Journal of the Neurological Sciences 371 (2016) 48–53

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Journal of the Neurological Sciences
journal homepage: www.elsevier.com/locate/jns

Clinical Short Communication

Novel compound heterozygous mutations in a child with
Ataxia-Telangiectasia showing unrelated cerebellar disorders
Maria Piane a,⁎, Anna Molinaro b, Annarosa Soresina c, Silvia Costa b, Marianna Maffeis c, Aldo Germani a,
Lorenzo Pinelli d, Roberta Meschini e, Alessandro Plebani c, Luciana Chessa a, Roberto Micheli b
a

Department of Clinical and Molecular Medicine, “Sapienza” University of Roma, Italy
Unit of Child Neurology and Psychiatry, Spedali Civili and University of Brescia, Brescia, Italy
Department of Pediatrics, Spedali Civili and University of Brescia, Brescia, Italy
d
Department of Neuroradiology, Spedali Civili, Brescia, Italy
e
Department of Ecological and Biological Sciences, University of Tuscia, Viterbo, Italy
b
c

a r t i c l e

i n f o

Article history:
Received 6 October 2015
Received in revised form 10 October 2016
Accepted 11 October 2016
Available online 13 October 2016
Keywords:
Ataxia-Telangiectasia
Low-grade cerebellar astrocytoma
Ischemic stroke
ATM gene

a b s t r a c t
We report the case of a 6-year-old female patient with Ataxia Telangiectasia, an extremely rare condition, who
developed in addition a left cerebellar astrocytoma and a right cerebellar infarction, considered as two independent events. Children with AT have an increased risk of developing cancer, but only few cases of glioma are
reported and, at our knowledge, no other case of unrelated cerebellar glioma and cerebellar infarction in with
the same AT patient have been described. The molecular analysis of ATM (Ataxia Telangiectasia Mutated) gene
showed that the patient is compound heterozygote for two previously unreported mutations: c.3291delC
(p.Phe1097fs) at exon 25 and c.8198ANC (p.Gln2733Pro) at exon 58. The role of the identified ATM gene mutations in the pathogenesis of Ataxia Telangiectasia and the coexisting cerebellar disorders is discussed.
© 2016 Published by Elsevier B.V.

1. Introduction
Ataxia Telangiectasia [AT] is a rare, progressive neurodegenerative
disorder caused by biallelic mutations in the ATM gene, located at
11q22–23 [1]. Homozygosity or compound heterozygosity for ATM mutations results in a multisystemic disorder, mainly involving nervous
and immune system. AT patients showing the classical phenotype present with early onset ataxia, oculocutaneous telangiectasias, immunodeficiency, recurrent sinopulmonary infections, radiosensitivity and
increased proneness to cancer, ranging from 10% to 25% [2,3,4]. The
mechanism of malignancy in AT is considered primarily related to impaired DNA damage repair and genomic instability; however, the role
of the various functions of ATM remain unclear. The most common malignancies in AT are hematologic tumours, with a temporal difference in
the incidence of various cancers: acute lymphoblastic leukemias and
Hodgkin lymphoma occur up to age 20 years, T-cell prolymphocytic leukemia and also solid tumours (breast, gastric, liver and thyroid) occur
from age 20 years onward; the non-Hodgkin lymphoma shows a
Abbreviations: AT, Ataxia Telangiectasia; ATM, Ataxia Telangiectasia Mutated gene;
ATM, Ataxia Telangiectasia Mutated protein; CNS, Central Nervous System; LCLs,
lymphoblastoid cell lines; MRI, magnetic resonance imaging; PBS, Phosphate Buffer
Solution; PCR, Polymerase Chain Reaction; WB, Western Blot; IRIF, Irradiation-induced
Foci.
⁎ Corresponding author.
E-mail address: maria.piane@uniroma1.it (M. Piane).

http://dx.doi.org/10.1016/j.jns.2016.10.014
0022-510X/© 2016 Published by Elsevier B.V.

