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Ataxia-telangiectasia (A-T) is an autosomal recessive
genomic instability syndrome characterized by progressive
cerebellar ataxia, oculocutaneous telangiectasias, immuno-
deficiency, hypersensitivity to ionizing radiation, and cancer
predisposition, with lymphoid malignancies predominating in
the first two decades of life1-10. Mutations in the Ataxia-
telangiectasia mutated (ATM) gene result in markedly decreased
or absent levels of ATM kinase, a protein that phosphorylates
many downstream targets. A deficiency of ATM kinase leads to
cell cycle defects, faulty repair of DNA damage, defective
apoptosis, and poor responses to oxidative stress1,3,11.

ABSTRACT: Background: The onset of progressive cerebellar ataxia in early childhood is considered a key feature of ataxia-
telangiectasia (A-T), accompanied by ocular apraxia, telangiectasias, immunodeficiency, cancer susceptibility and hypersensitivity to
ionizing radiation. Methods: We describe the clinical features and course of three Mennonite children who were diagnosed with A-T
following the completion of therapy for lymphoid malignancies. Results: Prior to cancer therapy, all had non-progressive atypical
neurological abnormalities, with onset by age 30 months, including dysarthria, dyskinesia, hypotonia and/or dystonia, without
telangiectasias. Cerebellar ataxia was noted in only one of the children and was mild until his death at age eight years. None had severe
infections. All three children were "cured" of their lymphoid malignancies, but experienced severe adverse effects from the treatments
administered. The two children who received cranial irradiation developed supratentorial primitive neuroectodermal tumors of the brain,
an association not previously described, with fatal outcomes. Conclusions: The range of neurological presentations of A-T is broad.
Ataxia and telangiectasias may be minimal or absent and the course seemingly non-progressive. The diagnosis of A-T should be
considered in all children with neuromotor dysfunction or peripheral neuropathy, particularly those who develop lymphoid
malignancies. The consequences of missing the diagnosis may be dire. Radiation therapy and radiomimetic drugs should be avoided in
individuals with A-T.

RÉSUMÉ: Mode de présentation atypique et toxicité du traitement anticancéreux chez les patients atteints d’ataxie-télangiectasie. Contexte :
L’apparition d’une ataxie cérébelleuse progressive dans la petite enfance est considérée comme une manifestation clé de l’ataxie-télangiectasie (A-T),
accompagnée d’apraxie oculaire, de télangiectasies, d’un déficit immunitaire, de susceptibilité au cancer et d’hypersensibilité aux radiations ionisantes.
Méthodes : Nous décrivons les manifestations cliniques et l’évolution chez trois enfants mennonites chez qui un diagnostic d’A-T a été posé après un
traitement pour cancer lymphoïde. Résultats : Avant le traitement anticancéreux, tous présentaient des anomalies neurologiques atypiques non
évolutives, dont l’âge de début se situait vers 30 mois, soit de la dysarthrie, des dyskinésies, de l’hypotonie et/ou de la dystonie sans télangiectasies.
Une ataxie cérébelleuse a été notée chez un seul des enfants et elle est demeurée légère jusqu’à son décès à l’âge de huit ans. Aucun n’a présenté
d’infection grave. Les trois enfants ont été « guéris » de leur cancer lymphoïde. Cependant tous ont présenté des effets secondaires du traitement. Les
deux enfants qui ont reçu une irradiation crânienne ont présenté des tumeurs cérébrales neuroectodermiques primitives sus-tentorielles, une association
jamais décrite auparavant, dont l’issue a été fatale. Conclusions : Le mode de présentations neurologiques de l’A-T est vaste. L’ataxie et les
télangiectasies peuvent être minimes ou absentes et sans évolution apparente. Le diagnostic d’A-T devrait être envisagé chez tous les enfants qui
présentent une dysfonction neuromotrice ou une neuropathie périphérique, surtout chez ceux qui présentent éventuellement un cancer lymphoïde. Si le
diagnostic n’est pas posé, les conséquences peuvent être sérieuses. La radiothérapie et les médicaments radiomimétiques devraient être évités chez les
individus atteints d’A-T.

