Neuropathology in classical and variant ataxia-telangiectasia

Original Article neup_1263 234..244

Neuropathology in classical and variantataxia-telangiectasia

Mijke M.M. Verhagen,1,2 Jean-Jacques Martin,7 Marcel van Deuren,3 Chantal Ceuterick-de Groote,7

Corry M.R. Weemaes,2 Berry H.P.H. Kremer,6 Malcolm A.R. Taylor,8 Michèl A.A.P. Willemsen1

and Martin Lammens4,5

Departments of 1Pediatric Neurology, 2Pediatrics, 3Internal Medicine and 4Neurology, Donders Institute for Brain,Cognition and Behaviour and 5Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, 6Department of

Neurology, University Medical Centre Groningen, Groningen, The Netherlands, 7Department of UltrastructuralNeuropathology and Biobank, Institute Born-Bunge, University of Antwerpen, Antwerpen, Belgium and 8Cancer

Research UK, Institute for Cancer Studies, Birmingham University, Birmingham, UK

Ataxia-telangiectasia (A-T) is classically characterized byprogressive neurodegeneration, oculocutaneous telang-iectasia, immunodeficiency and elevated a-fetoproteinlevels. Some patients, classified as variant A-T, exhibit amilder clinical course. In the latter patients extrapyramidalsymptoms, instead of cerebellar ataxia, tend to be thedominating feature and other classical disease hallmarks,like telangiectasia, appear later or even may be absent.Some patients with variant disease have clinically pro-nounced anterior horn cell degeneration. Neuropathologi-cal studies of genetically proven A-T patients are lacking.The aims of our study were to describe the neuropathologyof three A-T patients; in two of them the diagnosis wasgenetically confirmed. The neuropathological findings werecompared with those of all known published autopsy find-ings in A-T patients up to now. Two classical A-T patientsaged 19 and 22 and a 33-year-old patient with variantdisease were autopsied. In line with previous reports, ourpatients had severe cerebellar atrophy, less pronounceddegeneration of the dentate nucleus and inferior olive,degeneration of the posterior columns and neurogenicmuscular atrophy. In addition, all three had anterior horncell degeneration, which was most prominent at the lumbarlevel. Compared to the literature, the degenerative changesin the brain stem of the variant A-T patient were somewhatless than anticipated for his age. Degenerative changes in

the cerebellum and spinal cord were comparable withthose in the literature. Progeric changes were lacking. Inconclusion, compared to classical A-T, the variant A-Tpatient showed essentially the same, only slightly milderneuropathological abnormalities, except for anterior horndegeneration.

Key words: ataxia telangiectasia, neuropathology, spinalcord, variant.

INTRODUCTION

Ataxia-telangiectasia (A-T), recognized as a separatedisease entity in 1957, is a complex autosomal recessivemultisystem disorder, with severe neurodegeneration as animportant feature.

Neurologic signs include cerebellar ataxia, oculomotorapraxia, extrapyramidal symptoms, polyneuropathy andanterior horn cell degeneration.1 Other identified diseasecharacteristics are oculocutaneous telangiectasia, variableimmunodeficiency, endocrine abnormalities, respiratoryfailure, predisposition to malignancies, increased seruma-fetoprotein (aFP) levels, chromosomal translocationsand radiosensitivity.1 However, since the ATM gene wasidentified in 1995,2 it became apparent that the clinicalspectrum of A-T is variable. Some patients with an atypicalclinical course – those with slower disease progression,predominant extrapyramidal symptoms or later diseaseonset – appeared to have A-T.3,4 The milder A-T pheno-type, now classified as variant A-T, is associated withmissense mutations and splice site mutations leadingto residual ataxia-telangiectasia mutated (ATM)-proteinexpression and residual ATM-kinase activity. The severity

Correspondence: Martin Lammens, MD, PhD, Department of Pathol-ogy 825, Radboud University Nijmegen Medical Centre, PO Box 9101,6500 HB Nijmegen, The Netherlands. Email: [email protected]

Received 1 May 2011; revised 10 August 2011 and accepted 8September 2011; published online 24 October 2011.