continuous pattern of occurrence, starting before 10 years of age [5].
Only few cases of CNS cancer have been reported [6,7,8]. Here we
describe the case of a 6-year-old girl with Ataxia Telangiectasia who
developed a left cerebellar astrocytoma and a contralateral cerebellar
infarction, the latter a previously unreported feature of AT. The possible
coexistence of the two pathologies in relation to the ATM mutations
identified in the proband is discussed.
2. Material and methods
2.1. Case study
A 2-year-old female, who had uneventful antenatal and birth history, was referred to the Unit of Child Neurology of Spedali Civili, Brescia,
Italy, for gait disturbance. On neurologic examination, ataxic gait and
oculomotor apraxia were noted; laboratory examination revealed elevated serum α-fetoprotein level (20 IU/ml). Following the clinical suspicion of AT, ATM gene sequencing was performed; the detection of a
compound heterozygous genotype c.[3291delC];[8198AN C] confirmed
the clinical diagnosis of Ataxia Telangiectasia. A brain magnetic resonance imaging (MRI) showed a small intraxial lesion in the cortex of
the left cerebellar hemisphere, approximately 1 cm in diameter, with
nodular enhancement after i.v. contrast medium administration and
without mass effect (Fig. 1A and D); the lesion appeared stable on
short-term MRI follow-up (2 months). The main diagnostic hypotheses

M. Piane et al. / Journal of the Neurological Sciences 371 (2016) 48–53

49

Fig. 1. Brain MRI, axial T2-weighted images (A, B, C) and coronal T1-weighted images after i.v. paramagnetic contrast medium administration (D, E, F). The first examination (September
2008, images A and D) shows a small intraxial lesion (thick arrows) in the cortex of the left cerebellar hemisphere, without mass effect, and with nodular enhancement after i.v. contrast
medium administration. The main diagnostic hypotheses are a glial tumour, an inflammatory lesion, or a slow flow vascular malformation (capillary telangiectasia). In the second
examination (September 2012, images B and E) the nodular enhancement in the left cerebellar hemisphere has grown and it is associated to a cyst with CSF-like signal: the findings
are typical for pilocytic astrocytoma. In the post-surgery brain MRI (May 2013, images C and F) the pilocytic astrocytoma in the left cerebellar hemisphere is no longer visible (the
small signal abnormality with faint enhancement [thin arrow] is a normal post-operative finding). A new lesion with CSF-like signal intensity, sharp margins, no mass effect and no
enhancement after i.v. contrast medium administration appeared in the contralateral cerebellar hemisphere and adjacent vermis: the findings are consistent with focal cerebellar
malacia, possibly due to a previous infarction.

were a glial tumour, an inflammatory/demyelinating lesion, or a slow
flow vascular malformation (capillary telangiectasia) Longitudinal
neurological and immunological evaluations with no signs of disease
progression were performed up to the age of 6 years, when a followup brain MRI showed the enlargement of the lesion, with appearance
of a cystic component and clear mass effect (Fig. 1B and E), consistent
with a diagnosis of low-grade glioma. The patient underwent a complete surgical resection and a histologic diagnosis of pilocytic astrocytoma was achieved. The child quickly recovered from surgery, but 5
months later acute dysarthria and a worsening in ataxia, spontaneously
resolved in 3 days, were noted. Brain MRI performed 1 month later revealed a malacic area in the right cerebellar hemisphere, contralateral
to the resected glioma, consistent with a previous ischemic stroke (IS)
(Fig. 1C and F). Common risk factor for IS, both genetic and acquired,
were excluded.

bwh.harvard.edu/pph2/), SIFT (Sort in intollerant from tollerant:
http://sift.jcvi.org), Mutation Taster (http://www.mutationtaster.org)
and Align-GVGD (Align-Grantham Variation Grantham Deviation:
http://agvgd.iarc.fr/agvgd_input.php).

2.3. ATM level and kinase assay
ATM level and function were determined by Western Blot analysis
(WB). Protein lysates were obtained from Epstein Barr virus-transformed lymphoblastoid cell lines (LCLs) of the AT proband, parents
and control. LCLs were cultured in RPMI 1640 medium containing 20%

2.2. Molecular study
Genomic DNA was extracted from peripheral blood lymphocytes
using standard organic extraction procedures. To screen for mutations
in the ATM gene, all the exons and splice junctions were amplified
using the primers designed by Bernstein et al. [9]. PCR reactions for
direct sequencing of 50 ng of genomic DNA were done in 25 μl volumes
containing 100 mM each of dNTPs, 0.15 mM of each primer and
0.70 units of Taq DNA polymerase (Perkin-Elmer/ABI) in PCR buffer.
Purified PCR products were sequenced using the BigDye Terminator
chemistry and an ABI Prism 3100 automated DNA sequencer (Applied
Biosystems, Foster City, CA). Mutations were named based on cDNA
reference sequence U82828, with 1 + being the A of the initiation
start codon. Prediction of mutations pathogenicity was performed
using PolyPhen-2 (Polymorphism Phenotyping v2: http://genetics.

