Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites.
ABSTRACT To compare the phenotype of primary-appearing dystonia due to variant ataxia-telangiectasia (A-T) with that of other dystonia ascertained for genetics research.
Movement disorder specialists examined 20 Canadian Mennonite adult probands with primary-appearing dystonia, as well as relatives in 4 families with parent-child transmission of dystonia. We screened for the exon 43 c.6200 C>A (p. A2067D) ATM mutation and mutations in DYT1 and DYT6. Clinical features of the individuals with dystonia who were harboring ATM mutations were compared with those of individuals without mutations.
Genetic analysis revealed a homozygous founder mutation in ATM in 13 members from 3 of the families, and no one harbored DYT6 or DYT1 mutations. Dystonia in ATM families mimicked other forms of early-onset primary torsion dystonia, especially DYT6, with prominent cervical, cranial, and brachial involvement. Mean age at onset was markedly younger in the patients with variant A-T (n = 12) than in patients with other dystonia (n = 23), (12 years vs 40 years, p < 0.05). The patients with A-T were remarkable for the absence of notable cerebellar atrophy on MRI, lack of frank ataxia on examination, and absence of ocular telangiectasias at original presentation, as well as the presence of prominent myoclonus-dystonia in 2 patients. Many also developed malignancies.
Ataxia and telangiectasias may not be prominent features of patients with variant A-T treated for dystonia in adulthood, and variant A-T may mimic primary torsion dystonia and myoclonus-dystonia.
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ABSTRACT: We studied 10 Mennonite patients who carry the c.6200C>A missense mutation (p.A2067D) in the ATM gene, all of whom exhibited a phenotypic variant of ataxia-telangiectasia (A-T) that is characterized by early-onset dystonia and late-onset mild ataxia, as previously described. This report provides the pathogenetic evidence for this mutation on cellular functions. Several patients have developed cancer and subsequently experienced life-threatening adverse reactions to radiation (radiotoxicity) and/or chemotherapy. As the c.6200C>A mutation is, thus far, unique to the Mennonite population and is always associated with the same haplotype or haplovariant, it was important to rule out any possible confounding DNA variant on the same haplotype. Lymphoblastoid cells derived from Mennonite patients expressed small amounts of ATM protein, which had no autophosphorylation activity at ATM Ser1981, and trace-to-absent transphosphorylation of downstream ATM targets. A-T lymphoblastoid cells stably transfected with ATM cDNA which had been mutated for c.6200C>A did not show a detectable amount of ATM protein. The same stable cell line with mutated ATM cDNA also showed a trace-to-absent transphosphorylation of downstream ATM targets SMC1pSer966 and KAP1pSer824. From these results, we conclude that c.6200A is the disease-causing ATM mutation on this haplotype. The presence of at least trace amounts of ATM kinase activity on some immunoblots may account for the late-onset, mild ataxia of these patients. The cause of the dystonia remains unclear. Because this dystonia-ataxia phenotype is often encountered in the Mennonite population in association with cancer and adverse reactions to chemotherapy, an early diagnosis is important.Molecular Genetics & Genomic Medicine. 03/2014;
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ABSTRACT: Dopa-responsive dystonia (DRD) has a classic presentation of childhood or adolescent-onset dystonia, mild parkinsonism, marked diurnal fluctuations, improvement with sleep or rest, and a dramatic and sustained response to low doses of L-dopa without motor fluctuations or dyskinesias. However, there have been many papers on patients with a wide range of features, which report them as DRD mainly because they had dystonic syndromes with L-dopa responsiveness. Many mutations in the dopaminergic system have been found as molecular genetic defects. Therefore, the clinical and genetic spectra of DRD are unclear, which lead to difficulties in diagnostic work-ups and planning treatments. We propose the concept of DRD and DRD-plus to clarify the confusion in this area and to help understand the pathophysiology and clinical features, which will help in guiding diagnostic investigations and planning treatments. We critically reviewed the literature on atypical cases and discussed the limitations of the gene study.Current Neurology and Neuroscience Reports 07/2014; 14(7):461. · 3.78 Impact Factor
