The neuropathology of CAG repeat diseases: review and update of genetic and molecular features

Brain Pathology 7: 901-926 (1997)

The Neuropathology Review and Features

Update of CAG. Repeat of Genetic

Yves Robitaillel, lscia Lopes-Cendesl, Mark BecheP, Guy Rouleau', Arthur W. Clark'

1 Departments of Pathology, University of Montreal, and Neurosurgery and Neurology, McGill University, Montreal, Quebec, Canada Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Departments of Pathology and Clinical Neuroscience and the Neuroscience Research Group, University of Calgary, Alberta, Canada

Classification of inherited neurodegenerative diseases is increasingly based on their genetic features, which supplement, clarify, and sometimes replace the older clinical and pathologic schemata. This change has been particularly rapid and impressive for the CAG repeat disorders. In Huntington's disease, X-linked spinobulbar muscular atrophy, dentatorubropallidoluysian atrophy, and a series of autosomal dominant cerebellar atrophies, genetic advances have resolved many nosologic issues, and opened new avenues for exploration of pathogenesis. In this review, we summarize classic and current concepts in neuropathology of these CAG repeat diseases.

Introduction: the neuropathology of a genetically defined group of diseases

The CAG repeat diseases constitute the majority of so-called "trinucleotide repeat disorders." The first trinucleotide repeat diseases were defined as such in 199 1. Previous classifications relied on heterogeneous and overlapping clinical and pathologic features. Current classification is based on their genetic determinants, which are inherited expansions of trinucleotide repeat sequences at loci specific to each disorder (110, 174, 225). In most, trinucleotide repeat sizes can increase still further in offspring of an affected subject; and larger size of the repeat regions generally is associated with earlier age of onset of the disease (intergenerational anticipation). CAG repeat disorders have now been

Corresponding author: Yves Robitaille, Ste-Justine Hospital, Department of Pathology, 3701 CBte Ste-Catherine Road, Montreal, Quebec, Canada H3T 1C5; Tele.: 514/345-4649; Fax: 51413404545; E-mail: yes-robitaille Q algene.com

Diseases: and Molecular

linked to at least eight loci scattered through the human genome; and al. least four other loci cause non-CAG trinucleotide repeat diseases (La Spada and Clark, this symposium).

The CAG repeat sequences encode polyglutamine tracts in the respective genes. Relatively modest increas- es in size of the CAG repeat sequence (and polyglutamine tracts) is sufficient to produce disease (83, 174). Hence the expansions can be termed "small -scale repeat expansions" (82). By contrast, the non-CAG trinucleotide repea': disorders derive from trinucleotide repeat sequences which require much larger expansions to produce disease. These are located in noncoding regions of the respective genes (1 10, 225). The term "large scale repeat expansions" might be used to desig- nate this grou?, which includes fragile X syndrome (frax), myotonic dystrophy (MD), and Friedreichs ataxia (FA). Other large scale trinucleotide repeat expansions have been discovered, but the related disorders are less well studied ( 110, 225).

The three "classic't non-CAG trinucleotide repeat disorders are distingusihed by their triplets (CGG for frax, CTG for MD, GAA for FA) and their modes of inheritance (X -linked for frax, autosomal dominant for MD, autosomal recessive for FA). Recent paper s should be consulted (20, 21, 127, 131, 143). The proteins are defined for each of the genes (21, 127, 169, 189). Table I summarizes these features. The reader is referred to reviews and recent publications (13, 22, 26, 35, 42, 48, 49, 53, 67, 93, 97, 102, 110, 111, 153, 218, 220, 225, 230).

This symposium focuses on the CAG-repeat disorders because of the unifying theme inherent in the type of mutation they all share. They include X-linked spinobulbar muscular atrophy of Kennedy (SBMA), at least four autosomal dominant cerebellar ataxias, dentatorubro-pallic.oluysian atrophy (DRPLA), and Huntington's disease (HD). The affected proteins are distinct, and the mutated genes widely scattered in the genome. Given this diversity, and the shared feature of CAG repeat expansion, the pathogenetic mechanisms would be expected to include both features in common and features unique to each disorder.

. . ... . .