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Neuropathology 2012; 32, 234–244 doi:10.1111/j.1440-1789.2011.01263.x

© 2011 Japanese Society of Neuropathology

of the phenotype depends on the amount of residual kinaseactivity.4 Elevated aFP levels and cytogenetic abnormali-ties are excellent disease markers of both the classical andthe variant A-T phenotype.4

The majority of neuropathology studies in A-T datefrom the 1960s. Recent post mortem studies are sparse.More importantly, only one study was published after thediscovery of the ATM gene,5 but autopsy results have notbeen described in genetically confirmed A-T cases.

To gain more insight into the neuropathology of A-T, weevaluated nervous system findings of three autopsies ofA-T patients: two patients with classical A-T who died atages 19 and 22 years, while one patient of 33 years sufferedof variant A-T. Diagnosis was genetically confirmed in oneof the two classical A-T patients and in the variant A-Tpatient. In addition, we reviewed the literature for CNS-autopsy results of A-T patients and compared our datawith those published in the era before identification of thegenetic defect.

PATIENTS AND METHODS

Patients

The main clinical and laboratory findings of the patientsare listed in Table 1.

Patient 1

This boy’s early childhood psychomotor development wasnormal. However, from the age of 2 years his gait becameprogressively ataxic. There was IgA deficiency. Pneumoen-cephalography showed cerebellar atrophy. Electromyogra-phy and a muscle biopsy, at that age, were normal.

At presentation he was found to be small, cachectic andseverely dyspnoeic. Neurological investigation revealedcerebellar ataxia and dysarthria, distal paresis with amyo-trophy, and dystonic posture of the hands and fingers. Deeptendon reflexes were absent. Proprioception was mildlyaffected. He died 1 week after presentation, in 1981 at age19. Three siblings of the patient also suffered from A-T.Autopsy findings of one of his brothers were previouslypublished.6

Patient 2

This girl suffered in her early childhood from recurrentupper respiratory tract infections. Motor development wasdelayed. When she started to walk at the age of 18 months,the gait was ataxic. Increased aFP level, humoral andcellular immunodeficiency, typical rearrangements of chro-mosomes 7/14 and radiosensitivity were present. Electro-physiological studies revealed severe and progressiveaxonal sensorimotor polyneuropathy from the age of 14.7At

Table 1 Clinical and laboratory findings in three ataxia-telangiectasia patients

Patient 1 Patient 2 Patient 3

PatientGender Male Female MalePhenotype Classical Classical VariantGenotype NA c.1027_1031del5/ c.1660delA c.7838_7839dupGA/ c.8494C > TDied at age (years) 19 22 33Cause of death Respiratory failure Intractable urinary tract

bleeding/ respiratoryfailure

Bronchopneumonia/hepatocellular carcinoma

Disease onsetPresenting symptom Cerebellar ataxia Cerebellar ataxia Cerebellar ataxia and

myoclonic jerksSince the age of (years) 2 1.5 6

Wheelchair-bound since the age of (years) NA 10 18Extrapyramidal symptoms + + +Oculomotor apraxia NA + -Neuromuscular symptoms

Weakness + + +Atrophy + + +Sensory deficit + + +Absent deep reflexes + + +

Non-neurological featuresOcular telangiectasia since the age of (years) 6 7 -Malignancy - + +

Laboratory findingsIncreased a-foetoprotein level NA + +Immunodeficiency + + -Chromosomal instability NA + +Radiosensitivity NA + +

NA, data not available; +, present; –, absent.