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ABSTRACT: Background Pediatric cerebrocerebellar neurodegenerative disorders such as ataxia-telangiectasia (AT) have not been examined in detail for neuropsychological changes. Such studies may contribute to the further understanding of AT and to the role of the cerebrocerebellar system in the development of cognitive function in childhood. Methods Twenty-two patients with the classic phenotype of AT were grouped into early stage cerebellar disease (group AT-I) versus late stage cerebrocerebellar disease (group AT-II) and examined for neurocognitive features. Results were compared to healthy controls and standard norms. Results AT-I patients scored low average compared to standard norms on all tests, and were impaired compared to healthy controls for Verbal IQ (p < .001), Vocabulary and Comprehension (p = .007), processing speed (p = .005), visuospatial processing (p = .020) and working memory (p = .046). AT-II patients scored below average compared to standard norms on all tests, and impaired compared to controls for attention (p < .001), working memory (p < .001) and abstract reasoning (p < .001). Comprehension scores were lower in AT-II than in AT-I patients (p = .002) while vocabulary scores showed no difference between groups (p = .480). Conclusion Cognitive impairments in AT present early coinciding with cerebellar pathology, and are characteristic of the cerebellar cognitive affective syndrome (CCAS). Widespread and deeper cognitive deficits manifest in later stages of AT when additional non-cerebellar pathology develops. These results are the first indications of distinct cerebellar and extracerebellar / subcortical contributions to the range of cognitive domains affected in AT, and need to be confirmed in future studies.Pediatric Neurology 09/2014; · 1.50 Impact Factor
Variant ataxia-telangiectasia presenting as
primary-appearing dystonia in
D. Raymond, MS
A.J. Stoessl, MD
D. Hobson, MD
T. Nakamura, PhD
S. Pullman, MD
D. Lefton, MD
M.S. Okun, MD
R. Uitti, MD
R. Sachdev, MD
K. Stanley, BS
M. San Luciano, MD
J. Hagenah, MD
R. Gatti, MD
L.J. Ozelius, PhD
S.B. Bressman, MD
Objective: To compare the phenotype of primary-appearing dystonia due to variant ataxia-
telangiectasia (A-T) with that of other dystonia ascertained for genetics research.
Methods: Movement disorder specialists examined 20 Canadian Mennonite adult probands with
primary-appearing dystonia, as well as relatives in 4 families with parent-child transmission of
dystonia. We screened for the exon 43 c.6200 C?A (p. A2067D) ATM mutation and mutations in
DYT1 and DYT6. Clinical features of the individuals with dystonia who were harboring ATM muta-
tions were compared with those of individuals without mutations.
Result: Genetic analysis revealed a homozygous founder mutation in ATM in 13 members from
3 of the families, and no one harbored DYT6 or DYT1 mutations. Dystonia in ATM families
mimicked other forms of early-onset primary torsion dystonia, especially DYT6, with promi-
nent cervical, cranial, and brachial involvement. Mean age at onset was markedly younger in
the patients with variant A-T (n ? 12) than in patients with other dystonia (n ? 23), (12 years
vs 40 years, p ? 0.05). The patients with A-T were remarkable for the absence of notable
cerebellar atrophy on MRI, lack of frank ataxia on examination, and absence of ocular telangi-
ectasias at original presentation, as well as the presence of prominent myoclonus-dystonia in
2 patients. Many also developed malignancies.
Conclusion: Ataxia and telangiectasias may not be prominent features of patients with variant
A-T treated for dystonia in adulthood, and variant A-T may mimic primary torsion dystonia and
AFP ? ?-fetoprotein; A-T ? ataxia-telangiectasia; PD ? Parkinson disease.
Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder due to mutations in the ATM
gene,1–3typically presenting with progressive cerebellar dysfunction and unsteady gait in early
childhood and often requiring the use of a wheelchair by age 10. A-T may present in milder
variant forms, in which the neurologic features are not as rapidly progressive or as severe. Onset
is usually in childhood; however, in variant A-T, ocular telangiectasias may not be prominent,
and ataxia is more slowly progressive—only mild to moderately severe by adulthood.4–8Move-
ment disorders are usually the presenting feature of variant A-T; up to 40% of patients have
tremor by age 12–34.8Almost all patients with variant A-T had movement disorders by adult-
hood, including resting tremor or dystonia (60%) and choreoathetosis (70%).8Whereas sur-
vival into adulthood is more common than in classic A-T, malignancies remain frequent.
Neuropathy is almost always a later emerging feature.8Herein, we performed a rigorous cross-
sectional analysis of the clinical features of variant A-T in a cohort of adults with a dystonia-
From the Department of Neurology (R.S.-P., D.R., K.S., M.S.L., S.B.B.), Beth Israel Medical Center, New York, NY; Departments of Neurology
(R.S.-P., S.B.B.) and Radiology (D.L.), Albert Einstein College of Medicine, Bronx, NY; Department of Neurology (A.J.S.), University of British
Columbia, Vancouver, Canada; Department of Neurology (D.H.), University of Manitoba, Winnipeg, Canada; Departments of Pathology and
Laboratory Medicine and Human Genetics (T.N., R.G.), Geffen School of Medicine, UCLA, Los Angeles, CA; Department of Neurology (S.P.),
Columbia University, New York, NY; Department of Neurology (M.S.O.), University of Florida, Movement Disorders Center, College of Medicine,
Gainesville; Department of Neurology (R.U.), Mayo Clinic Jacksonville, Jacksonville, FL; Department of Neurology (J.H.), University of Luebeck,
Luebeck, Germany; and Departments of Genetics and Genomic Sciences and Neurology (L.J.O.), Mount Sinai School of Medicine, New York, NY.
