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taxia With Oculomotor Apraxiaei Liu, MD, PhD,* and Vinodh Narayanan, MD†

Ataxia-telangiectasia (AT) belongs to a group of recessively inherited disorders character-ized by progressive ataxia and oculomotor apraxia. Included in this group are AT, ataxia-telangiectasia–like disorder (ATLD), ataxia with oculomotor apraxia type 1 (AOA 1), ataxiawith oculomotor apraxia type 2 (AOA 2), and the recently described AOA3. Common to thisgroup is the underlying cellular defect in the recognition and repair of double-strand orsingle-strand DNA breaks. Clinical and laboratory features allow one to distinguish be-tween these various disorders. In this report, we describe a child with early onset progres-sive ataxia, oculomotor apraxia, ocular telangiectasia, and white-matter changes by mag-netic resonance imaging, which appears to be yet another novel form of AOA. Wedesignate this condition as AOA-WM to call attention to the central demyelination seen inthis variety of ataxia with oculomotor apraxia.Semin Pediatr Neurol 15:216–220 © 2008 Elsevier Inc. All rights reserved.

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10-year-old boy was first seen in our office because ofpoor balance, difficulty walking, and a visual distur-

ance. In retrospect, he might have had difficulty with hisait as early as age 5, and his speech has always been difficulto understand. He had a subacute worsening of his symptomsover 3-4 weeks) when he was 8.5 years of age, resulting inim being admitted to a hospital where a computed tomog-aphy scan suggested a brainstem lesion. His neurologic find-ngs at that time included “hyperkinetic behavior, oculo-

otor dysfunction, gait ataxia, dysmetria, and long-tractysfunction.” Magnetic resonance imaging at that time waseported to show patchy signal changes within the brainstemnd subcortical white matter leading to the diagnosis of acuteisseminated encephalomyelitis (ADEM). He was given aourse of steroids, with improvement in his stability andalance.He apparently did not recover completely after completing

n 8-week course of steroids and has had a gradual deterio-ation over the last 2 years in gait, speech, and visual func-ion. He needs help with bathing and dressing himself; he istill able to walk, but his gait has worsened. His speech re-ains difficult to understand.There were no problems during the pregnancy that re-

ulted in his birth nor were there any perinatal complica-

rom the *Department of Neurology, Children’s Health Center, St. Joseph’sHospital and Medical Center, Phoenix, AZ.

Division of Child Neurology, Children’s Health Center, St. Joseph’s Hospi-tal and Medical Center, Phoenix, AZ.

ddress reprint requests to Vinodh Narayanan, MD, Barrow NeurologicalInstitute, St. Joseph’s Hospital and Medical Center, 500 Thomas Rd,

eSuite 400, Phoenix, AZ 85013. E-mail: Vinodh.Narayanan@chw.edu

16 1071-9091/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.spen.2008.10.014

ions. He achieved his early milestones at an appropriateime. He walked at 9 months, spoke in single words by 1 year,nd progressed normally, although his speech has alwayseen difficult to understand. He is functioning slightly belowrade level in school and is undergoing speech therapy.

He was evaluated by an optometrist who prescribed eye-lasses. He did not have a history of frequent upper-respira-ory infections.

He is the youngest of 8 children. The oldest sibling isealthy and has 3 of her own children, all healthy. The sec-nd child died at age 10 from either tuberculosis or leukemiaparents are uncertain). The fourth child (now age 20) isealthy now but has been treated for tuberculosis. The fifthhild died at age 13 months; this death was also thought to beaused by tuberculosis. The sixth child died after a gastroin-estinal infection. The other siblings are healthy.

At the time of his initial examination, his height and weightere at the 15%, and his head circumference was at the 55%.is general physical examination did not reveal any abnor-ality. His heart and lung sounds were normal, his spine was

traight, and there were no abnormal skin markings.His neurologic examination was significant for oculomotor

praxia, fairly dramatic gait ataxia, dysmetria, normal muscleone and strength, and normal tendon reflexes (elbows,nees, and ankles). He was unable to initiate a horizontalaccade and needed to make a head movement (thrust) toefixate on an object. Vertical gaze movements were betterut were performed with some difficulty. Oculocephalic re-ex responses were intact, with full lateral eye movements.isual fields were normal by confrontation testing, as wasisual acuity. Pupillary response to light and funduscopic

xamination were normal. There was prominent telangiecta-

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Ataxia with oculomotor apraxia 217

ia of the bulbar conjunctiva on the right eye (Fig 1). Initialaboratory tests showed normal levels of serum �-fetoproteinAFP), lactate, pyruvate, and immunoglobulins. Brain mag-etic resonance imaging (MRI) (Fig 2A-D) showed cerebellartrophy, with multiple foci of cerebellar and cortical white-atter T2 hyperintensity. Involvement of dorsal pons, mid-le cerebellar peduncle, and the white matter around theourth ventricle was also noted.