Neuropathology in A-T 235


age 16, a B-cell non-Hodgkin’s lymphoma was diagnosed inthe epipharynx. Treatment with vincristine, methotrexate,doxorubicine and prednisone in mitigated dosages, resultedin complete remission. However, since that time B-cell lym-phopenia and agammaglobulinemia persisted,necessitatinggammaglobulin substitution. In addition, a deterioration ofneurological functions was seen after chemotherapy. Shedeveloped pedes equines, claw position of the hands, con-tractures of both knees and hips, severe muscle weaknessand atrophy, while the choreiform movements of her limbsand head became worse. Pulmonary function tests revealeda severe and progressive restrictive pulmonary functionfrom the age of 17 years onwards. She developed diabetesmellitus type 2. She died in 2005, at age 23 of an intractableurinary tract hemorrhage and respiratory failure.

Patient 3

Part of the medical history of this patient was publishedpreviously.8 His psychomotor development was normaluntil the age of 6 years. Thereafter he developed progres-sive cerebellar symptoms and myoclonic jerks. Clinicalexamination at age 22 showed distal amyotrophy, paresisand areflexia. Gnostic and vital sensation was distallyimpaired. Cerebral imaging revealed pontocerebellaratrophy. Nerve conduction studies and electromyographyrevealed a progressive axonal sensorimotor neuropathy.Neither oculocutaneous telangiectasia nor oculomotorapraxia nor immunodeficiency were observed. He devel-oped diabetes mellitus type 2. Laboratory findings includedan elevated aFP level, chromosomal instability andincreased radiosensitivity of DNA synthesis. At the age of33 the patient was diagnosed with metastasised hepatocel-lular carcinoma. He died 1 week thereafter of bilateralbronchopneumonia in 1993.

Molecular genetic studies

Mutation analysis of the ATM gene and measurements ofATM-protein expression and ATM-kinase activity wereperformed as previously described.9,10

Pathological analysis

The brains and the spinal cords were examined macro-scopically and fixed in 10% formalin for several weeks.After the CNS was sectioned, blocks were taken from thecerebral neocortex from each separate cerebral lobe, hip-pocampus, cingulated gyrus, amygdala, basal ganglia, thala-mus, hypothalamus, cerebellum, midbrain, pons, medullaoblongata and the spinal cord at cervical, thoracic andlumbar levels. These blocks were embedded in paraffin.Sections from these blocks were stained with HE,LFB-cresyl violet or LFB-hematoxylin. Additional silver

impregnations were performed. Immunohistochemistry ofspinal cord sections was performed using the immuno-peroxidase technique with antibodies against ubiquitin(DAKO, Leuven, Belgium; pAB Z0458), AT8 (Innogenet-ics, Ghent, Belgium), phosphorylated TDP43 (ProteinTech, Manchester, UK; pAB 10782–2-AP) and unphospho-rylated alpha-synuclein (syn211, NeoMarkers, Fremont,CA, US).

Literature search

The paper of Sedgwick and Boder1 was indicated as a keypaper on the neuropathology of A-T. All referred articlesof this study were critically reviewed and autopsy studies of“A-T patients” CNS findings were retrieved. Additionalpapers were searched, using the PubMed database of theUS National Library of Medicine, with the key words:ataxia telangiectasia AND autops*, ataxia telangiectasiaAND neuropatholog*, ataxia telangiectasia AND histopa-thology*, ataxia telangiectasia AND nervous. Relevantarticles were identified from the reference lists.

RESULTS

Molecular genetic studies

From patient 1 no material was available for molecularstudies.

Patient 2 was compound heterozygous for two trun-cating mutations: c.1027_1031del5 in exon 10, leading toa frame shift in the protein at position Glu343, andc.1660delA in exon 13 causing a frame shift at Thr554. Celllines from patient 2 showed no ATM-protein expression orATM kinase activity.

In patient 3 ATM mutation analysis revealed a truncat-ing mutation in exon 55, c.7838_7839dupGA (p.Pro2614fs),and a missense mutation in exon 60, c.8494C > T(p.Arg2832Cys). Cell lines showed some ATM-proteinexpression, with residual ATM-kinase activity.

Neuropathological studies

The main neuropathological findings of the patients arelisted in Table 2.