Study funding: Supported by NIH (NS26636 to S.B.B., K23NS047256 to R.S.-P.), the Bachmann-Strauss Dystonia & Parkinson Foundation, and
the Parkinson’s Disease Foundation (to S.P.).
Disclosure: Author disclosures are provided at the end of the article.
Correspondence & reprint
requests to Dr.
Copyright © 2012 by AAN Enterprises, Inc.
predominant phenotype, by comparing these
individuals with 23 patients with dystonia
without the mutation.
METHODS Standard protocol approvals, registra-
tions, and patient consents. The internal review boards at
Beth Israel Medical Center and Columbia University approved
Genetics and molecular methods. In all the multiplex fam-
ilies, dystonia was present in 2 generations and was consistent
with a dominant mode of transmission with reduced penetrance
(although there was consanguinity in 2 of the families); there-
fore, testing for mutations in DYT6 and DYT1 was performed.
No individuals had ataxia or telangiectasia, and the diagnosis of
A-T was not considered until a distant relative in one family was
diagnosed with A-T after poor outcome from irradiation of a
lymphoid malignancy that began at 3 years of age. He had early
balance and walking difficulties, which subsequently improved,
as well as dystonia.9We then determined that the homozygous
exon 43 c.6200 C?A (p. A2067D) ATM mutation found in this
relative was the etiology for the dystonia in the proband of one of
the families and therefore screened the other individuals from
this family, as well as all other patients and family members to
determine whether they shared this A-T mutation. For ATM
testing, DNA was extracted using the Puregene procedure
(Qiagen, Valencia, CA), followed by targeted screening of the
mutation c.6200 C?A (p. A2067D).10A 345-bp product en-
compassing exon 43 was amplified using the following intronic
primers: forward 5?-cacccagctgatattttggga-3? and reverse 5?-
tgtttagaatgaggagagaggc-3?. The c.6200 C?A mutation was de-
tected by digestion with HaeIII followed by agarose gel
electrophoresis. Sanger sequencing verified all homozygous ge-
notypes and a representative sample of heterozygous carriers.
Probands were also screened for mutations in DYT1 and DYT6,
as described previously.11,12Radiosensitivity assays and screening
for ATM levels were performed in C:301, C:302, and D:301
using methods described previously.13,14
Participants and clinical methods. In our study, initially
undertaken to identify the DYT6 gene in Amish and Menno-
nites with dystonia,15,1620 probands with dystonia and with
Canadian Mennonite heritage (4 from the multiplex families
and 16 others) were ascertained through referring movement
disorder neurologists and response to research advertise-
ments. Probands and available family members were inter-
viewed and examined in person at family homes or medical
centers and videotaped according to previously published
protocols17from 1998 to 2010. Blood for DNA extraction
Movement disorder neurologists who were blinded to ge-
notype information made final decisions regarding the pres-
ence of definite, probable, possible, and no dystonia after
considering the evaluations of on-site examiners, video review
examiners, and any additional information available from
medical records.17Information regarding other movement
disorders (e.g., myoclonus, chorea, and parkinsonism) was
also noted in the video review.
A total of 156 family members had clinical information and
DNA available for analysis, and 35 were definitely affected with
dystonia, including 19 individuals from 4 multiplex Canadian
Mennonite families (figure 1) and 16 others. All examinations
and video reviews were completed as part of dystonia studies
before the determination that dystonia was due to a founder A-T
mutation in 3 of the families.
Variant A-T. After determination that A-T was the causative
disease in families A, B, and C, reports of telangiectasias and
malignancies were ascertained from medical records and follow-up,
and 2 individuals from family C had ?-fetoprotein (AFP)
assessed (C:301 and C:303) and video rereview to assess chorea.
Brain pathology reports were available for one subject (family A)
and 2 previously deceased family members (from family C).
C:301 had extensive testing after the diagnosis of A-T, including
neuro-ophthalmologic examination and quantitative motor
physiology testing (tremor analysis18and spiral analysis19).
