Ataxia Telangiectasia

Thomas O. Crawford

The cloning of ATM in 1995, the gene responsible for ataxia-telangiectasia, opened a dimension of biological
research that is as complex and intriguing to cell biologists as this classic disorder has been to clinicians for four
decades. The phenotype is both variable and stereotyped, with significant differences between patients in the rate
of progression or appearance of the multiple features yet consistent in their characteristic nature. Ataxia
telangiectasia usually has been misdiagnosed for the first few years of life, while accurate diagnosis might most
impact family planning. Newly produced ATM-deficient transgenic mice express most of the cellular features of the
disorder but have yet to mimic the distinctive neurodegeneration.
Copyright 9 1998 by W.B. Saunders Company

HE DISTINCTIVE and striking features of ATM gene are unique. 6,7 The reason why this gene
T ataxia telangiectasia (AT; MIM 208900) give it is vulnerable to expression of disease from multiple
different mutational events, whether because it is a
a prominerfce in Biology and Medicine that belies
its rarity. Beyond its neurological and dermatologi- hotspot for mutation or because of uncharacterized
cal facets, which have led to its name and inclusion heterozygote selection advantage, or instead be-
on the list of neurocutaneous disorders to be cause of some more complex biological phenom-
reviewed in this issue of Seminars in Pediatric enon, is unknown.
Neurology, AT results in a strong disposition to In the last 3 years, as part of the multidisciplinary
specific malignancies, distinctive immunological AT Clinical Center at Johns Hopkins Hospital, I
abnormalities, a range of endocrine problems, have had the honor and opportunity to evaluate
sensitivity to ionizing radiation, and chromosomal almost 100 children and young adults with AT. This
instability. Cells cultured from patients with AT experience, coupled with the rich clinical literature
express multiple distinctive features including radio- now spanning 5 decades has led me to appreciate
resistant DNA synthesis, abnormal cell cycle check- both the complexity--and the consistency within
point regulation, apparent constituitive activation defined limits--of this simultaneously distinctive
of multiple oxidative stress pathways, and early and variable disease.
senescence. The recently described pathogenic HISTORICAL ASPECTS
ataxia telangiectasia mutated (ATM) gene includes
a region with homology to phosphatidylinositol-3 In 1957, the syndrome was first recognized
kinase (PI-3 kinase), one of a group of internal cell widely, and named ataxia telangiectasia, in a report
signaling proteins involved in cell-cycle regulation, by Elena Boder and Robert E Sedgwick on 8 cases
from 6 families) The early onset of progressive
DNA damage responses, genetic recombination,
ataxia, characteristic telangiectasia, involution of
and control of telomere length. Thus, it is not
the thymus, and abnormalities in the ovaries were
surprising that since the cloning of ATM by Shiloh
the then-defining features. Sedgwick and Boder 9
and his team in 19951 well over 300 papers listing
continued their careful descriptive work in multiple
AT as a subject have been referenced in Med-
reports for 34 more years. However, as usually
line--a number that roughly approximates the
happens with common or distinctive disorders,
number of patients in the United States known to
there were earlier papers of individuals with AT
the AT Children's Project?
that failed to achieve wider recognition. 1~ Addi-
Estimates of lifetime incidence in the United
tional cases were quickly recognized and reported,
States range between 1 in 300,0003 to 1 in 40,0004
so that by 1963 Boder and Sedgwick compiled a
individuals. The corresponding prevalence of heter-
table of 101 known cases. 12 It is notable in light of
ozygotes, given pure recessive genetics and a low
incidence of consanguineous cases, would be calcu-
lated to be between 1 in 275 to 1 in 100 though in a From the Department of Neurology and Pediatrics, Johns
few isolated populations, there may be a higher Hopkins University School of Medicine, Baltimore, MD.
incidence due to founder effects. 5 Although epide- Address reprint requests to Thomas O. Crawford, MD, The
Johns Hopkins Hospital, Harvey 811, 600 North Wolfe St,
miological data are scant, AT is known to occur in Baltimore, MD 21287-8811.
all races on all continents. Summary analysis Copyright 9 1998 by W.B. Saunders Company
indicates that most pathogenic mutations of the 1071-9091/98/0504-000758.00/0