Patient 1

Except for a slight pallor of the myelinated structures in thepallidum the supratentorial structures were almost normal.Both the hemispheric and the vermian cerebellar cortexwere atrophic, more so dorsally than ventrally, with severeloss of the Purkinje cells, slightly more than the loss ofinternal granular neurons.The nuclei of Goll and the bulbarolivae were severely degenerated.Also,fibrillary gliosis wasfound in the median raphe and in the spinal radix of the

236 MMM Verhagen et al.


trigeminal nucleus. The gracile fascicle (Fig. 1a–c) showedsevere loss of myelinated fibers and important fibrillargliosis, most severely so at the cervical level and with aventral to dorsal gradient within each level. At the lowerthoracic and lumbar levels, a paramedian region corre-sponding to the descending fibers of the posterior funiclesremained relatively spared. The cuneate fascicle was lessinvolved. The tractus semilunaris was also better sparedthan the ascending tracts of the posterior funiculus. In thelateral cords, astrocytes with large irregular nuclei werefound. The anterior horns (Fig. 2a,b) showed some fibrillargliosis and there was some neuronal loss with proliferationof astrocytes and microglia and some neuronophagia in thelumbar cord. In the nucleus of Clarke a few neuroaxonalspheroids were present.

Muscle biopsies of the triceps surae and the bicepsfemoris muscles, taken at 6 years of age, already showedsigns of neurogenic atrophy. There were no signs of mito-chondrial disorder. The cervico-brachial plexus, lumbarplexus and sciatic nerve showed some signs of axonaldegeneration but no signs of segmental demyelination onlight microscopic examination; electron microscopy wasnot available.

Patient 2

Supratentorial examination did not reveal any signifi-cant lesion. The cerebellum, the nuclei of Goll and theinferior olivary nuclei showed important degeneration.Severe, to almost complete loss of myelinated fibers inthe gracile fascicle was seen at all levels of the spinal cord(Fig. 1d–f). The only regions with almost normal remain-ing myelination of this fascicle were found in the para-median zone at the lumbar level and in subpial locations.Moderate to severe loss of myelinated fibers in thecuneate fascicle was noted. The tractus semilunaris wasbetter preserved. There was mild loss of myelinatedfibers in the lateral corticospinal tract and in the spinoc-erebellar tracts. In the anterior horns some neuronal loss,one ballooned neuron and several neurons with chroma-tolysis were found. This was complemented by mild astro-cytosis and swollen axons. The anterior horn lesions(Fig. 2c,d) were most prominent in the lumbar segmentsand almost absent at the cervical level. Some neuronalloss, a sporadic neuron with central chromatolysis and afew neuroaxonal spheroids were seen in the Clarkes’columns.

Table 2 Neuropathological autopsy findings in three ataxia-telangiectasia patients

Patient 1 Patient 2 Patient 3

PatientSex Male Female MalePhenotype Classical Classical MilderDied at age (years) 19 22 33

Supratentorial structuresVenous congestion + - -Thalamus, hypothalamus, putamen and caudate nucleus abnormalities - - -Degeneration and demyelinisation in the pallidum internum Mild - -

CerebellumCortical atrophy Severe Severe Moderately- severeLoss of the internal granular layer Important loss Moderate – severe Light – severePurkinje cell loss Severe Slight – moderate Moderate – severeDislocation of Purkinje cells + +Empty baskets + + +Hypertrophy of the Bergman glia + + +Degeneration of the dentate nucleus Mild Mild Mild

BrainstemDegeneration and gliosis in the nuclei of Goll + +Degeneration of the bulbar olivae Severe Mild ModerateNeuronal loss in the substantia nigra - - -

Spinal cordPosterior column demyelination and degeneration Severe Severe SevereParamedian sparing of myelinated fibers in the gracile fascicle + + +Cuneate fascicle less involved compared with the gracile fascicle + + +Lateral cord degeneration Mild Mild MildAnterior horn cell degeneration Slight Slight Slight – moderateDegeneration of Clarke’s columns Mild Mild Moderate

MusclesNeurogenic atrophy Slight No – severe Severe

NervesAxonal degeneration Slight -Segmental demyelination - -

NA, data not available; +, present; –, absent.



