disease onset.” (opens the source at this quote in a new tab)

“Forty‐two individuals used a wheelchair and 15 were still ambulant. Median age at first getting a wheelchair was 20 years (range, 8–51; Fig 1C).” (opens the source at this quote in a new tab)

“The longer life expectancy in variant A-T than in classic A-T can be attributed to less progressive neurologic decline, typical absence of respiratory and immunologic features, and older age of occurrence of malignancies” (opens the source at this quote in a new tab)

Classic A-T beyond 30 years of age

“In the Dutch cohort, seven classic A–T patients survived beyond 30 years of age. Fourteen additional patients were retrieved by the literature search.” (opens the source at this quote in a new tab)

“Most patients had pulmonary, endocrine, cardiovascular, and gastro-intestinal problems. All patients had a tetraparesis with contractures. This led to immobilization and frequent hospital admissions.” (opens the source at this quote in a new tab)

“One patient died before the age of 30 years, but five patients had survived beyond this age.” (opens the source at this quote in a new tab)