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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

Diagnosis

15 evidence topics · 17 sources

Diagnostic criteria and genetic confirmation

“No consensus clinical diagnostic criteria for ataxia-telangiectasia (A-T) have been published.” (opens the source at this quote in a new tab)

“The diagnosis of A-T is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in ATM identified by molecular genetic testing” (opens the source at this quote in a new tab)

“The diagnosis of A-T is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability) with one or more of the following which may vary in their appearance: telangiectasia, frequent sinopulmonary infections and specific laboratory abnormalities (e.g. IgA deficiency, lymphopenia especially affecting T lymphocytes and increased alpha-fetoprotein levels).” (opens the source at this quote in a new tab)

“A diagnosis of A-T can be confirmed by the finding of an absence or deficiency of the ATM protein or its kinase activity in cultured cell lines, and/or identification of the pathological mutations in the ATM gene.” (opens the source at this quote in a new tab)

Yield of molecular genetic testing of ATM
MethodProportion of pathogenic variants identified
Sequence analysis“90%-95%”
Deletion/duplication analysis“5%-10%”
Serum alpha-fetoprotein

“Serum concentration of alpha-fetoprotein (AFP) is the most important blood biomarker in individuals with classic A-T. In all individuals with classic A-T, serum AFP is elevated (>10 ng/mL, range: 200-1,000 ng/mL)” (opens the source at this quote in a new tab)

“Because serum AFP concentrations are high at birth in all persons and only reach normal values around age two years, it is unreliable as a diagnostic marker in young children” (opens the source at this quote in a new tab)

“We have followed 12 patients (five girls and seven boys) for 1-12 years (mean 5.5 years) measuring in each patient AFP 2-8 (mean 4) times. Serum AFP levels were increased in all patients, mean 168.7 (range 40-373) kU/L, and without significant differences between the patients.” (opens the source at this quote in a new tab)

“A positive linear relationship (r=0.61, p=0.04) could be found between AFP level and age.” (opens the source at this quote in a new tab)

“All 60 tested showed increased sensitivity to ionizing irradiation, 43 of 48 had an elevated alpha-fetoprotein level and 14 of 21 had an immunoglobulin deficiency.” (opens the source at this quote in a new tab)

Alpha-fetoprotein in variant A-T and its relation to severity

“Mean serum AFP was 176 μg/l (range, 2–600; SD, 146) in 45 individuals with a result available. Three (6.6%) had levels in the normal range” (opens the source at this quote in a new tab)

“Although AFP is considered a reliable diagnostic biomarker for the disease, in a small proportion of variant A-T patients, AFP can be normal” (opens the source at this quote in a new tab)

“Furthermore, there is no clear association of AFP levels with disease severity” (opens the source at this quote in a new tab)

Laboratory abnormalities supporting the diagnosis
Test categoryAbnormality as listed
Alpha-fetoprotein“Elevated and slowly increasing serum alpha-fetoprotein levels after two years of age”
Immunology“Low serum levels of immunoglobulins (IgA, IgG, IgG subclasses, IgE) and lymphopenia (particularly affecting T-lymphocytes)”
Cytogenetics“Spontaneous and X-ray induced chromosomal breaks and rearrangements in cultured lymphocytes and fibroblasts”
Radiosensitivity“Reduced survival of cultured lymphocytes and fibroblasts after exposure to ionizing radiation”
Neuroimaging“Cerebellar atrophy detected by MRI”
ATM protein and kinase activity assays

“The diagnosis of A-T can be confirmed by the absence or deficiency of ATM protein and/or ATM kinase activity in cultured cell lines established from lymphocytes or skin biopsies” (opens the source at this quote in a new tab)

“These more specialized tests are not always needed, but are particularly helpful if an individual’s symptoms are atypical.” (opens the source at this quote in a new tab)

“A lymphoblastoid cell line (LCL) is made from the blood sample and a western blot carried out to look for loss of ATM protein.” (opens the source at this quote in a new tab)

“There is a strong phenotype-genotype correlation in A-T and patients with some residual A-T kinase activity generally have a milder clinical course.” (opens the source at this quote in a new tab)