The anterior tibial muscle showed in the same sectionboth normal appearing areas and one severely abnormalarea with signs of advanced denervation atrophy. The ili-opsoas muscle displayed several small or atrophic fibers,intermingled with normal-sized fibers. On average, type IIfibers were smaller than type I fibers and some atrophictype II fibers were noted. The quadriceps muscle appearedquite normal except for a relative increase in the numberof type 2 fibers, but no signs of denervation atrophy. Nervespecimens were not available for examination.

Patient 3

An old hemorrhage, with a gliotic reaction, resided in thewhite matter of the precentral gyrus, in conjunction with afew microscopic old necrotic cortical lesions. There was

cerebellar atrophy with mild to severe loss of the internalgranular layer, sometimes more pronounced at the top ofthe folia, and moderate to severe loss of Purkinje cells. Theinferior olives showed moderate gliosis. A few focal micro-glial nodules were seen in the pes pontis. There was mildpallor of the locus coeruleus.

There was severe to almost complete loss of myelinatedfibers in the gracile fascicle (Fig. 1g–i). Also, moderate tosevere loss of myelinated fibers occurred in the cuneatefascicle, with the most severe loss in its cervical part, andincreasing loss from ventral to dorsal. Some loss of myeli-nated fibers in the corticospinal tract and in the spinocer-ebellar tracts was observable. At the spinal lower thoraciclevels relative sparing of a paramedian layer in the gracilefascicle was noted. Slight to moderate neuronal lossof motor neurons in the anterior horn was observed

a

d

g

b

e f

ih

c

Fig. 1 Loss of myelinated fibers in the posterior funicles is more pronounced at the cervical level (a,d,g) than at the thoracic (b,e,h) andlumbar (c,f,i) levels. Patient 1 (a,b,c) and patient 2 (d,e,f) with classical type A-T show more severe loss than patient 3 (g,h,i) with varianttype A-T. Inserts in b,e and h: relatively more spared short descending fibers of the posterior columns at the thoracic levels (HE-LFB,bar = 1 mm).



(Fig. 2e,f), with some of the remaining neurons showingcentral chromatolysis while some swollen axons and some-times small groups of glial cells were present.A gradient ofseverity of anterior horn cell loss from cervical to lumbarlevels existed. In the Clarkes’ columns moderate neuronalloss, sporadic chromatolytic neurons and some axonalspheroids were observed. Compression of the spinal cordwas seen at the upper thoracic level by an epidural tumor(length 3 cm ¥ width 2 cm ¥ thickness 0.5 cm) which turnedout to be a metastasis of a hepatocellular carcinoma.

Muscle biopsy at age 22 showed severe chronic neuro-genic atrophy with fiber type grouping. Electron micro-scopic examination of a biopsy of a branch of the fibularnerve at age 22 showed a loss of thick myelinated axonswithout segmental demyelination and without signs ofacute axonal degeneration.

Immunohistochemical study

In none of the three patients abnormal inclusions werefound with tau, ubiquitin and alpha-synuclein in anteriorhorn neurons.With TDP-43, the nuclei of the anterior horn

neurons stained normal and no cytoplasmic TDP-43 inclu-sions were present.

Literature data

Twenty-seven of the 28 reviewed autopsy reports in theneuropathology chapter in Sedgwick and Boder1 and fiveadditional papers with detailed neuropathological data,traced by Pubmed search, were retrieved5,11–14 (Table 3).Two papers were excluded because of the highly atypicalpresentation of the patients in the absence of cytogeneticor genetic abnormalities that would support a diagnosis ofA-T.12,13 In none of the patients aFP serum concentrationswere mentioned, while radiosensitivity was reported in onepaper,5 and chromosomal instability in two patients.31,32

ATM gene mutation analysis was not reported in any of thestudies identified by us.