Statistical analysis. Clinical features of individuals with
dystonia homozygous for the ATM c.6200 C?A mutation were
compared with those of mutation-negative individuals, using
generalized estimating equation models for dichotomous vari-
ables and random effects models for continuous or ordinal vari-
ables (STATA8; StataCorp, College Station, TX).
RESULTS A total of 35 individuals from 20 families
of Canadian Mennonite background with definite
dystonia were identified. Nineteen of the individuals
with definite dystonia were from 4 multiplex fami-
lies. The remaining 16 individuals did not have an
history suggestive of dystonia.
No individuals harbored either a DYT1 or DYT6
mutation. Twelve subjects with definite dystonia
from families A–C harbored homozygous 6200
C?A ATM mutations. Twenty-three others with
dystonia were noncarriers (family D and all other af-
fected individuals) (table 1). There was only one ad-
ditional homozygous carrier among the family
members with possible or no dystonia. She had pos-
sible right leg dystonia, minimal balance problems,
and normal tandem gait on examination at age 8. In
addition, her family had noted swaying of her trunk
while sitting at 13 months that improved with age.
Two families were determined to be related; the third
Clinical features. Among the subjects with dystonia
with the 6200 C?A ATM mutation, most had early
lar tremor, and some had myoclonus (table 2 and video
[on the Neurology®Web site at www.neurology.org]).
Movements were compatible with a highly active
lifestyle in all. Although some had clumsy gait, none
were described as ataxic (table 2). Two mutation-
positive subjects reported ataxia in early childhood
Age at onset of dystonia was younger in the A-T
group (median 12 years, range 1–20 years) than in
the group without A-T (median 40, range 9–59
years) (p ? 0.001) (figure 2). Site of onset of dysto-
nia did not differ between the 2 groups, with neck
onset being most common for both homozygous
Neurology 78February 28, 2012
mutation carriers and noncarriers. In contrast, final
distribution of dystonia varied markedly among
groups (p ? 0.03) with that in the mutation group
more likely to be generalized (58.3% vs 13%) and
92% of the homozygous mutation carriers having
brachial dystonia, whereas only 26.1% of noncarriers
had arm involvement. Leg dystonia was more frequent
a walking aid, and none used a wheelchair.
Cranial involvement was common in both groups
(66.7% in the AT group and 52.2% in the noncar-
rier group), but tongue and jaw involvement were
different, with 58.3% of homozygous individuals
having dystonia in these sites, compared with only
21.7% of the noncarriers. Speech was rated as abnor-
mal in 91.7% of the patients with A-T but in only in
35% of the noncarrier patients. Because definite la-
ryngeal, jaw, or tongue dystonia was not noted in all
patients with speech involvement, we cannot fully
exclude the possibility that, in addition to dystonia,
there may be a cerebellar component.
Although dystonia was the primary movement in
all patients, nondystonic features were also noted in
some and more frequently in the patients with A-T
than in the noncarriers. Two of the 12 ATM homozy-
gotes had a phenotype consistent with myoclonus-
dystonia, whereas none of the mutation-negative
subjects did. Facial choreiform movements were also
noted in the patients with A-T, although these could
also be seen in DYT6 dystonia (video).
Additional clinical features. In all 3 A-T mutation
families, there was at least one family member who
Figure 1Pedigrees for multiplex families
Families A–C harbored the mutation; family D did not. ? demarcates individuals examined. A shaded circle or square designates an individual with dystonia.
No ? indicates individuals affected by history.
Neurology 78February 28, 2012
reported unsteady gait in early childhood that spon-
taneously improved. None of the individuals exam-
ined complained of persistent walking problems in
adulthood. Frank ataxia was not noted in any of the
affected individuals with the exception of inability to
tandem in C:301 at age 59 along with sensory neu-
ropathy. However, among the A-T mutation carriers
with dystonia, several had clumsy or lumbering gait
not solely attributable to dystonia.
Neuropathy occurred in 3 individuals (table 2).
One noncarrier had apraxia of eyelid opening, but
this did not occur in mutation carriers. After the dis-
covery that C:301’s dystonia was due to A-T, he had
a formal neuro-ophthalmologic evaluation, which
did not demonstrate ocular dysmetria or ocular mo-
tor apraxia; he had slightly saccadic pursuits and
occasional 2-step saccades, without nystagmus or
square wave jerks. In C:302, no telangiectasias were
noted initially, although after the diagnosis of A-T,
telangiectasias on the inner lower lip were discovered.