About 8 months after his initial evaluation, he was admit-ed to our hospital after a prolonged episode of unresponsive-ess and drooling. He was sitting at home on his couch dur-

ng this episode, and it was preceded by a complaint of eyeain. There was no jerking or incontinence during this epi-ode, but the possibility of a prolonged complex partial sei-ure was considered. Cerebrospinal fluid (CSF) examinationevealed 17 white blood cells (100% lymphocytes), 0 redlood cells, glucose of 59 mg/dL, protein 39 mg/dL, CSF

actate of 1.0 mEq/L, and pyruvate of 0.109 mmol/L (0.03-.107). CSF was positive for oligoclonal bands, but CSF lymeiter, immunoglobulin G synthesis rate and index, levels of

igure 1 Telangiectasia of R bulbar conjunctiva. (Color version ofgure is available online.)

Figure 2 Brain MRI images. A through D were selectedB through D were flair images at different levels of the bra

after the first one. E and F are flair images at different levels. G

ngiotensin-converting enzyme, and amino acid quantifica-ion were normal or negative. The serum ammonia level,lbumin, immunoglobulin G subclass, and cholesterol pro-le were normal. A serum extended antinuclear antibodyANA) panel was negative. A second brain MRI was per-ormed (Fig 2E-I) and showed more patchy areas of T2 hy-erintensity in the subcortical white matter (occipital re-ion), with contrast enhancement. An electroencephalogramhowed paroxysmal bursts of generalized 3- to 3.5-Hz spikend wave discharges seen both spontaneously and in re-ponse to stimulation procedures. Nerve-conduction studies/lectromyography did not show signs of a neuropathy. Aisual-evoked potential study suggested retroretinal visualonduction block.

Because of our suspicion that this child had either ataxia-elangiectasia (AT) or a form of ataxia with oculomotorpraxia (AOA), further biochemical and molecular testingas undertaken. Colony radiosensitivity assay (performed inr Richard Gatti’s laboratory, UCLA) was normal. Westernlot analysis of cell lysates prepared from this patient’s im-ortalized lymphoblasts showed normal levels of the follow-

ng proteins: ATM, nibrin, Mre11, aprataxin, and senataxin.NA sequencing of the ATM, APTX, and SETX genes wereormal. He was homozygous at 3 single nucleotide polymor-hisms (SNPs) within the ATM gene, suggesting either trueomozygosity at each of these SNPs or a large deletion of onellele. These SNPs are located at intron 4, intron 25, and exon2. A subsequent assay showed that this patient did not havelarge deletion on one of the alleles of the ATM gene.

iscussione describe a patient with early-onset progressive cerebellar

taxia, dysarthria, oculomotor apraxia, ocular telangiectasia,nd a single prolonged event of decreased alertness. Brain

e MRI done at age 10 years. A is T1 sagittal plane image.res E through I were from a second MRI done 6 months

from thin. Figu

through I are contrast-enhanced T1 images.

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218 W. Liu and V. Narayanan

RI showed cerebellar atrophy and patchy areas of T2 hy-erintensity in the subcortical, cerebellar, and brainstemhite matter. He does not have mental retardation, periph-

ral neuropathy, immune deficiency, or cardiomyopathy.evels of serum AFP, immunoglobulins, cholesterol, and al-umin were normal. Biochemical studies showed normal lev-ls of ATM, Mre11, aprataxin, and senataxin protein. Se-uencing of the ATM, APTX, and SETX genes was alsoormal.This patient shares clinical features with AT, ataxia-telan-

iectasia–like disease (ATLD), and ataxia with oculomotorpraxia type 1 and 2 but does not qualify for any of thesether diagnoses. This leads us to conclude that this patientepresents a new form of AOA, which we designateOA-WM to call attention to the central demyelination onrain MRI.There are at least 4 known disorders that are characterized

y progressive cerebellar ataxia, oculomotor apraxia, invol-ntary movement, and peripheral neuropathy. They are au-osomal recessive diseases caused by mutations in differentenes, but can be differentiated from each other based onlinical and laboratory features (Table 1).