Seminars in Pediatric Neurology, Vol 5, No 4 (December), 1998: pp 287-294 287

288 THOMAS O. CRAWFORD

our present-day debate on the neuroanatomy of the problems in each organ system. Variations from
disorder that the earliest cases called attention to this range are unusual and may raise doubt about
the prominent chorea and often considered the the diagnosis. Nonetheless, children with AT differ
disorder to be one primarily of the basal ganglia. from one another, 21 sometimes quite remarkably, in
In the first decade of research (1957 to 1966) the constellation of these fixed features, the rate of
came the recognition of specific humora113 and the progressive features, and the occurrence of the
cell-mediated 14 immune abnormalities, absence or abrupt-onset complications. Because expression of
depletion of peripheral lymphoid tissues, associa- the ATM gene is ubiquitous in both diseased and
tion with lymphoreticular malignancies, 12 abnor- apparently normal tissues, this sometimes dramatic
malities of the gonads, association with insulin difference in clinical manifestation raises the prob-
resistant diabetes, 15 and formal recognition of a ability that environmental influences or other genes
near 25% segregation ratio confirming simple auto- have a significant role in morbidity. This, in turn,
somal recessive. 16 So also came the recognition of raises the possibility that there may be many
the distinctive neuropathological features of selec- different pathways to alter the pathophysiological
tive Purkinje cell depletion with partial thinning of processes therapeutically.
the granule cell layer and absence of recognizable
pathology in the basal ganglia and cortex. In the Neurological Manifestations
second decade (1967 to 1976) came recognition of Ataxia remains the sine qua non among the many
t h e characteristic cytogenetic abnormalities of ex- neurological features of AT. It is usually the earliest
cessive chromosomal breakage, 17 clinically appar- manifestation of the disorder and a chief complaint
ent 18 and cellular 19 radiosensitivity, and elevated that parents raise with doctors. Most children are
e~-fetoprotein (AFP). 20 not obviously abnormal at birth and walk at a
By the end of these 20 years, the major aspects of normal age. However, a frequent story is that the
this multifaceted and often variable disorder were early instability of walking fails to improve with
recognized in essentially the same way as they axe age, so that falls and bumps persist despite develop-
today. That so much could be compiled so quickly ment. Children differ--and parents' histories often
is testimony to the clinical acumen of these early fail to agree with one another--but the story of
investigators and the coherence of the sentinel stable motor function or small improvements for a
features of early ataxia, ocular telangiectasia, sus- time until ages 3 to 7 years is common. This
ceptibility to sinopulmonary infections, and oculo- stability or mild improvement with time is respon-
motor abnormalities in defining a nosologically sible for the too-common misdiagnosis of cerebral
distinct entity. Later descriptions of small numbers palsy or other stable static encephalopathies.
of patients lacking one or more of these features Gait and Posture. The instability of gait has
have since blurred the margins of the original certain unusual characteristics. Most children walk
clinical diagnostic criteria such that absolute clini- on what seems to be an inappropriately narrow
cal diagnostic criteria are difficult to formulate. base, and early in the disorder generally have a
However, these features have remained important regular stride length but err in excessive adduction
for identifying the population from which the new of the leg during the passing phase or on foot strike,
"gold standard" molecular tests that probe for causing a stagger to the outside of the base. Despite
errors in the gene are emerging. this error, children frequently compensate for their
missteps well. One father described it well, "for
CLINICAL FEATURES someone with his problems with walking, he has
The widely disparate features of AT include the best balance." Children often prefer to walk
some that are fixed in time, some that are progres- quickly or run, the advantages of momentum
sive in nature, and some, like the development of apparently reducing errant steps or aiding balance
cancer, that are variable in incidence and occur in the same manner that riding a bicycle quickly is
abruptly. However, other than the identity of the more stable than riding one slowly. With the
responsible gene, the common pathophysiological passage of time, each step becomes less predictable
thread responsible for each of these various mani- as stride length errors are added to the gait cycle. In
festations is not apparent. Despite the wide range of many, the foot position assumes a dystonic posture
problems, there is a restricted range of manifesting with excessive varus and sometimes equinus, lead-
ATAXIA TELANGIECTASIA 289