Fig. 2. Pedigree of the proband's family. The filled symbol denotes the affected patient who
is compound heterozygous c.[3291delC];[8198ANC] in ATM gene, each of them inherited
from one of the parents. The parents are heterozygous carriers (half-filled symbol): I:2
heterozygous for c.3291delC mutation and I:3 heterozygous for c.8198A NC. Square
symbols denote males, the circles denote females. NA = not analyzed. c.[=];[=]
referred to II:1 and II:3, genotyped for mutations, denote normal coding DNA reference
sequence on both chromosomes.

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M. Piane et al. / Journal of the Neurological Sciences 371 (2016) 48–53

Fig. 3. Molecular study. (A) Western Blot analysis of ATM protein in LCLs lysates from: normal control, lanes 5 and 7; mother (I:3), lane 1; AT proband (II:2), lane 2; father (I:2), lane 3;
brother (II:3) lane 4; AT control, lane 6. MagicMark (Invitrogen) lane 8. (B) Sequencing analysis. The mutations on electropherograms are indicated with black arrows.

foetal calf serum (Gibco BRL), 2 mM L-glutamine, 100 U/ml Hepes buffer
(Fluka) and 100 U/ml streptomycin and maintained in a 37 °C incubator
(Forma Scientific) in a 5% CO2 atmosphere and 100% nominal humidity.
To test whether expressed ATM protein was functional, the autophosphorylation of ATM-Ser1981 and phosphorylation p53Ser15 were determined by WB and phosphorylation of γ-H2AX by Irradiationinduced Foci (IRIF) assay. Cells were X irradiated in a Gilardoni RadGil
instrument at a dose rate of 5 Gy and harvested after 1 h. Untreated
and treated cells were washed with PBS plus 1 mM Na3VO4, pelleted

and lysed with RIPA buffer supplemented with Complete Mini EDTAfree protease Cocktail and PhosStop phosphatase inhibitor tablet cocktail (Roche Diagnostics, Burgess Hill, UK). Aliquots containing proteins
(10 to 50 μg/ml) were size fractionated by Tris Acetate 3–8% gel electrophoresis (Invitrogen). After blocking with 5% BSA in phosphate-buffered saline plus 0.1% Tween (Invitrogen), the membranes were
incubated with polyclonal antibody to ATM (a gift of D. Delia), ATM
(phospho S1981) (AbCam 2888), Phospho-p53 (Cell Signaling 9284),
anti-β-actin (A2066 SIGMA) and anti-vinculin (V9131 SIGMA) for

Fig. 4. Western Blot showing levels of ATM kinase activity in lysates from AT proband compared whit AT and normal control. There are two lanes for each cell line, dependent on the
absence (−) or presence (+) of ATM kinase activation by exposure of cells to 5 Gy. Normal cells show activation of ATM kinase by autophosphorylation of ATM Ser1981, and
phosphorylation of p53Ser15. AT patient's cells show neither autophosphorylation of ATM Ser1981 nor ATM kinase activity for failure to phosphorylation of p53.

M. Piane et al. / Journal of the Neurological Sciences 371 (2016) 48–53

normalisation. After incubation with a peroxidase conjugated secondary
antibody, the immunoreactive bands were visualised by ECL
Supersignal on autoradiographic films. To examine by immunofluorescence the IRIF of γ-H2AX 1 h after irradiation (5 Gy) aliquot of the II:2,
AT and normal control LCLs unirradiated an irradiated were resuspended in 70% ethanol and maintained at 20 °C until the time of γH2AX immunostaining and analysis. After fixation the cells were
washed with TST (Tris-HCl pH 7.5 plus 4% foetal bovine serum and
0.1% Triton X-100) and incubated for 1 h at 37 °C with antiphosphoH2AX monoclonal antibody (Millipore) diluted 1:500 in TST. After,
cells were rinsed twice in TBS (Tris-HCl pH 7.5 plus 2% foetal bovine
serum) and incubated for 1 h at 37 °C with goat anti-mouse IgG conjugated with FITC (Molecular Probes, Eugene OR, USA) diluted 1:500. Finally, after two washing in TBS, cells were counterstained with
Vectashield with 0.2 μg/ml 4′,6-diamidino-2-phenylindole (DAPI, Vector Laboratories, Inc. Burlingame, CA, USA). Slides were analyzed using
an Olympus fluorescence microscope at 1000 magnification. Nuclei
were classified as γ-H2AX positive or negative, positive nuclei being
those with at least one large focus or a granular pattern of green