DISCUSSION

Ataxia telangiectasia is a disease characterized by severehistological CNS abnormalities and a relatively homog-

Fig. 2 Anterior horn at the lumbar levelof patients 1 (a,b) and 2 (c,d) with classicalA-T and of patient 3 (e,f) with variant A-T.There is some diffuse loss of neurons withsmall groups of gliotic cells (asterisks) inall patients (a,c,e). Degenerating neurons(arrows) are more easily found in the variantA-T patient (f) than in the classical A-Tpatients (b, d) (HE, bar = 100 mm).

a b

d

f

c

e



enous but still variable clinical presentation. The presentstudy describes CNS-autopsy results of three A-T patients,two of whom were confirmed genetically. Previously des-cribed post mortem results have not previously been sup-ported by molecular genetic testing.All previously reported24 autopsy reports, 23 of which were published before thediscovery of the genetic defect in 1995, lack this geneticinformation. Therefore, it is difficult to determine whetherthe previously reported patients were diagnosed correctlyand whether they had the classical or variant phenotype.

The gross neuropathological findings in our patients,that is, cerebellar degeneration, particularly of the cortexand with relatively well-preserved deep cerebellar nucleiand inferior olives, degeneration of the posterior columns,specially of the gracile fascicle, and axonal degeneration ofthe peripheral nerves with subsequent muscle atrophy, arein line with the literature.5,6,11,14–17,19–22,24–32,34 However, someinteresting differences are found in the 33-year-old patientwith variant A-T (patient 3) who displayed some residualATM-kinase activity. In addition, the finding of abnormali-ties in other parts of the spinal cord is of interest (Table 2).

Previously published studies confirmed the clinicalobservation that neuropathological abnormalities become

more advanced and severe with increasing age.1 However,there is considerable individual variation.20,30 In general,cerebellar atrophy, degenerative changes of the Clarkes’columns and inferior olives, loss of myelinated fibers of theposterior columns, degeneration of the dorsal root ganglia,axonal degeneration of the peripheral nerves and muscleatrophy, are already visible in patients who die around theage of 10 years (Table 3). By advancing age, the abnor-malities progress and extend, and new lesions appear.In older patients, gliosis of the posterior columns in thespinal cord is more common, loss of myelinated fibers inthe spinal cord extends to the spinocerebellar and corti-cospinal tracts.14,16,17,22,23,26,31,32,34 Furthermore, with ad-vancing age progressive anterior horn cell degenerationdevelops.5,14,21,26,29–32,34 In the brainstem degeneration of thecranial nerves,30–32,35 depigmentation of the locus caer-uleus14,30,31 and degenerative changes in the substantia nigrahave been described.14,16,30–32

The neuropathological findings in our A-T patient withthe milder phenotype (patient 3), who displayed someresidual ATM-protein expression with minimal ATM-kinase activity, are in general comparable with thosereported from patients who survived into the fourth

Table 3 Summary of neuropathologic autopsy findings in the literature

Authors Patient Age (years) Sex Cerebrum Cerebellum Brain stem Spinal cord† Peripheral nerve Muscle

Boder et al.15 1‡§ 10 F - + NA - NA NACenterwall et al.16 1 12 M + + + NA NA NABiemond et al.17 B 12 F + + + NA NA NA

C 12 MBowden et al.11 1 15 F - + - - NA NAOstetowska et al.18 1 7 F + + + NA NA NADunn et al.19 2 17 F - + - + NA 1

Strich20 1 15 M 1 + + + + +2 11 F 1 + + + + +3 12 F 1 + + + + +

Sourander et al.21 1 14 F - + - + NA NACenterwall et al.22 2 23 M - + - + NA -Thieffry et al.23 1 3 F - + - NA NA NASolitare et al.24 1 13 F - + - + NA 1