Can. J. Neurol. Sci. 2009; 36: 462-467

Ataxia-Telangiectasia: Atypical
Presentation and Toxicity of Cancer
Treatment
Rochelle A. Yanofsky, Sashi S. Seshia, Angelika J. Dawson, Kent Stobart,
Cheryl R. Greenberg, Frances A. Booth, Chitra Prasad, Marc R. Del Bigio,
Jens J. Wrogemann, Francesca Fike, Richard A. Gatti

From the Section of Pediatric Hematology/Oncology (RAY, KS), Department of
Pediatrics & Child Health (RAY, AJD, CRG, FAB), Departments of Biochemistry &
Medical Genetics (AJD, CRG), Division of Laboratory Medicine & Pathology, Section
of Genetics and Metabolism (AJD), University of Manitoba & Health Sciences Centre
(AJD, MRD, JJW), Winnipeg, MB; Section of Pediatric Neurology (SSS), Department
of Pediatrics, University of Saskatchewan, Saskatoon, SK; Department of Pediatrics,
Northern Alberta Children’s Cancer Program (KS), University of Alberta, Edmonton,
AB; Department of Pediatrics (CP), University of Western Ontario, London, ON,
Canada; Department of Pathology (MRD), Diagnostic Imaging, Section of Pediatric
Radiology (JJW), Departments of Pathology & Laboratory Medicine and Human
Genetics (FF, RAG), UCLA/Geffen School of Medicine, Los Angeles, CA, USA.

RECEIVED FEBRUARY 4, 2009. FINAL REVISIONS SUBMITTED MARCH 25, 2009.
Correspondence to: Rochelle A. Yanofsky, Section of Pediatric Hematology/Oncology,
CancerCare Manitoba, 675 McDermot Ave., Winnipeg, Manitoba, R3E 0V9, Canada.

ORIGINALARTICLE

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We describe three Mennonite children who were diagnosed
with A-T after completing treatment for lymphoid malignancies.
All had mild, atypical, seemingly non-progressive pre-existing
neurological abnormalities, without telangiectasias. Subsequently,
all suffered severe adverse effects of cancer therapy; two
developed supratentorial primitive neuroectodermal tumors
(PNET) of the brain following cranial irradiation.

CASE REPORTS
Patient 1 (Index case)

This child was born at term to a Mennonite mother and a
Salvadorian father. Consanguinity was denied. The family
history was positive for dystonia in several maternal male and
female cousins, many of whom are now over 30 years old; none
were available for examination. The child was noted to be
clumsy at age one year, when he began to walk. Speech was
delayed. He was diagnosed with T-cell acute lymphoblastic
leukemia (T-ALL) without central nervous system involvement
at age 20 months. He was treated with multiagent systemic
chemotherapy, intrathecal chemotherapy, cranial irradiation
(1800 centiGray [cGy]) and mediastinal irradiation (300 cGy),
according to Pediatric Oncology Group Protocol 9404. He did
not experience excessive toxicity during treatment. His care was
transferred to our center three months after he completed
therapy. Dysarthria, jerky movements of the eyes, face, head and
neck, generalized dyskinesia, and mild ataxia were noted at that
time, with no telengiectasias. He drooled continually. His mother
did not feel that his neurological function had deteriorated since
infancy.

A serum alpha-fetoprotein (AFP) level was performed as a
screening test for A-T when he was four years and four months
old, and was elevated (Table). Subsequent testing confirmed the
diagnosis of A-T (Table and Figure 1). Magnetic resonance
imaging (MRI) of the brain was normal, as were his serum IgG,
IgA, and IgM levels.