51

fluorescence. The analysis of the significance for γ-H2AX foci and of
the effect of the X-rays versus the control samples was performed
with the Student's t-test (ts) for paired samples (p b 0.01).

3. Results
At sequencing the patient was found to be compound heterozygote
c.[3291delC];[8198ANC] for two mutations in ATM gene (Fig. 3B), never
described previously in AT patients (http://chromium.liacs.nl/LOVD2/
home.php, http://www.hgmd.cf.ac.uk/ac/index.php). The c.3291delC
mutation located in exon 25 of ATM gene is predicted to lead to a frameshift with a premature termination codon (p.Phe1097fs), resulting in a
truncated protein. The missense mutation c.8198AN C in exon 58 leads
to a Gln to Pro non-synonymous substitution at position 2733
(p.Gln2733Pro) in the phosphatidyl-inositol-3 kinase domain of ATM
protein. Scores from SIFT, Polyphen and Mutation Taster (0.00, 0.903
and 76 respectively) were indicative of a deleterious variant. In contrast,
Align-GVGD predicts this missense mutation as neutral (Class C0).

Fig. 5. Irradiation-induced Foci (IRIF) within 1 h after 5 Gy irradiated cell. γ-H2AX foci in LCLs from normal control (A, B), AT control (C, D), AT proband II:2 (E, F).

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M. Piane et al. / Journal of the Neurological Sciences 371 (2016) 48–53

WB for ATM protein expression showed a band of 360 kDa corresponding to the size of ATM protein in normal control cell line. The
cells from the AT proband (II:2) when compared with the normal control show an amount of 50% of ATM protein. The analysis was performed
also in the cells from the patient's father (I:2), heterozygous for the
c.3291delC null mutation, and from the mother (I:3), heterozygous for
the c.8198ANC missense mutation; they showed respectively 50% and
normal amount of ATM protein (Fig. 3A). The kinase assay performed
by WB on LCLs from the proband and controls at 1 h after a dose of
5 Gy X-rays showed no detectable ATM pSer1981 autophosphorylation
and absence of phosphorylation in p53 Ser15 in the proband (Fig. 4).
The phosphorylation of H2AX was performed in normal control, AT control and AT proband (II:2) LCLs at 1 h after a dose of 5 Gy X-rays. Respect
to their relative un-irradiated controls, the irradiated samples (Fig. 5)
show a statistically significant (p b 0.01) induction of γ-H2AX foci/cell
only in the wild type cell line, while in both the AT control and in the
AT proband cell lines no increase was observed (Fig. 6).
4. Discussion
The increased risk of developing cancer in AT patients has triggered
several investigations on the role of ATM mutations in the pathogenesis
of neoplastic lesions both in patients and in sporadic tumours. It is well
known that ATM protein plays a key role in regulating the cell cycle and
repairing DNA double-strand breaks (DSBs) [10,11,12]. Errors in the repair of DSBs, the major form of DNA damage, give rise to small deletions
or insertions at the lesion site that may result in chromosomal translocations and genomic instability and finally in cancer [12].
In our patient the sequencing of ATM gene showed a compound heterozygous genotype c.[3291delC];[8198ANC] for a null and a missense
mutation (Fig. 3B). At our knowledge, none of these mutations have
been previously reported in AT patients. The c.3291delC (Fig. 2C) is a
frameshift mutation in the exon 25 of ATM gene predicted to lead to
the premature termination of the translation (p.Phe1097fs), resulting
in the absence of expression of ATM protein. Cells from the proband's father, heterozygous for this mutation, showed only 50% of the normal
amount of ATM protein, consistent with the presence of a null allele
(Fig. 3A).
The second mutation was an A to C transition at nucleotide 8198 in
exon 58 (Fig. 3B) that leads to a glutamine to proline substitution

Fig. 6. Induction of γ-H2AX foci in LCLs from AT proband (II:2), AT and normal control.
Histogram showing the level of induction of γ-H2AX foci; the columns represent the
mean value of positive cells from un-irradiated and irradiated control cells and AT
proband at 1 h after 5Gy irradiation. *Student's t-test, X-rays versus control, p b 0.01.