! Fragile X Mytonic Dystro,uhy .criQdreiC,* S 4!i?XM' Fragile X (FRAXA) (FRAXE)

_ _ _. __ . ... . . __ . . .- . - I

Hereditary transmission

Gene locus

Triplet repeal

Encoded protein

Principal clinical fealures

Principle types of I e s i o n s

Main neuroanalomic distribution of the lesions

X-IinKed

Xq27 3

C G G

FMR-I (RNA-binding protein)

Mer.lal Retarda!ion Epilepsy Prograthism Enlarged ears Macrogenitalia

Selective hypertrophy of ! cerebral structures

Atrophy posterior fossa on MFI Microcephaly Neuronal heterotopias Dendritic spine abnormalities

Hippocampi, Striatum Cerebellum

' :;ECSSsI:T I Autoscrral Dominant X-:inked

XqPE

G C C

:5q132-13 S ! I C T G

unknown Myotonin Protein Kinase

Mental Retardation ~ Distal Myopathy wit? milder ihan in FFAXA ' Myolonia

I

Mental Fe:arda:ion ' Frontal Baldness i Hypogcnadisn

unknown Myopathic !eatures in skeletal muscle Cerebral a:rophy with overexpression of Tau epitopes. hyperphosphorylate6

unknown I I Distal skeletal rnusc:e , Temporal lobes

C313.q:: '

I GAA

Frataxin-Fhosphatidyl- iosilol Kinase

Ptaxia gait 1 Dysarthna Hyporeflexia Babinski signs

: Lcss of prcpr:ocepl.cr Carciomyccathy

Neuronai loss and glicsis Waillerian degenera!ion 31 long trac!s. spinal Cora Sensory axonopathy

I

Dorsal root ganglia Spinocerebellar tracts Posterior columns Lateral & Clarke's cdumns

. . . - .. .

'Freidreich's A:axia with vitamin E deficiency: locus mapped on ch. B q not associated with triplet repeats. see Belal S et al (1995) Clin Neurosc 3: 39-42

Table 1. Non-CAG Trinucleotide Repeat Disorders

The specific disease-associated proteins include the androgen receptor for SBMA, well characterized before its involvement in SBMA was discovered; and a series of proteins discovered as a result of the genetic investigations on the corresponding disease: ataxins 1, 2, and 3 (in SCA1, SCA2, and SCA3, respectively), atrophin (DRPLA), and huntingtin (HD). Recently the CAG expansion of SCA6 was identified in the gene for the human CY 1 A voltage-dependent calcium channel protein. The gene affected in SCA7 has not yet been characterized.

Increasing size of the CAG repeat expansion does correlate with increasing pathologic severity for several of these disorders. But the genes affected, the anatomic sites targeted, and other clinicopathologic features differ, as summarized in Table 2. Homozygosity has been associated with more severe disease in DRPLA (177) and SCA3MJD (29, 192) but not in HD (133, 226). Although recent genetic advances have clarified many nosologic issues, they have also raised a series of questions about the pathologic correlates which previous pathologic studies either were not designed to answer, or could not have answered because the methods were not available.

Neuropathology in the twenty first century must aim to integrate morphologic and molecular features with

molecular genetics, to advance understanding of basic mechanisms, specific diagnosis, and effective therapy. Geneticists have given us a whole series of questions. What are the functions of the proteins containing the trinucleotide repeat-encoded sequences, and the cellular effects of overexpression or knockout? What are the in vivo morphologic consequences of progressive expansion in size of the repeat regions? In which cell populations are the disease-associated proteins located? With what other proteins might they interact? In what subcellular compartments can they be found? Other papers in this symposium deal with molecular aspects of the CAG repeat disorders. This review of neuropathology emphasizes anatomic pathology, with the ultimate aim of facil- itating insight into molecular pathophysiology. An essential reference for developments in neurogenetics is available on the World Wide Web (23 ).

X-linked spinobulbar muscular atrophy (neuronopa-

Spinal and bulbar muscular atrophy, or Kennedy's disease, is an X-linked bulbar and spinal motor neuron disorder. It was mapped to ch Xqll-q12 (56) , and linked to the androgen receptor gene. It was the first of the CAG-repeat disorders to be defined as s uch (109).

Both its pattern of inheritance and its clinicopatho-

thy)

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902 Robitaille et al: Review and Update of Molecular and Genetic Features

logic features distinguish i t from other motor neuron degerative diseases such as infantile spinal amyotrophy (Werdnig-Hoffman disease), juvenile hereditary spinal muscular atrophy (Wohlfart-Kugelbeg-Welander disease), and amyotrophic lateral sclerosis (ALS). It has onset in the third to fifth decade, but a very late onset case from Japan has been reported (39). The disorder is slowly progressive, with a near-normal longevity (77, 101). Occasional cases manifest a more rapid presentation (5). Cramps may precede the onset of weakness, which is usually proximal at first. Fasciculations are widespread, notably including facial muscles. Clinical onset correlates with CAG repeat size; there is dispute over whether this is true of clinical seventy (5, 40, 85, 138).