Hassler25 1 17 F - + - + NA +Aguilar et al.26 1 21 M - + + + NA NA

2 10 F - + + + NA NA3†‡ 10 F - + + + NA NA4 19 M NA NA NA + NA 1

5 ? M - + - NA NA NASolitare27 1 22 F - + - + - +Itatsu et al.28 1 10 F + + + - + NATerplan et al.29 1 18 F + + + + NA NANavarro et al.6 1 9 M + + + + + +De León et al.30 1 17 M + + + + NA +Agamanolis et al.31 1 31 M + + + + + +Amromin et al.32 1§ 32 F + + + + + +Casaril et al.33 1 26 M + + NA NA NA NAPerry et al.34 1 25 M - + + + NA NAMonaco et al.14 1 26 M + + + + NA NAOpeskin et al.5 1 34 M + + NA + NA +

† Spinal cord: general spinal cord findings; ‡ the same patient; § siblings. F, female; M, male; NA, data not available; –, no abnormalities; +,abnormalities; 1minimal abnormalities described.



decade. To what extent the epidural tumoral mass inpatient 3 influenced the neuropathological changes, espe-cially in the long tracts, is difficult to estimate, but thetumor was fast growing and the findings were quite sym-metric and in line with findings in the other patients.

Progeric changes – such as Lewy bodies, Alzheimerplaques, neurofibrillary tangles and gliovascular abnor-malities – have been described in older A-Tpatients,5,14,31,32,34 but were not present in our patients. Inaddition, the lesions in the brain stem were less widespreadand somewhat milder in our milder A-T patient, than inpreviously described age-matched patients. The neuronaldegeneration in the anterior horn were somewhat morepronounced in the latter case than in the two other patientswith classical A-T, but the patient was also more than 10years older. Occasionally cerebral glial nodules and gliosisof the white matter of the gyrus precentralis were observedin our patient with the milder phenotype. However, thesesmall cortical anoxic lesions, the old small scar with hemo-siderin in the white matter of the gyrus precentralis, andthe few distributed foci of neuronophagia in the “griseumpontis” are most likely due to respiratory distress. Glialnodules were also observed in four other A-T patients, withages between 11 and 17 years, who died due to respiratoryproblems.20,30

Clinical signs of anterior horn cell disease have alsobeen described in A-T patients who survived into the third

decade of life.18,35 However, descriptions of neuropatho-logical findings of the anterior horn cells are sparse(Table 4). Loss of anterior horn neurons due to aninterfering disease such as ALS, tauopathy, or alpha-synucleinopathy could be excluded by immunohisto-chemistry in our patients. The precise role of anterior horncell disease in (younger) classical A-T patients is difficult toestablish: the severe signs of the progressive sensorimotorpolyneuropathy precludes conclusions about the addi-tional presence of anterior horn cell disease.7 In variantA-T patients, anterior horn cell degeneration is clinicallymore pronounced and could be the presenting and pre-dominating feature of A-T.4,36

The first signs of anterior horn cell involvement havealready been described in the lumbar levels in a 9-year-oldboy (the brother of patient 1).6 In the patients described inthe present paper, the anterior horn involvement becamemore widespread by advancing age. In the 22-year-oldfemale (patient 2) and 33-year-old male (patient 3),anteriorhorn cell degeneration was also visible at the cervical level.The extent and severity of the neuropathological findingsin the anterior horn cells of the patient with the milderphenotype were comparable with those of classical A-Tpatients. Neurogenic muscle atrophy was present in all andmore pronounced in the distal muscles, whereas peripheralnerve biopsies revealed signs of axonal degeneration.Thus,anterior horn cell degeneration and axonal sensorimotor

Table 4 Anterior horn cell findings in the literature

Authors Case Age (years) No information No lesions Neuronal loss Ghost cells Gliosis

Boder et al.15 1 10 +Bowden et al.11 1 15 +†Ostetowska et al.18 1 7 +Dunn et al.19 2 17 +Strich SJ.20 1 15 -

2 11 -3 12 -

Sourander et al.21 1 14 +Centerwall et al.22 2 23 +Thieffry et al.23 1 3 +Solitare et al.24 1 13 +Hassler25 1 17 +Aguilar et al.26 1 21 + + +