AT (OMIM #208900) is the most common of the 4 disor-ers, with an estimated prevalence of 1 to 2.5/100,000. It isharacterized by progressive ataxia, oculocutaneous telangi-ctasia, immune deficiency, and predisposition to lymphore-icular malignancy.1,2 Laboratory abnormalities in AT in-lude elevated serum AFP, increased sensitivity to ionizingadiation, and absence of the ATM protein. Cytogenetic anal-sis shows a 7:14 chromosomal translocation in 5% to 15%atients. Linkage studies in familial cases of AT allowed for

ocalization of the ATM gene to chromosome 11q23.3,4 TheTM protein is a nuclear serine/threonine protein kinase that

s activated by autophosphorylation after DNA damage. Itctivates the G1-S, S, and G2-M cell-cycle checkpoints byhosphorylation of many target proteins that are required forNA repair in mitotic cells.5 Many of these downstream pro-

able 1 Comparisons of the Clinical and Biological Characte

A-T

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erebellar ataxia �culomotor apraxia �horea/dystonia �eripheral neuropathy �elangiectasia �ecurrent upper respiratory infections �alignancy �adiation Sensitivity �levated �-fetoprotein �

mmunoglobin deficiency �ypoalbuminemia �ausative gene ATM

AOA type 2 has increased gamma immunoglobins.

eins may also have a role in postmitotic neurons. In neurons, s

TM may have a neuroprotective role against oxidativetress, probably via activating and stabilizing p53.6,7 Morehan 85% of patients with classic AT are compound heterozy-otes for mutations that result in truncation of the ATM pro-ein. Missense or splice-site mutations of the ATM gene thatead to a decreased expression of the protein are associatedith milder symptoms.8 More than 400 different mutations,

cattered through the entire ATM gene, have been reported.9

utation analysis or sequencing of the gene is required toonfirm the diagnosis if ATM protein levels are normal by

estern blot.Neuroradiologic features of AT include cerebellar and ver-al atrophy, which are confirmed by neuropathological

tudies. Recently, areas of T2 hyperintensity within the cere-ral white matter have been reported in cases of AT.10-12

hose apparent areas of extracerebellar demyelination arehought to be caused by gliovascular lesions consisting ofctatic veins and capillaries and hemosiderin deposits sur-ounded by focal demyelination.

ATLD (OMIM #604391) is a rare disease, with only 17ases reported as of 2008.13,14 ATLD shares some clinicaleatures with AT including progressive cerebellar ataxia, dys-rthria, and oculomotor apraxia. In contrast to the AT, ATLDatients have a later age of onset, slower progression, andilder neurologic symptoms. Patients with ATLD do notave telangiectasia, immunoglobulin deficiency, or abnormal

evels of AFP. Although lymphoblastoid cells collected fromatients with ATLD show increased radiation sensitivity, it isnknown if they are predisposed to cancer. The causativeene, Mre 11 on chromosome 11 encoding the Mre11 pro-ein, maps very close to the ATM gene. A protein complexonsisting of Mre11-Rad50-Nbs1 (MRN complex) is in-olved in the cellular response to DNA double-strand breaks.t appears to act by sensing double-strand breaks and as anffector in regulating cell-cycle checkpoints and downstreamffects.15 Interestingly, ATLD, which is caused by a deficiencyf Mre 11, is clinically quite distinct from Nijmegen breakage

of Different Ataxia With Oculomotor Apraxia Disorders

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ijmegen breakage syndrome is characterized by microceph-ly, growth retardation, immunodeficiency and susceptibil-ty to cancer.