At age seven years and nine months, he presented with
recurrent vomiting and lethargy. Magnetic resonance imaging of

the brain showed two mixed cystic and solid tumors with
peripheral enhancement, including one in the left
temporoparietal region (5.2 to 5.8 cm diameter) and one in the
left occipital lobe (2.5-3.1 cm diameter) (Figure 2). The
histologic diagnosis was supratentorial PNET (Figure 3). Gross
residual tumor remained following surgery. The family opted for
palliation. The child died four months later. An autopsy was not
performed.

Patient 2
This child was born at term to Mennonite parents, who were

second cousins. The family history was positive for familial
dystonia in several paternal male and female relatives, including
the father’s sister, who is now over 50 years old and has cervical
dystonia. The child was noted to have poor balance and
coordination when he started to walk at age one year. He

Table: Results of testing for Ataxia-Telangiectasia (A-T)

Patient 1 2 3
Age at diagnosis of A-T 4 y, 4 mo 10 y 17 y
Serum AFP* (µg/L) 135 32 178
Rearrangements of
chromosomes 7 & 14† Increased Increased Increased
Colony Survival Assay
(Survival fraction)‡ 19% 20% 6%
ATM Protein§ Absent Absent Absent
*Serum Alpha-fetoprotein: Normal range 0-7 after age two years;
†Cytogenetic analysis of spontaneous and bleomycin-treated peripheral
blood lymphocytes57; ‡Radiosensitivity assay. Diagnostic range is
<21%60,61; §Ataxia-telangiectasia mutated protein (immunoblot)35.

Figure 1: Immunoblot of nuclear lysates, developed with antibodies to ATM and Aprataxin (APTX) (loading control). Note absence
of ATM protein in Patients 1, 2 and 3.

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exhibited choreiform posturing of his hands and twisting
movements of his mouth. He was diagnosed with familial
dystonia. He did not have telangiectasias, then or subsequently.
His development was normal.

He was diagnosed with high-risk T-cell ALL with central
nervous system involvement at age 31 months. Computed
tomogram scan of the brain performed with and without contrast
revealed no significant abnormalities. He received multiagent
chemotherapy, intrathecal methotrexate, and craniospinal
irradiation (2400 cGy to the brain and 600 cGy to the spine),
according to regimen C of Children’s Cancer Group protocol
1882. He exhibited neurodevelopmental regression ten months
after starting therapy, and was considered to have severe
treatment-related leuko-encephalopathy, a diagnosis supported
by MRI of the brain. He completed therapy at age six years.
Seizures, growth hormone deficiency, hypothyroidism,
precocious puberty, bilateral conductive hearing loss, and
scoliosis were diagnosed between ages eight and ten years.

Because of the severe adverse effects that he experienced
from radiation therapy, his pre-existing neurological abnor-
malities, and our experience with the index case, he was
evaluated for A-T at age ten years. His serum AFP level was
elevated (Table). Subsequent testing confirmed the diagnosis of
A-T (Table and Figure 1).

The child developed a right hemiparesis and lethargy at age
12 years. An MRI of the brain showed two mixed solid and

cystic tumors, including one in the left parieto-occipital lobe (4.3
to 6.2 cm in diameter), and one in the left parietal region (1.7 to
2.8 cm diameter) (Figure 4). The solid portion of the masses
showed avid gadolinium enhancement. The histologic diagnosis
was supratentorial PNET (Figure 5). Gross residual tumor
remained following surgery. The family opted for palliation. The
child died six months later. An autopsy was not performed.

Patient 3
This child was born at term to an Australian mother and a

Mennonite father. Patients 2 and 3 were second cousins. Patient
3 was not related to Patient 1 by family history. Generalized
hypotonia was evident by age 30 months, accompanied by
delayed fine motor skills, clumsiness, and slurred speech. His
handwriting was subsequently noted to be slow and
disorganized. At age 12 years he presented with generalized
lymphadenopathy and was diagnosed with stage IV T-cell
lymphoblastic non-Hodgkin lymphoma, with bone marrow
involvement, but no central nervous system involvement. He
was lymphopenic, with an absolute lymphocyte count of 0.675 x
109/L (normal 1.2 to 5.2). Serum IgG, IgA, and IgM levels were
normal. He received intensive multiagent chemotherapy and
intrathecal methotrexate, without radiation therapy, according to
Children’s Cancer Group protocol 5941. He completed
treatment at age thirteen years and six months. He had significant
problems with peripheral neuropathy, a toxicity which was likely
due to vincristine, and which has still not completely resolved.