ing to a toe-toe gait. Many children discontinue or develop normal speech articulation and prosody.
restrict independent walking between the ages of 8 Like the development of the gait, worsening of the
and 12 years, although differences in personal dysarthria is often noted only after 5 or more years
preference affect the defined "age of wheelchair of relative stability. The speech is often slow with
dependence" as much or more than does motor emphasis placed inappropriately on words or syl-
capacity. lables in a manner very suggestive of cerebellar
The instability of seating also Often has highly dysfunction. There are, in addition, equal contribu-
distinctive features. Children may sway from one tions of lingual, labial, and palatal dysfunction to
direction to another, often tipping to the edge of the dysarthria. Drooling is common in children but
stability and holding that edge for a prolonged time is often at its worst in earlier years with improve-
before correcting or overcorrecting. With time and ment noted in many. This may, in part, reflect
progression many teenagers will develop smaller improvements with learning.
abrupt co~ections of the trunk that may be either Though often unrecognized, progressive diffi-
adventitious postural-induced jerks or excessive culty with chewing and swallowing are nearly
uncoordinated postural corrections. Head instabil- universal in children with AT. The time required for
ity has many of the same features, often with meals increases, partly out of problems with self-
prolonged deviation of position to one or the other feeding, but also because of increasing oral motor
side, in extreme extension or flexion before correct- dysfunction. Silent aspiration becomes increas-
ing or overcorrecting. Though this movement may ingly more prominent in the second decade. Weight
appear to be related to diminished postural tone, it for height often drops late in the second decade. We
is notable that attempts to correct this head instabil- are currently investigating to what extent provision
ity passively will usually meet active resistance. for adequate nutrition will improve anthropomor-
Adventitious Movements and Ataxia. At all phic and other measurements of nutritional status.
ages, abnormalities in movement and coordination The face is normally expressive in most young
in AT are the most variable dimension of the children with AT. Virtually all will develop progres-
neurological phenotype. From toddler age on, most sive hypomimea that at first affects the small and
will have small, "fidgety" choreiform movements subtle facial expressions. In school-aged children, a
of the hands and feet when asked to lie still. This masklike appearance may contribute to the impres-
movement is rarely noted by the parent or child. sion of mental subnormality. However, in many it is
With time, difficulties with finger-nose-finger can punctuated by broad and pleasant smiles or promi-
be undermined by end-point dysmetria, intentional nent furrowed-brow frowns, each of which decay
or ballistic ataxia, postural instability, or a combina- slowly. Later in the second decade, these larger
tion of all of these. By age 10 years, most will expressions become less vigorous.
display typical choreaform movements of the hands Oculomotor. A number of distinctive oculomo-
with arms outstretched. Most children will enjoy tor abnormalities are found in AT, most of which
coloring in preschool years, sometimes doing so can be localized to the flocculus. The earliest
very well, but will cease to write for communica- feature, found in almost all patients except those of
tion by age 10 years because of difficulties in very young age, is impairment of the vestibular
legibility and speed. ocular response cancellation by fixation on an
In the teenage years, the range of abnormal object held at primary position while the head is
movements increases even further. We have seen rotated. By school age, most patients precede; or
disabling intention and essential tremor, "over- sometimes follow, saccades with an abnormal head
flow" cerebellar phenomena, apparent multifocal movement. Unlike classic oculomotor apraxia, these
and chaotic myoclonus, tics, and advanced chorea. head movements rarely pass the target and are
In many, motivation appears to have a perverse generally not used to reposition gaze in the absence
effect, so that with increasing intent performance of a saccade by dragging the eye at the limit of
diminishes, often with intervening jerks that are not excursion to the target. Other common abnormali-
apparent in other circumstances. ties include increased saccadic latency, saccadic
Bulbar Function and Facial Expressiveness. hypometria, and saccadic intrusions, and all will
Abnormalities of articulation are prominent in develop impairment of pursuits by school age. The
virtually all patients with AT. Most children never vestibular ocular response is rarely impaired, and
290 THOMAS O. CRAWFORD