Because the expansion is located in the gene for the androgen receptor, it is also unique among the CAG repeat disorders in the volume of prior information available on the encoded protein. Gynecomastia (an early sign of the disease), elevated gonadotrophic hor- mones, and testicular atrophy are among the clinical features indicative of mild feminization (1 80).

The sensory system is not altogether spared. Sensory nerve action potentials in the lower extremities are diminished or absent, and there is vibratory sense loss, less often loss of pain and temperature modalities, in the lower extremities. Hence the term X-linked bulbospinal neuronopathy has been proposed as more appropriate than SBMA(77,228).

Pathologic findings include severe depletion of lower motor nuclei in spinal cord and brainstem (but not affecting the oculomotor nuclei 111, IV, and VI). Upper motor neurons and corticospinal tracts appear unaffected (101, 138, 193). In the sensory system, there is a distal axonopathy affecting both the peripheral and the central branches of dorsal root ganglion neurons of lum- bosacral segments. Thus the sural nerve shows a marked depletion of large myelinated fibers, and the tractus gracilis shows pallor at rostra1 much more than caudal levels; whereas the tractus cuneatus is little affected (118, 193, 228). Morphometry revealed atrophy of neuronal perikarya in the dorsal root ganglia (1 18).

The androgen receptor is expressed in lower motor neurons, both in normals and in SBMA subjects (147). However, no changes in expression are reported to account for the disease process. Mosaicism for length of the CAG repeats within the nervous system does not account for the pattern of neurodegeneration (2 12).

Spinocerebellar ataxia type 1 (SCA1) Classification of the hereditary ataxias has bewil-

Figure 1. Olivary nuclei in autosomal dominant spinocerebellar degenerations. A. x 200, KlOver-Banera stain in representative area of SCA l-linked subject. Neuronal loss and gliosis are quite marked in the end-stage. B. x 200, Kliiver-Barrera stain in representative area of SCA 3-linked subject. Neuronat loss and gliosis are less severe compared to SCAl .

dered neurologists for generations (76, 202). Historically, orie group had been designated olivopontocerebellar atrophy, OPCA (14), which could be sporadic or inherited. Fifteen years ago, Harding proposed a classification whic:h included those OPCAs which were of adult onset and transmitted in autosomal dominant pattern of inheritance. The designations autosomal dominant cerebellar atrophy (ADCA) types I, II, I11 and IV were proposed. Type I referred to those with ophthalmoplegia, optic atrophy, dementia, or extrapyramidal signs in addihon to the cerebellar deficits. Type I1 referred to a group with cerebellar ataxia and pigmen- tary retinal degeneratation. Type I11 referred to a pure cerebellar syndrome of late onset (over 60 years). Type IV referred 1.0 a cerebellar ataxia associated with myoclonus and deafness (75). Despite this contribution, classification remained fraught with uncertainties, which impeded pathogenetic understanding.

Recent genetic advances represent an important step toward resolving this confusion (84, 122, 124, 217).

Robitaille et al: Review and Update of Molecular and Genetic Features 903

Within Harding's ADCA I group, SCAl. SCA2, and SCA3, and others have now been distinguished on genetic criteria. With the genetic markers to define subgroups, clinicopathologic comparisons were more meaningful. For example, the olivary nuclei, cerebellar cortex, and dentate nuclei were affected in ADCA I; but with genetic markers to distinguish SCA1, SCA2, and SCA3, it was possible to distinguish histologic patterns of preferential damage (Figures 1-3).

SCA 1 corresponds to OPCA 1, or the progressive and dominantly inherited ataxia as described by authors such as Menzel, Schut. Jackson, and others (23, 202). The disease develops in the second decade or later, as a progressive ataxia. This is followed by selective cranial nerve deficits and oculomotor abnormalities. Amyotrophy of all limbs is also characteristic of later stages of the disease. Extrapyramidal signs and retinitis pig- mentosa are not features of SCAl (54, 61).

The disease mapped to the short arm of chromosome 6 (94, 164,235). It was traced to a CAG repeat expansion in a previously unknown gene (9, 151). Age of onset and to some extent disease duration, is inversely proportional to CAG repeat amplitudes in 50- 60% of affected subjects (96, 163). The mutated gene codes a protein, ataxin 1, of still unknown physiological significance. There is little or no correlation between sites of expression of ataxin 1 and the sites in rhombencephalon and spinal cord, where most SCAl-vulnerable neurons are localized. Furthermore, mosaicism (regional differences in CAG repeat expansion size) does not account for the pattern of SCAl neuropathology. We found the CAG repeat expansion size to be essentially the same among 20 different brain regions in each of three subjects with SCAl, with one exception: the cerebellar cortex had a slightly smaller CAG repeat expansion size (123).