In C:301, quantitative physiologic analysis re-
vealed a low-frequency tremor varying from 3 to 7
Hz, irregular postural, and action tremors of his
head and hands, worse on the right side, driven by
short and long duration (100–500 msec) proximal
neck and cocontracting forearm antagonist EMG
bursts. There were infrequent short-duration (25–50
msec) cocontracting EMG bursts in the right fore-
arm antagonists consistent with myoclonus. Com-
puterized spiral analysis revealed mild to moderate
overall degrees of severity, worse on the right, with
low-frequency 4–5 Hz irregular multiaxial tremors.
Spiral executions were of normal speed, without evi-
dence for micrographia but with mildly increased
loop width variability. MRI and transcranial sonog-
raphy imaging for C:301 is shown in figure 3.
spasms and pain with cervical botulinum toxin A injec-
tions. Improvement occurred with anticholinergics (1
subject) and diazepam (3 subjects). No response oc-
curred to baclofen (Lioresal) (1 subject), tetrabenazine
(2 subjects), or carbidopa/levodopa (3 subjects).
Evaluation of heterozygous carriers. Among the fam-
ily members in the dystonia families, 37 individuals
(mean ? SD age 44 ? 24 years, range 8–86 years)
carried one copy of the founder mutation. None of
the heterozygous carriers demonstrated definite
dystonia. One carrier had definite parkinsonism and
was subsequently treated with levodopa with im-
provement. C:201, an obligate carrier, died at the age
of 82 without evidence of parkinsonism.
Historical information in families with ATM muta-
tions. C:204 died of a sarcoma at age 51, at which
time movements interfered with ambulation. Au-
topsy did not show cerebellar or brainstem degen-
eration. C:203 had movements that slowly but
progressively worsened with age. Speech was nor-
mal until the later phases of illness, and just before
death he could walk with great difficulty but was able
to drive a car. It is not clear whether the gait diffi-
culty was secondary to neuropathy or ataxia. He died
at age 51 from a malignancy of unknown type, and
autopsy showed atrophy of the olivary nucleus and a
reduction of large Betz cells in the motor cortex.
A:314 had arm and neck movements. Of 5 unexam-
ined siblings of C:201 (an obligate carrier) who sur-
vived to adulthood, one brother reportedly had
levodopa-responsive Parkinson disease (PD) diag-
nosed at age 42 and died at age 77, another had par-
kinsonism with prominent postural instability, and a
sister had PD and died at age 77.
DISCUSSION Our data suggest that dystonia, espe-
cially early-onset dystonia with cervical and brachial
Table 1 Clinical features: Comparison of clinical features in ATM mutation and
nonmutation dystonia cases
cases (n ? 12)
(n ? 23)p Valuea
Age at examination, y, median
51.5 (12–64)52.0 (23–84)0.129
Age at onset, y, median
12 (1–20)40 (9–59)
Site onset, %b
Sites affected, %
Speech affected, %
aAll positive vs negative.
bSome individuals had more than one site of onset.
Neurology 78February 28, 2012
onset and prominent cranial involvement, is a major
feature of variant A-T; it may occur without frank
ataxia and may be misdiagnosed in adults with
primary-appearing dystonia. Both the age at onset
and frequency of cranial involvement in the variant
A-T group overlap with that seen in DYT6 dysto-
nia18: median age 12 years vs 14 years and 67% vs
70% of individuals with variant A-T and DYT6, re-
spectively.16The phenotype also overlaps with
Our subjects differ from those with classic A-T in
their overall preserved gait in adulthood and absence
of prominent telangiectasias, oculomotor apraxia,
and ataxia.3,8,20–25However, ataxia that was present
in early childhood and spontaneously remitted was
present in 2 individuals, and some individuals had
clumsy gait that was not solely attributed to dystonia.
Therefore, absence of ataxia does not exclude a diag-
nosis of variant A-T, but mild clumsiness, possible
ataxic features, childhood history of a remitting
ataxia, and family history, even in a dominant-
appearing transmission pattern, could support a vari-
ant A-T diagnosis. Because no subjects had ocular
telangiectasias, but oropharyngeal telangiectasias
were noted in our subject and in another subject with
mild A-T, examination should include thorough
evaluation for oropharyngeal telangiectasias, and
their presence should heighten the suspicion of A-T.