Because of his pre-existing neurological abnormalities and
his relationship to Patient 2, he was screened for A-T at age
seventeen years. His serum AFP level was elevated (Table).

Figure 2: Patient 1: Axial T2-weighted MRI at level of basal ganglia
showing multifocal PNET (arrows) and white matter injury from
previous chemotherapy and radiotherapy (arrowheads).

Figure 3: Patient 1: Microscopic examination of the tumor showed a
highly cellular small cell neoplasm with brisk mitotic activity and
necrosis. The cells were immunoreactive for S100, neuron specific
enolase (NSE), synaptophysin, protein gene product 9.5 (Pgp9.5),
neuronal nuclei (NeuN) (regional), Ki67 (>50%) and glial fibrillary
acidic protein (GFAP) (very rare), but not epithelial membrane antigen
(EMA) or cytokeratin CAM5.2. The final diagnosis was supratentorial
PNET (WHO grade IV).

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Subsequent testing confirmed the diagnosis of A-T (Table and
Figure 1). At age 23 years, his neurologic status is stable. He
remains cancer-free.

DISCUSSION
Individuals with “classic” A-T are usually ataxic by age two

years, and are often wheelchair-bound by age ten years.
Telangiectasias are typically evident by age six to ten years1,11-13.
Our patients had seemingly non-progressive neurological
abnormalities, including dysarthria, dyskinesia, generalized
hypotonia and/or dystonia, and drooling, without telangiectasias.
Only Patient 1 was ataxic when first referred. None had
excessive problems with recurrent infection, even while
receiving treatment for their lymphoid malignancies.

Milder phenotypes or atypical presentations of A-T have been
described in the literature1,11,13-28. Some individuals with A-T
have no neurological signs or symptoms17. Others have no
telangiectasias, even in adulthood1,11,13. Mild ataxia, the onset of
ataxia in adulthood,21,23, slow neurological deterioration20, a
progressive axonal sensorimotor polyneuropathy29-32, and late-
onset spinal muscular atrophy25 have also been described.
Extrapyramidal features are more prominent in older children.
Dystonia22,28 or chorea26 may be the initial or most prominent
manifestation of A-T. Oculomotor apraxia33,34, drooling,
progressive hypomimia, slow speech with abnormalities of
articulation, and progressive difficulty with chewing and

swallowing are commonly seen2,4-6,12,23. Handwriting is typically
affected by age eight years11.

Milder A-T phenotypes are sometimes associated with
missense mutations and/or reduced (but detectable) amounts of
ATM protein1,14,19-21,24,27,35. Our A-T patients had a “milder”
neurological phenotype. However, they had no ATM protein and
did not have missense mutations, nor did they have the c.5932
G>T ATM mutation previously reported in other Mennonite
families36,37. The results of their genotyping and haplotying
analyses are beyond the scope of this paper and will be reported
subsequently.

The lifetime frequency of cancer in A-T patients approaches
38%9, with 5% of patients developing more than one
malignancy3. As exemplified by our patients, the diagnosis of
malignancy may precede the diagnosis of A-T38,39; management
of the cancer may be confounded by increased sensitivity to
ionizing radiation and radiomimetic drugs39-45.

Patients 1, 2, and 3 were cured of their lymphoid
malignancies. However, all had severe adverse effects from the
treatment that they received. Patient 3 had a severe peripheral
neuropathy which was likely due to vincristine. This is in
keeping with the reported heightened sensitivity to the
neurotoxic effects of vincristine seen in individuals with
neuromuscular disorders43.