saccadic velocity is generally normal. Sometime

between ages 10 and 14 years, many patients will
follow a head thrust with a slow, nonvestibular
conjugate movement that brings the eyes to the
target. 22
Neuropathy. A mixed sensorimotor, length-
dependent axonal polyneuropathy appears around
age 10 years manifested by the loss of ankle-deep
tendon reflexes. Demonstrable increase in vibra-
tory and position sense thresholds and distal amyot-
rophy usually present later. Despite the prominent
sway that can be seen in standing or sitting, there is
usually little enhancement of the instability with
eye closure in Romberg's maneuver. Absence of
this sign is a prominent discriminate to Friedreich's Fig 1. Characteristic ocular telangiectasia.
ataxia, where nighttime enhancement of gait insta-
bility is a prominent symptom. The neuropathy of
AT rarely participates in the overall nem'ological appearance, may appear on the external ears; malar
dysfunction to any meaningful degree, because aspects of the face, neck, antecubital, or popliteal
motor impairments due to central causes are usu- fossae; or occasionally on the dorsum of the hands
ally limiting at a much earlier age. and feet.9
The initial varus and equinus foot deformity Progeric changes of the hair and skin are the
associated with AT has a dystonic origin. Though other major progressive dermatological abnormal-
similar to the pes cavus foot of Friedreich's ataxia, ity in AT. This begins with the appearance ot
Charcot-Marie-Tooth disease, or other slowly pro- occasional grey hairs, even in young school-aged
gressive length dependent neuropathies, the foot children, and increases in many to become dif-
deformity in AT is often exaggerated with walking; fusely grey in the early twenties. The facial, hand,
not associated with an inflexible high arch, forefoot and feet skin, in particular, become atrophic and
atrophy, or hammer toe; and is often found in taut, with diminished subcutaneous tissue. Vitiligo-
younger patients despite the retention of ankle like hypopigmented areas may appear early and be
tendon reflexes. Some young adult patients with relatively nonprogressive in a few, whereas many
"variant" forms of AT who have milder central will have more subtle and progressive mottling ot
manifestations nonetheless have the full expression hypopigmented and hypelqgigmented areas with the
of peripheral neuropathy and may be limited by passage of time.
symptomatic pes cavus. 23
Immunological Manifestations
Dermatological Manifestations Diminished levels of immunoglobulin classes
The sentinel ocular telangiectasia (Fig 1) are immunoglobulin A (IgA) or IgG2 are found in 60%
almost but not always present. Unfortunately, they to 80% of cases25; less frequently, IgE or IgM will
usually do not manifest in the eyes in the earliest be decreased. Most patients have diminished cell-
years, which often results in delayed diagnosis by mediated response to intradermal antigens and
those physicians whose only knowledge of AT is its atrophy of the thymus. Lymphopenia is significant
name. In our first 50 patients at the AT Children's and progressive. However, despite these abnormali-
Center at Johns Hopkins Hospital, the recognition ties and despite helper T-cell counts that are often
of ocular telangiectasia and the diagnosis were in the range of patients with AIDS defining ill-
synchronous events and occurred an average of 4 to nesses, clinical expression of cellular immunodefi-
5 years after the first symptom of ataxia was ciency is lacking. In our experience, there have
recognized and brought to the attention of a doc- been no infections with opportunistic pathogens,
tor. 24 Telangiectasia appear first in the exposed such as Pneumocystis carinii, no invasive fungal
portions of the medial and lateral bulbar conjunc- infections, no difficulty with live virus vaccines,
tiva. Later, fine telangiectasia, almost petechial in and no systemic spread. Curiously, some patients
ATAXlA TELANGIECTASIA 291