Brain magnetic resonance imaging at presentation

“Most children in whom there is a suspicion of cerebellar ataxia, dystonia, or chorea will have an MRI brain scan, and this will be grossly normal early on in A-T.” (opens the source at this quote in a new tab)

Newborn screening by T-cell receptor excision circles: proportion of classic A-T detected

“Newborn screening (NBS) for severe combined immunodeficiency (SCID), a severe but treatable immunologic disorder, relies on the identification of reduced T-cell receptor excision circle (TREC) levels in blood spots.” (opens the source at this quote in a new tab)

“NBS for SCID most likely identifies about 50% of children with classic A-T” (opens the source at this quote in a new tab)

“Since variant A-T is not associated with immunodeficiencies, NBS for SCID does not detect variant A-T.” (opens the source at this quote in a new tab)

“Of 13 older AT patients for whom newborn DBS had been stored, 7 samples tested positive for SCID under the criteria of California’s newborn screening program.” (opens the source at this quote in a new tab)

“Based on the fact that 24/31 (77.4%) of retrospectively analyzed newborn screening cards of patients with AT were below the cutoff values for an abnormal SCID screening result, we expect that the number of screening-identified AT cases will continue to increase as SCID newborn screening programs expand globally.” (opens the source at this quote in a new tab)

“To date, 15 newborns with an early diagnosis of AT identified after SCID newborn screening have been published” (opens the source at this quote in a new tab)

“AT is not a target disease in NBS programs. Additionally, since the screening is not designed to detect AT, not all patients with AT will be identified through NBS-SCID.” (opens the source at this quote in a new tab)

Newborn screening: cases identified in the Ontario program

“Four patients were diagnosed with AT as a result of low TRECs on NBS.” (opens the source at this quote in a new tab)

“One case was identified per year, while the total rate for SCID has been five new cases per year.” (opens the source at this quote in a new tab)

Parent views on diagnosis in the neonatal phase

“Twenty-six (74%) parents felt that the advantages of an early diagnosis outweighed the disadvantages, five parents thought that the disadvantages would outweigh the advantages (14%), and four parents did not indicate a preference.” (opens the source at this quote in a new tab)

Diagnostic delay and misdiagnosis: United States referral center

“In 48 patients with AT, who were the index cases in their respective families, the median age of diagnosis (78 months) occurred after the onset of gait abnormalities (15 months) and closely corresponded to the development of telangiectasia (72 months).” (opens the source at this quote in a new tab)

“The most common misdiagnosis was cerebral palsy (29/48 cases).” (opens the source at this quote in a new tab)

“We recommend the use of routine serum alpha-fetoprotein testing for all children with persistent ataxia.” (opens the source at this quote in a new tab)

Diagnostic delay: United Kingdom national pediatric clinic

“At presentation, 71 children (90%) had ataxia. The median presentation delay (from first parental concern to presentation) was 8 months (range 0-118 months), and the median diagnostic delay (genetic confirmation of diagnosis) was 12 months (range 1-109 months).” (opens the source at this quote in a new tab)

Age at diagnosis in published cases
GroupMedian (IQR, range) age at diagnosis in months
All cases, 329 cases“72.0 (36.0–120.0, 0.7–720.0)”
Variant cases only, 14 cases“354.0 (231.0–456.0, 24.0–720.0)”
Classical cases only, 315 cases“72.0 (36.0–108.0, 0.7–528.0)”
Diagnostic delay in variant A-T

“There was a diagnostic delay of more than 10 years in 68% and more than 20 years in one third of probands.” (opens the source at this quote in a new tab)

“our data suggest the condition may sometimes be mis‐ or underdiagnosed because of atypical features, including exclusive extrapyramidal symptoms, normal eye movements, and normal alpha‐fetoprotein levels in some individuals.” (opens the source at this quote in a new tab)

“Patients with variant A-T were only correctly diagnosed in adulthood.” (opens the source at this quote in a new tab)

“Measurement of serum alpha-fetoprotein and chromosomal instability precipitates the correct diagnosis.” (opens the source at this quote in a new tab)

Differential diagnosis in early childhood

“In early childhood A-T can mimic cerebral palsy, especially dyskinetic types, cerebellar ataxia from a number of other causes, and developmental co-ordination disorder or developmental dyspraxia.” (opens the source at this quote in a new tab)