Patients 1 and 2 received cranial irradiation; both developed
a second malignant neoplasm (a supratentorial PNET of the
brain). This was likely radiation-induced, and had a fatal
outcome. While medulloblastomas41,46,47, astrocytomas9,46,48-51,
craniopharyngiomas52, and primary central nervous system
(CNS) lymphomas53 have been described in individuals with A-
T, supratentorial PNET’s have not. Also of note is that ATM gene
mutations do not appear to play a role in the pathogenesis of

Figure 4: Patient 2: Axial T2-weighted MRI at level of lateral ventricles
showing multifocal PNET (arrows) and white matter injury from
previous chemotherapy and radiotherapy (arrowheads).

Figure 5: Patient 2: Microscopic examination of the tumor showed a
highly cellular small cell neoplasm with brisk mitotic activity and
endothelial hyperplasia. The cells were immunoreactive for Pgp9.5,
synaptophysin (regional), NeuN (rare), and Ki67 (~20%), but not GFAP
or cytokeratin CAM5.2. The final diagnosis was supratentorial PNET
(WHO grade IV).

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medulloblastoma in children who do not have A-T54. The
development of a PNET of the brain following cranial irradiation
has been described in individuals without A-T, but is very
uncommon; it is usually fatal55. To our knowledge, our patients
represent the first published cases of a second malignant
neoplasm in the radiation field in patients withA-T, as well as the
first published cases of a supratentorial PNET of the brain
following cranial irradiation in individuals with A-T. It is
intriguing that the brain tumors seen in these two patients
appeared to be multifocal.

Patient 2 also experienced many other adverse effects of
craniospinal irradiation, including leukoencephalopathy, growth
hormone deficiency, precocious puberty, hypothyroidism,
bilateral conductive hearing loss, and scoliosis. Leuko-
encephalopathy has been described in children with A-T after
prophylactic cranial irradiation56 as well as in children without
A-T.

Serum alpha-fetoprotein is a simple, rapid, and reliable
screening test for A-T; it is elevated in more than 90% of A-T
cases1. Cytogenetic studies reveal rearrangements involving
chromosomes 7 and 14 in 5 to 15 percent of normal peripheral
blood lymphocytes in individuals with A-T57-59. However,
karyotyping can be technically difficult because the patients are
often lymphopenic and the lymphocytes may not respond well to
phytohemagglutinin (PHA). Confirmatory tests for A-T include
the colony radio-sensitivity assay and identification of the ATM
protein by immunoblotting1,35,60-62. These tests currently take
three months to complete. DNA sequencing is usually not
definitive because the full spectrum of ATM mutations has not
yet been established and not all mutations are detected by any
single laboratory platform63. A new flow cytometry-based assay
that detects ATM kinase activity in peripheral blood
mononuclear cells promises to shorten diagnostic testing to three
days64.

The range of neurological presentations of A-T is broad.
Ataxia may be minimal or absent and the course seemingly non-
progressive. The diagnosis of A-T should be considered in all
children with neuromotor dysfunction or peripheral neuropathy,
especially those who develop acute lymphoblastic leukemia,
non-Hodgkin lymphoma or Hodgkin lymphoma. Radiation
therapy and radiomimetic drugs such as bleomycin are best
avoided in A-T patients with cancer3,39,46,65. The observations
herein suggest that cranial irradiation may be especially
dangerous. The need for a cooperative experience in the
treatment of A-T patients who develop cancer is being addressed
by the A-T Cancer Clinic at St. Jude Children’s Research
Hospital24.

ACKNOWLEDGEMENTS
The authors thank Dr. Shareef Nahas for his technical

assistance; Diane Riordan for her cytogenetic expertise; Dr. Sara
Israels for critiquing the manuscript; and Florinia Vicente for her
assistance in preparing the manuscript.

FUNDING SOURCES
Dr. Gatti’s work was supported by grants from the Ataxia-

Telangiectasia Medical Research Foundation (Los Angeles), the
A-T Ease Foundation (New York), and USPHS grants NS
052528 and AI 067769.

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