may have problems with persistent and dissemi- to that seen in AT, is associated with mutation of
nated warts. ATM. Even if AT heterozygotes prove to have an
In contrast to the lack of opportunistic infections, increased relative risk for T-PLL, the absolute risk
sinopulmonary bacterial infections are common. will nonetheless remain low because of the rarity of
Bacterial pneumonia is the major cause of death. 9 this tumor, even relative to the low frequency of
In a minority of patients, the tendency for pneumo- ATM mutations in the population.
nia and sinusitis correlates with severe hypogamma-
globulinemia. However, we have also observed a Genomic Instability
strong correlation with the chewing and swallow- Lymphocytes show frequent breaks and recombi-
ing difficulties that develop during the second nations, particularly at the sites of chromosomes 7
decade. We hypothesize that pneumonia should be and 14, which encode genes for T-cell and B-cell
preventable in many patients by fastidious preven- antigen receptors. It is in these regions where
tative efforts but expect that pneumonia will con- double-stranded DNA recombinations occur to pro-
tinue to be a significant problem with advanced duce immunological diversity. Other cell types
neurodegeneration. show an increase in random chromosome breaks
and recombinations. The telomere of chromosomes
Cancer Predisposition is abnormally shortened in AT cells, 32 whereas
Children and young adults with AT have a chromosomes frequently show telomeric fusions.
substantial increased risk for lymphoreticular malig-
nancy. In the earliest series, malignancies were
Endocrine Manifestations
responsible for approximately 30% of deaths: this No specific hormonal deficit is known that would
may increase if antibiotics and control of aspiration account for the tendency of children with AT to
increases survival. Leukemia and lymphomas that grow less than normal. However, many also have
are of T-cell lineage are fourfold to fivefold more delayed or absent pubertal changes, often associ-
common than those of B-cell lineage. A leading ated with gonadal atrophy. In later years, insulin-
hypothesis for these malignancies is that absence of resistant diabetes is seen in a significant minority of
ATM leads to an increase in abnormal double- patients.
stranded DNA recombination events within lym-
phoid tissues Undergoing generation of immunologi- NEUROPATHOLOGY
cal diversity.26,27 Because of the tendency for Progressive atrophy of the cerebellar cortex is a
abnormal persistent DNA synthesis following irra- hallmark of AT, though it is not specific for the
diation and the enhanced susceptibility of AT disorder. At autopsy, the most prominent findings
patients to ionizing radiation, radiotherapy dosages are a diminished Purkinje cell population and
should be reduced substantially, but the tumors will thinning of the granule cell layer. 9 That this is a
be relatively more sensitive. postnatal loss is suggested by the presence, in some
The issue of heterozygote risk for malignancy cases, of persistent basket cells lining up to em-
was raised by Swift et al,28 who found an increased brace empty spaces from which Purkinje cells have
risk for breast cancer in first-degree relatives. With apparently been depleted. 33 An early finding 34 that
flanking marker identification of heterozygosity in has recently gained in importance because of its
relatives of AT patients, the odds ratio for breast recapitulation in ATM-deficient mice is the fre-
cancer was 2.9 in those less than 60 years old and quent appearance of abnormal Purkinje cells, lo-
6.4 in those over 60 years old, although the number cated within the molecular layer rather than at the
of cases were small. 29 However, in stark contrast is border of the molecular and granule cell layers, and
the paucity of ATM mutations found by protein often possessing abnormal multiple dendritic ar-
truncation screening in random patients with breast bors branching off in odd, angled directions in
cancer. 3~This quandary is unresolved, and the role contrast to the normally highly ordered, parasagit-
of AT heterozygosity as a risk factor for breast tal array (Fig 2). This finding suggests that there is a
cancer is not yet established beyond doubt. More dysgenic component to the neuropathology of AT
recent evidence31 suggests that T-cell prolympho- as well as the more prominent degenerative aspect.
cytic leukemia (T-PLL), which frequently harbors a Pathological changes outside of the cerebellum
genetic recombination at the T-cell receptor similar are much less prominent. The basal ganglia have
292 THOMAS O. CRAWFORD