The presence of parkinsonism in a heterozygous
family member as well as in 3 siblings of an obligate
carrier and prior reports of rest tremor in variant
A-T,8raise the question of whether parkinsonism
may be part of a motor phenotype in heterozygous
and homozygous A-T mutation carriers. There is se-
lective loss of dopaminergic nigrostriatal neurons in
ATM-deficient mice,26and substantia nigra Lewy
bodies occurred in a 31-year-old individual with
A-T.27Although no nigral cell loss was reported in
Table 2 Clinical and testing features in all ATM carriers affected with dystonia
of A-T: protein
M64 13ArmUFNAMRGLNCranialStomach (56)
M5616Neck UFJTNAMCranial Renal (51)
F431Both legs UFLNAMKRGNNeck,
F 52Unknown UnknownAMRGCranial
M 26 15 ArmNAMRG FAM Cranial
F40 20 NeckUFNAACranial
M 12 11 NeckN
M 601 Neck, legsLUFNAMKNCranial,
SensorimotorProstate (59)ATM trace
F5312NeckLUFTNAGN ArmStomach (58)ATM lacking
Abbreviations: AFP ? ?-fetoprotein; A-T ? ataxia-telangiectasia; A ? right arm; F ? lower face; G ? left leg; J ? tongue; K ? trunk; L ? larynx; N ? neck; M ?
left arm; R ? right leg; U ? upper face.
aMedical conditions also included Sjögren syndrome, polyclonal gammopathy, history of leukopenia, positive rheumatoid factor, protein S deficiency and
deep vein thrombosis, and renal tubular acidosis.
bProtein assay and radiosensitivity: C:302: cells were found to be lacking in ATM protein and were radiosensitive; C:301: lymphoblastoid cells showed
radiosensitivity of 19 (normal range 50 ? 13; radiosensitive range 14 ? 7) and Western blot of ATM protein showed only a trace amount (?5 of wild-type
controls on same blots) of ATM protein. For D:301 (no c.6200 C?A mutation), activity was in the normal range.
cAutopsy showed mild loss of Purkinje cells in cerebellum.
dImpaired vibration and joint position sense as well as lower extremity areflexia. EMG/NC at age 43 was reported to be normal and at age 51 showed
There were normal compound muscle action potentials in median and extensor digitorum brevis muscle, but slightly reduced tibial, consistent with axonal
eSurgery for congenital shortening of the forearm bones (Keinbock disease).
Neurology 78February 28, 2012
any of the autopsies, there was nigral hyperechoge-
nicity on transcranial sonography in C:301, a non-
specific marker present in ?90% of individuals with
PD that may represent nigral iron deposition.28Sub-
stantia nigra hyperechogenicity is also increased in
DYT6 dystonia,29although it may be present in
10% of controls. Parkinsonism in the heterozy-
gous relatives cannot be specifically attributed to
abnormalities in ATM, as DNA was not available,
and PD is a common disorder. Therefore, it is not
clear whether PD relates to the heterozygous ATM
mutation, a PD gene segregating in this family, or
a chance association.
The etiology of dystonia in both classic and vari-
ant A-T is not well understood. Classic A-T is usually
caused by null ATM alleles that truncate or severely
destabilize the ATM protein, resulting in a lack of
functional ATM.30,31ATM protein kinase is a major
regulator of multiple signaling cascades that react to
and repair DNA strand breaks, and lower levels of
ATM may lead to a failure of activation of cellular
checkpoints. Consequently, some hypothesize that
the clinical presentation may result from faulty DNA
repair.5,32The postulated mechanism of variant A-T
is that it is due to mutations that result in higher
residual levels of ATM protein than those that cause
to segregate within families, and the family as a whole
may present with movement disorders rather than
ataxia as the primary feature. The pA2067D missense
mutation identified in these families (personal commu-
nication, T. Nakamura, The Gatti Laboratory, UCLA,
2009) was reported in the heterozygote state in a Ger-
man patient with A-T (Ae003),10and in the homozy-
gous state in Canadian Mennonites.5,9Although our
families support the idea that variant A-T has a milder
phenotype that segregates within families, our data do
not fully support the proposed mechanism of milder
etiology, because ATM enzyme activity was either very
low or nonexistent in the 2 cases studied.
The relationship between decreased ATM activity
and prominent dystonia in variant A-T is unclear.
Classic A-T occurs with cerebellar and extracerebellar
pathology33,34and imaging abnormalities,35–37with
cerebellar granular and Purkinje cell loss being the
most consistent feature.35MRI examinations in clas-
sic A-T revealed, in 1 of 2 patients with prominent
movement disorders, obvious basal ganglia pathol-
ogy37; 1 patient with prominent dystonia had a uni-
lateral putaminal hyperintensity on T2-weighted
images and bilateral decreased striatal [123I]iodoben-
zamine binding with SPECT imaging.24It is unlikely
that dystonia in variant A-T can be attributed solely
to cerebellar atrophy, because this feature was not
prominent on MRI in any of our subjects, and in
another subject with variant A-T with prominent
early-onset dystonia, nonspecific cerebellar atrophy
without a cerebellar functional correlate was present.22
Thus, although the phenotype suggests primary basal
with minimal or no cerebellar atrophy on MRI, the eti-
ology remains uncertain as pathologic findings suggest
sic A-T. With the exception of nigral hyperechogenic-
ity, markers of striatal pathology were also not present
on structural imaging in our subjects nor were they
noted on autopsy.