(p.Gln2733Pro) in the PI3-kinase domain of ATM protein. This mutation
is not present in 200 control chromosomes that we have screened by
DHPLC analysis. Using Align-GVGD algorithm, which predicts substitution effects based on assessment of chemical dissimilarity between residues and phylogenetic conservation, this variant is considered unlikely
to be pathogenic (Class C0), but in silico tools SIFT, Polyphen and
Mutation Taster classify this mutation as probably damaging and not
tolerated. LCLs derived from our proband show the presence of mutant
ATM protein (Fig. 3A) without detectable kinase activity. Fig. 4 shows
the absence of autophosphorylation at ATM Ser1981 and the absence
of phosphorylation in p53Ser15 in the proband cell line when compared
to AT and normal control. The results of X-ray-induction of γ-H2AX detected by immunocytochemistry and fluorescence microscopy in the
LCLs clearly show an enhancement of γ-H2AX foci in presence of a functional ATM protein and no induction when ATM is absent, as well as in
the cell line with the missense/truncation mutations. The phenotypic
manifestations in Ataxia Telangiectasia show a continuous spectrum
from severe classical AT to a relatively mild disorder depending on the
presence of ATM protein and kinase activity. The allelic heterogeneity
in ATM gene results in clinical heterogeneity: age of onset, clinical presentation, occurrence and type of tumours in AT patients depends on
the type of mutations and retention or absence of kinase activity of
ATM protein [13,14]. The development of tumours in childhood (lymphoid and brain) is associated almost exclusively with absence of ATM
kinase activity [15].
The cancer predisposition particularly to lymphoid tumours in AT
has been known since the time of the full description of the disorder.
In a retrospective analysis of 279 AT patients were reported 69 patients
(24.5%) with cancer, the majority hematologic cancers [5]. Reiman et al.
[15] presented similar observations, with cancer occurring in 25% of 296
AT patients analyzed; primarily lymphoma or leukemia, but also breast,
gastric and other solid tumours. The reported incidence of various cancer types in AT is 13% for non-Hodgkin's lymphoma, 2–8% for leukemia,
4% for Hodgkin's lymphoma, 2–3% for breast cancer, b 1% for pancreatic
carcinoma, b1% for thyroid carcinoma. Single case of adenocarcinoma of
stomach, dysgerminoma, gonadoblastoma, medulloblastoma and colon
cancer were described [5,15,16,17].
In our study we present the case of a young AT patient with a left cerebellar astrocytoma and a right cerebellar infarction. Approximately
one-third of AT patients develop a malignancy during their lifetimes,
usually with a characteristic trend: hematopoietic and lymphoid neoplasms account for the majority of neoplastic lesions in younger patients, while a wide range of solid tumours have been reported after
the first 15 years of life (dysgerminomas, breast, gastric, pancreatic
and hepatic carcinomas) [7,8]. Our AT patient developed a primary
CNS tumour earlier than the expected age, since it was already detected
by the first MRI when she was 1y7m old. Moreover, though low-grade
cerebellar astrocytomas represent 12–18% of all paediatric brain
tumours [18], they are an uncommon condition in patients with AT
[15]. Concerning the CNS, at our knowledge only few cases of medulloblastoma, craniopharyngioma and glioma have been reported in the literature as associated with AT [6,7,8]. After 5 months from the complete
surgical resection and recovery, our patient developed an ischemic
infarction in the contralateral cerebellar hemisphere, considered as an
independent event, as the post-operative brain CT performed the
same day of surgery did not show any hematoma or ischemia in the
right cerebellar hemisphere.
This study reports for the first time a case of AT young patient with
cerebellar astrocytoma complicated by contralateral cerebellar infarction and expands the phenotypic and mutational spectrum of Ataxia
Telangiectasia.
Funding
The financial support of Sparks (grant 14SAP01 to L.C.) is
acknowledged.

M. Piane et al. / Journal of the Neurological Sciences 371 (2016) 48–53

Conflict of interest
The authors report no conflicts of interest.
Acknowledgments
The authors thank Camilla Savio for technical support in immunoblotting and sequencing analysis.
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