AOA type 1 (AOA 1, OMIM #208920) is characterized byymptom onset between ages 2 and 6 years. Oculomotorpraxia is the earliest symptom, followed by ataxia and cho-eoathetosis. Peripheral sensorimotor neuropathy is a featuref this disease, manifested by diminished vibratory sensation,reflexia and slowly progressive decline in motor functionnd superficial sensation.16 Patients have distal symmetriceakness and wasting. Clinical laboratory findings in AOA 1

nclude normal AFP level, hypoalbuminemia, and hypercho-esterolemia. In contrast to Friedreich’s ataxia, which is alsoharacterized by ataxia, areflexia, and hypoalbuminemia, pa-ients with AOA1 do not develop cardiomyopathy. Patientsith AOA 1 do not have the oculocutaneous telangiectasia,

mmunodeficiency, or predisposition to lymphoreticular ma-ignancy that is observed in AT. The causative gene for AOA

is APTX on chromosome 9p13.3. It encodes aprataxin, abiquitously expressed nuclear protein that contains a histi-ine-triad domain.17,18 Aprataxin catalyzes the hydrolytic re-

ease of DNA end-blocking lesions, serving as a proofreaderor the cellular single-strand DNA repair. Most mutations inPTX occur within the histidine-triad domain, which inter-

eres with its proofreading function, resulting in accumula-ion of 5=-DNA adenylates. Unlike proliferating cells, post-itotic neurons lack alternative means to remove those 5=

denylates, which, in turn, might interfere with transcriptionnd results in apoptosis. This condition represents a uniquexample of a single gene defect causing neuron-specific celleath and could provide a good model to study the relation-hip between DNA repair and neurodegeneration.

AOA type 2 (AOA 2, OMIM #606002) differs from AOA 1y later onset of symptoms, typically between 11 and 20ears age. This condition is characterized by cerebellar ataxia,horeoathetosis, and dystonia on walking. Oculomotorpraxia has been reported in 50% of cases. Patients haveyporeflexia, distal amyotrophy, and decreased vibratoryensation because of axonal sensorimotor neuropathy. Inter-stingly, patients with AOA 2 also have elevated serum AFPut do not develop cardiomyopathy, oculocutaneous telan-iectasia, or immunodeficiency. Creatine kinase and gammammunoglobulins are elevated in AOA2. The causative geneor AOA 2 is SETX on chromosome 9q34. It encodes sena-axin, whose C-terminus contains the 7-motif helicase do-ain found in the superfamily 1 of helicases. Senataxin is auclear protein involved in the cellular response to DNAamage, although its precise function remains unknown.ore than 30 different mutations of SETX have been reported

n patients with AOA 2.19-21 Although the role of senataxin isot fully understood, recent evidence suggests it responds toxidative stress-induced double-strand DNA damage but noto irradiation-induced double-strand DNA or single-strandNA damage.22

Recently, another form of AOA, called AOA 3, has beeneported in a single patient.23 This patient developed ataxiand oculomotor apraxia at 8 years of age. He was dysarthric

nd had a mild immunodeficiency. He did not have ocular

elangiectasia and had normal levels of AFP, albumin, andholesterol. His brain MRI showed cerebellar atrophy. Thereas no mutation in the ATM, APTX, SETX, or p53 genes. Cells

rom this patient showed defective p53 response to DNAamage,24 but the precise gene defect for AOA3 remains un-nown.

onclusionshe case reported here shares key clinical features that are

ound in AT and the AOAs including progressive ataxia, oc-lomotor apraxia, and ocular telangiectasia. Based on theegative results from a comprehensive panel of genetic, met-bolic, and electrophysiologic tests, we conclude that there isore heterogeneity in this group of disorders than currently

ppreciated. In addition, normal AFP and the absence ofardiomyopathy distinguish it from Friedreich’s ataxia withetained reflexes. A lack of spasticity and hypermyelination ofetina makes the diagnosis of Charlevoix-Saguenay unlikely.

lack of ophthalmoplegia and the presence of oculomotorpraxia are atypical for spinocerebellar atrophy.

The brain MRI of our patient not only shows cerebellar andermal atrophy, which is typical for AT and its variants, butlso reveals patchy areas of T2 hyperintensity within thehite matter. There was no objective evidence of demyelina-

ion involving the peripheral nervous system. There are onlycases of AT reported with such white-matter changes.10-12

he majority of patients with AT do not show white-matterbnormalities. A single report exists of multiple sclerosis oc-urring in a family with low levels of the ATM protein. In theatient we describe, there is clear progression of white-matterhanges in his MRIs, and he had oligoclonal bands in theSF. We have contrasted the features of this case of AOA with

he other disorders in this group and designate this disorders AOA-WM (ataxia with oculomotor apraxia and white-mat-er abnormality).

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220 W. Liu and V. Narayanan

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