Even though neurologic disease is milder overall
in variant A-T than in classic A-T, the burden of
Figure 2Age at onset in individuals with variant ataxia-telangiectasia (A-T) compared with those with
nonmutation primary dystonia
Neurology 78February 28, 2012
malignancy remains high. It is therefore imperative
to make the diagnosis of variant A-T, because malig-
nancies occur frequently and may be triggered by ra-
diation exposures that might be avoided. Screening
for AFP should be considered, and it is elevated
(greater than 10 ng/mL) in 95% of individuals with
classic A-T. AFP was abnormal in our subjects and a
relative,9but at a much lower range than that in clas-
sic A-T. Although normal AFP levels can be seen in
variant A-T,20AFP may be a useful low-cost screen-
ing tool with excellent sensitivity for A-T and could
be followed by immunoblotting for ATM protein
and a radiosensitivity assay.5,8,30Gene mutation stud-
ies, although supportive, are not necessary for the
diagnosis, because mutations are not identified in all
patients, and the causality of many missense DNA
changes is often elusive.38–40Therefore, AFP screen-
ing should be considered in patients with early-onset
dystonia, even with normal eye movements and
without ataxia or telangiectasia. Our data suggest
that not only should A-T be included in the differen-
tial diagnosis of early-onset primary-appearing dysto-
nia but also the non-neurologic oncologic disease
burden, which may be worsened by radiation, war-
rants screening for early identification.
Study design and conceptualization: Dr. Saunders-Pullman, D. Ray-
mond, Dr. Ozelius, Dr. Bressman. Analysis and interpretation of the data:
Dr. Saunders-Pullman, D. Raymond, Dr. Stoessl, Dr. Hobson, Dr. Naka-
mura, Dr. Pullman, Dr. Lefton, Dr. Okun, Dr. Uitti, Dr. Sachdev, K.
Stanley, Dr. San Luciano, Dr. Hagenah, Dr. Gatti. Statistical analysis: Dr.
Saunders-Pullman. Drafting and revision of the manuscript: Dr.
Saunders-Pullman. Revision of the manuscript: D. Raymond, Dr. Stoessl,
Dr. Hobson, Dr. Nakamura, Dr. Pullman, Dr. Lefton, Dr. Okun, Dr.
Sachdev, Dr. San Luciano, Dr. Hagenah, Dr. Gatti, Dr. Ozelius, Dr.
The authors thank all patients and family members who graciously partic-
ipated in this study; Amber Clark for genotyping and sequencing and
Francesca Fike for technical expertise; Dr. Myles Behrens for performing
the neuro-ophthalmologic examination; Dr. Rowena Desailly-Chanson,
Camille Costan-Toth, and Gary Heiman for help with examining the
families and Jeannie Soto-Valencia, Kristina Habermann, and Deborah
de Leon for assistance in organizing and coordinating family visits; and
Carol Moskowitz for her work in facilitating autopsy, as well as the pa-
thologists at Columbia University and University of British Columbia
who performed the autopsies.
Figure 3 Brain MRI (A) and transcranial ultrasonography (B) images
(A) 1.5-T nonenhanced and enhanced MRI of the brain (for C:301) at age 59 revealed several small unidentified bright
objects in the white matter of the cerebral hemispheres bilaterally as well as minimal dilatation of the ventricles and sub-
arachnoid spaces consistent with aging, but was otherwise normal, without cerebellar atrophy. After the radiologist was
informed of the diagnosis, possible vermian atrophy was noted on rereview. (B) Transcranial sonography of the midbrain:
image results for a patient with Parkinson disease (left) and C:301 (right). Yellow encircling demarcates area of hyperecho-
genicity. In C:301 there was hyperechogenicity compared with laboratory controls.29
Neurology 78February 28, 2012
Dr. Saunders-Pullman serves on the Scientific Advisory Board of the
Dystonia Medical Research Foundation; has received research support
from the NIH/NINDS (K23NS047256 and K02NS073836), the Mi-
chael J. Fox Foundation for Parkinson’s Research, the Thomas Hartman
Foundation for Parkinson’s Research, the Bachmann-Strauss Dystonia &
Parkinson Foundation, and the Marcled Foundation. D. Raymond re-
ceives research support from the Michael J. Fox Foundation for Parkin-
son’s Research, the Thomas Hartman Foundation for Parkinson’s
Research, Inc., and the Marcled Foundation. Dr. Stoessl serves on a scien-
tific advisory board for Biovail Corporation/Medgenesis; has received
funding for travel and speaker honoraria from Novartis, Teva Pharmaceu-
tical Industries Ltd., Allergan, Inc., and Abbott; serves on the editorial
boards of Annals of Neurology, Lancet Neurology, and Parkinsonism & Re-
lated Disorders; and receives research support from CIHR, the Michael
Smith Foundation for Health Research, and the Pacific Alzheimer Re-
search Foundation. Dr. Hobson serves on a scientific advisory board for
Parkinson’s Society Canada and serves on the editorial board of Parkin-
sonism and Related Disorders. Dr. Nakamura reports no disclosures. Dr.