2 10 +3 10 + +4 19 + +

Solitare27 1 22 + +Itatsu et al.28 1 10 +†Terplan et al.29 1 18 +Navarro et al.6 1 9 + + +De León et al.30 1 17 + + +Agamanolis et al.31 1 31 + + +Amromin et al.32 1 32 + -Casaril et al.33 1 26 +Perry et al.34 1 25 +Monaco et al.14 1 26 + +Opeskin et al.5 1 34 +

† Spinal cord findings have only been described as normal.



polyneuropathy, are disease features of both classical andvariant A-T. It may be assumed that the muscle weaknessdue to anterior horn cell degeneration is clinically moreimpressive in milder A-T patients, as compared to classicalpatients in whom the earlier and more pronounced cerebel-lar and extrapyramidal symptoms may partly mask theweakness.

The longest tracts appear to be most severely affected inA-T. The gracile fascicle is more severely affected than thecuneate fascicle, with the most severe abnormalities atthe cervical level. In the gracile fascicle a slight ventral todorsal gradient of loss of myelinated fibers was observed.The short descending fibers of the posterior funiclesremained relatively more spared at the different levels: thetractus semilunaris at the cervical level and the oval field ofFlechsig at the low thoracic and lumbar levels. Interest-ingly, at the lumbar level the anterior horn cell degenera-tion is more prominent. The present study does not allowdifferentiation of changes secondary to the polyneuropa-thy in these patients from changes due to neuronal loss, forexample in the nucleus of Goll.

As in all previous studies,5,6,11,14–17,19–22,24–32,34,37,38 also in ourpatients the cerebellar Purkinje cells are crucially affected.Demonstration of abnormal arborization of Purkinje cellsand the presence of displaced Purkinje cells in the molecu-lar layer of the cerebellum, as we also observed in twopatients, suggested that Purkinje cells are affected as earlyas during the midgestational period, but after they are fullydeveloped.37,38 ATM has been found to be concentrated inthe nucleus of Purkinje cell neurons in the normal juvenilehuman brain and is absent in the cerebellar Purkinje cellsfrom A-T patients.39 This is consistent with the hypothesisthat, as in all other cell types examined, also in fully differ-entiated Purkinje cells a major function of ATM may be todetect and repair nuclear DNA damage. If this mechanismalso plays a role in anterior horn cells remains open toresearch, as detailed information on the presence of ATMin anterior horn cells is lacking. It remains also unclearwhich other factors play a role as ATM expression is notlimited to neuronal cell types that are affected in A-Tpatients.39

In conclusion, we describe the neuropathological find-ings of DNA-proven A-T patients. In line with theliterature the main neuropathological abnormalities arecerebellar atrophy, degeneration of the posterior columnsand an axonal sensorimotor polyneuropathy. Withadvancing age, the abnormalities progress and becomemore advanced and prominent. Anterior horn cell degen-eration seems to occur already in young A-T patients, andto progress with advancing age, and is more prominent atthe lumbar level. Residual ATM-kinase activity, whichis associated with a milder clinical phenotype, leads tosimilar but somewhat less pronounced neuropathological

abnormalities than in patients without any ATM-kinaseactivity.

ACKNOWLEDGEMENTS

We are grateful to Dr W. Wuyts (Department of MedicalGenetics, University of Antwerp, Belgium) for sendingmaterial, F. Hogervorst (Department of ExperimentalTherapy, The Netherlands Cancer Institute, Amsterdam)for performing ATM mutation analyses and J. L. Last(Department of Cancer Research UK, Institute for CancerStudies, Birmingham University, UK) for measurements ofATM protein expression and kinase activity. We thankEvelyn de Leenheir, Edith Peeters and Linda Dewit fortechnical help.

Funding

This work was supported by Stichting A-T (Gilze, theNetherlands) and by the Sheid-Van Bogaert Foundation.

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Neuropathology in classical and variant ataxia-telangiectasia

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