It is our experience that the finding of an elevated

level of o~-fetoprotein (AFP) two times the upper
limit of normal is so common that diagnosis in its
absence necessitates a higher standard of labora-
tory, clinical, and molecular genetic evidence. AFP
is of little use before the first birthday because it is
normally elevated. On occasion, borderline Values
in the second year need be repeated after a period of
6 to 12 months to make the diagnosis more clear.
We have found an increase in characteristic lympho-
cyte chromosomal breaks following irradiation to
be a specific laboratory test useful in the proper
clinical setting, especially in younger patients or
Fig 2. Cerebellar cortex has a paucity of Purkinje cells. those with so-called "variant!' AT phenotype with
Those that remain are frequently maloriented above the mar- milder clinical manifestations. Because most AT
gin of the molecular and granule cell layers and have multiple patients have absent ATM protein, Western blot
or dysplastic major dentrites,
analysis of lymphoblastoid cells may become the
been investigated carefully, given the frequent most useful test.
extrapyramidal movement difficulties, but no repro-
GENETICS OF ATM
ducible changes have been identified. Degenerative
changes of the medullary olive may reflect a Earlier findings in AT that suggested there may
secondary degeneration due to loss of the target be as many as five multiple different pathogenic
Purkinje cell dendrites. In older patients, there may genes, each capable of complimenting another,
be degeneration of sensory and motor brainstem were undermined first by classic genetics locating
nuclei, as there is consistent evidence of degenera- the three most common forms to a single chromo-.
tion of dorsal root ganglion cells and motor neurons somal location 11@2-2336 and then by location of a
of the spinal cord. A striking finding in ganglion single gene, ATM, responsible for all cases. ATM is
satellite cells, Schwann cells of the peripheral a large gene, 9.3 Kb with 66 exons, encoding a
nerve, the anterior pituitary, and numerous other large protein of 3,056 amino acids. 1 Most muta-
locations is nucleomegaly, suggestive of poly- tions are unique 6 so that in the absence of consan-
ploidy in these cells. guinity, most patients are compound heterozygotes.
Most of the mutations are nonsense, producing
DIAGNOSIS early termination of translation and a likely un-
By school age, once AT is considered, the stable, rapidly degraded, protein. Some mutations
clinical diagnosis is straightforward in most cases produce splicing variants. Incomplete variant splic-
because of the constellation of characteristic fea- ing, a "leaky mutation," underlies most of the
tures. Unfortunately for the development of an milder cases of AT for whom a genetic explanation
absolute standard, otherwise typical patients display- is available. 37
ing all but a single sentinel feature (except for
ataxia) have been described. 35 With the description CELLULAR PHENOTYPES
of ATM, a new molecular standard of diagnosis is AND BIOLOGY OF ATM
conceivable, but the large size of the gene, the fact AT cells in culture display a range of abnormal
that most mutations are unique, and the possibility features that suggest that ATM has a role in many
that missense mutations could theoretically disable disparate processes of cell physiology. Among the
gene function but not alter protein size or immuno- more striking features are reduced-lif~span and
genicity make this a highly labor intensive enter- early senescence of cultures, chromosomal instabil-
prise that remains more specific than sensitive. ity, and defective radiation-induced delay at the cell
Certainly, the finding of a disabling mutation of one cycle checkpoints G1, S, and G2. The best under-
allele of ATM that is coupled with characteristic stood of these is the G1 cell cycle checkpoint,
clinical features is highly suggestive of the diagno- which is influenced by the tumor suppressor p53.
sis by Bayesian criteria. AT cells do not increase p53 in response to ionizing
ATAXIA TELANGIECTASIA 293

radiation, 38 which in turn fails to initiate the G1 cell the specialized structure along the meiotic single-
cycle checkpoint, blocking DNA synthesis. DNA strand chromosome where recombination occurs.
breaks appears to be a major signal for p53 Recombination, requiring heteroduplex formation
induction in normal cells. It appears that ATM- of sister chromosomes followed by strand ex-
deficient cells lack a sensor of double-stranded change, does not proceed normally in the absence
DNA breaks, which should normally induce p53 to o f A T M . 40
suppress the mitotic cycle pending repair. This ATM-deficient mice, created in several different
absence of p53 induction in AT leads to cell l a b o r a t o r i e s i n d i f f e r e n t b a c k g r o u n d strains, 41,42,43
division despite persistence of broken DNA, which r e p r o d u c e m a n y o f the f e a t u r e s o f the d i s e a s e
may be directly responsible for the frequent chromo- including diminished growth, defective immune
somal rearrangements seen in AT cells. d e v e l o p m e n t , infertility w i t h m e i o t i c failure in
In other cell-signaling pathways, ATM-deficient immature gonads, and propensity for lymphoreticu-
cells behave, in a number of dimensions, as though lar m a l i g n a n c y , T h e m i c e are u n c o o r d i n a t e d , b u t
they are chronically undergoing oxidative chal- demonstration of a progressive neurodegeneration
lenge. The gene NF-KB plays a key role in gene is difficult g i v e n l i m i t e d life s p a n o f t h e a n i m a l s . 41
regulation response to reactive oxygen species and Cells f r o m t h e s e a n i m a l s s i m i l a r l y r e p r o d u c e t h e
redox state of the cell, and is constitutively ex- h u m a n p h e n o t y p e w i t h s l o w g r o w t h , early senes-
pressed in AT cells. A number of other genes cence, a n d a b n o r m a l c h e c k p o i n t s i n r e s p o n s e to
reactive to oxidative stress or to ionizing radiation i o n i z i n g radiation.
behave similarly in AT cells. 39This state of chronic
induction is hypothesized to be important to many
ACKNOWLEDGMENTS
of the widespread features of the disease.
The gonadal dysgenesis may be due, in part, to a The author is indebted to the AT Children's Project for
support and encouragement, and to the many families and
prominent role of ATM in synapsis of meiotic children with AT who have traveled to Baltimore for evaluation.
chromosomes undergoing recombination. ATM lo- Howard Lederman and Don Gilbert assisted in reviewing the
calizes to sites along the synaptonemal complex, manuscript.

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