Pullman serves on scientific boards for Musicians with Dystonia and the
Dystonia Medical Research Foundation; serves on the editorial boards of
Neurological Bulletin and Tremor and Other Hyperkinetic Movements;
holds a patent re: System and method for clinically assessing motor func-
tion; conducts motor physiology studies (40% effort), performs intraoper-
ative mapping for deep brain stimulator implantation (20% effort),
administers botulinum toxin (30% effort), and performs EMG studies
(10% effort); receives research support from the NIH, Parkinson Disease
Foundation, and the Michael J. Fox Foundation; and receives royalties for
technology re: Computerized spiral analysis from Columbia University.
Dr. Lefton serves on scientific advisory boards for Ceregene and VasSol,
Inc. Dr. Okun serves/has served on scientific advisory boards for the
Dystonia Medical Research Foundation and the National Parkinson
Foundation and the Medical Advisory Board for the Tourette Syndrome
Association; has received funding for travel and speaker honoraria from
Medtronic, Inc. prior to 2010; serves on the editorial boards of Parkinson-
ism and Related Disorders; is a founder of the COMPRESS software used
for deep brain stimulation (DBS) screening and has filed patents regard-
ing double lead DBS, DBS targeting, and COMPRESS; receives royalties
from the publication of Ultimate Neurology Review (DEMOS, 2007), Par-
kinson’s Disease (Manson, 2009), and Deep Brain Stimulation for Neurolog-
ical and Psychiatric Diseases (Humana Press, 2009); serves as Medical
Director of the National Parkinson Foundation and as a member of the
Ask the Expert Forum; and has received research support from
Medtronic, Inc. (devices and training fellowship grants), the NIH, the
University of Florida Foundation, the Michael J. Fox Foundation, Tyler’s
Hope for a Dystonia Cure, and the National Parkinson Foundation. Dr.
Uitti served as a Continuing Medical Educator for the AAN and serves as
an Associate Editor of Neurology®; has received research support from
Advanced Neuromodulations Systems, the NIH, PARRF, PSG, and
Noscira, Inc.; and his institution receives annual royalties from Lundbeck
Inc. from the licensing of the technology related to PARK8/LRRK2. Dr.
Sachdev was supported from a Fellowship from the Bachmann-Strauss
Dystonia & Parkinson Foundation. K. Stanley reports no disclosures.
Dr. San Luciano was funded by an American Academy of Neurology
Foundation Award. Dr. Hagenah has received speaker honoraria from
GlaxoSmithKline. Dr. Gatti receives research support from the NIH, the
Ataxia-Telangiectasia Medical Research Foundation, and the Ataxia-
Telangiectasia Ease Foundation. Dr. Ozelius serves on scientific advisory
boards for the Dystonia Medical Research Foundation, the Bachmann-
Strauss Dystonia & Parkinson Foundation, the Benign Essential Blepha-
rospasm Research Foundation, and the National Spasmodic Dysphonia
Association; is listed as an author on patents re: Torsin, Torsin genes and
methods of use, and Nucleic acids, methods and kits for the diagnosis of
DYT6 primary torsion dystonia; receives research support from the NIH,
the Dystonia Medical Research Foundation, and the Bachmann Strauss
Dystonia & Parkinson Foundation; and receives royalties from Athena
Diagnostics, Inc. for a patent re: Torsin, Torsin genes and methods of use.
Dr. Bressman serves on scientific advisory boards for the Bachmann
Strauss Dystonia & Parkinson Foundation, the Michael J. Fox Founda-
tion for Parkinson’s Research, and the Dystonia Medical Research Foun-
dation; holds a patent re: THAP1 gene testing; and receives research
support from the NIH and the Michael J. Fox Foundation for Parkinson’s
Received April 4, 2011. Accepted in final form October 26, 2011.
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