The wild protein and the mutated SCAl variant are both found as intranuclear in all brain regions. In the cerebellar cortex of SCAl subjects, however, its epitopes are also found in the cytoplasm of Purkinje cells (184). Western blot studies of lymphoblastoid cell lines of SCAl subjects revealed that the

. . . .


length of polyglutamine stretches included within ataxin 1 protein residues also was inversely proportional to age of onset, with pathological threshold estimated to span 37-40 glutamines (217).

The neuropathology of end-stage SCAl is characteristic. We have described in detail the neuropathologic features, and compared them to the findings in SCA?, and SCA3IMJD (171). Gross examination may reveal mild to moderate widening of sulci, chiefly frontotem- poral; mild neuronal cell loss in cerebral cortex, with gliosis, was seen in a few cases. Subcortical white matter of the cerebral hemispheres was unremarkable. Atrophy of the pons and cerebellum, and loss of the bulge of the inferior olive, were obvious in all cases. The spinal cord also showed loss of the cervical and lumbar enlargements and atrophy of ventral roots. Basal ganglia appeared grossly normal, except for one case with mild discoloration of the internal globus pallidus. Sections of b rainstem and cerebellum revealed the substantia nigra and locus coeruleus to be normally pig- mented, whereas the dentate nucleus and cerebellar cortex were grossly atrophic.

There is severe loss of Purkinje cells and dentate neurons (Figures 2A, 3A), with atrophy of the dentatofugal pathway, a feature SCAl shares with DRPLA. Unlike DFWLA, however, SCAl shows only infrequent and mild to moderate involvement of the globus pallidus. The inferior olive (Figure 1A) and nuclei basis pontis are both severely affected in SCA1. Hence the superior, middle, and inferior cerebellar peduncles (outflow pathways of the severely affected nuclei) all undergo auo- phy. Purkinje cell loss showed a reproducible regional pattern, with maximal depletion in the verrnis, less severe changes in the lateral hemisphere, and only mild to moderate neuronal loss in the flocculo-nodular lobes.

There was a remarkably severe loss of neurons from the cholinergic system of the basal forebrain, including the diagnonal band of Broca. The striatum may show mild neuronal loss and gliosis; the substantia nigra is normal or shows at most only mild cell loss. Despite sparing of the substantia nigra on histologic evaluation, there was evidence that nigrostriatal pathways were affected. All cases had sub-threshold but significant decreases (range= 45-75%) of dopamine levels in caudate nucleus and putamen, compared to normal age- matched controls.

Neuronal loss and gliosis of the third, tenth, and twelfth cranial nerves was identified. There was severe loss of spinal anterior horn motor neurons and of neurons from the Clarke's columns. Degenerative changes of the posterior columns preferentially involved the

Figure 2. Cerebellzr cortex in autosomal dominant spinocerebellar ataxias. A. x 200, Klijver-Barrera stain in representative area of laterial cerebellar cortex from an SCA 1-linked subject. Loss of Purkinje cel's is quite extensive. Severity is emphasized by a continuous line of reactive proliferation of Bergmann's glia. 6. x 200, Kl9ver-Barrera stain in representative area of lateral cerebellar cortex ,in SCA 3-linked autosomal dominant ataxia. Depletion of Purkinje cells is much less extensive and marked.

tractus gracilis. Corticospinal tracts underwent distal degeneration. There is immunohistochemical evidence of gliosis in layer 5 of the motor cortex in some Japanese SCAl subjects, but in our cases the upper motor neuron system effect appeared to be a dying-back process. The pattern of lower motor neuron degeneration shared with ALS a sparing of Onufs nucleus, but differed in that the neurofilament-filled swellings of proximal motor x o n s seen in rapidly progressive ALS were not a feature of SCA1. The findings are in general accord with prekious reports of SCAl (61, 183, 196) and with a recent comparison of two cases of SCA 1 with two cases of SCA3MJD (44).

In our view, these changes represent a phenotype which is distinguishable from SCA2 and SCA3NJD. For example, the substantia nigra is severely affected in SCA2 and SCA3/MJD, but spared in SCAl . Conversely, the dentatofugal pathways are far more

- .-


Figure 3. Dentate nucleus in autosomal dominant cerebellar ataxias. A. x 200, KlGver-Barrera stain in representative area of dentate nucleus from an SCA I-linked subject. Loss of neurons is quite extensive. B. x 200, Klliver-Barrera stain in representative area of dentate nucleus in SCA 3-linked autosornal dorni- nant ataxia. Neuronal depletion is mild, as well as reactive gliosis.

severel y affected in SCAl than in SCA2; SCA3MJD has an intermediate level of involvement, but generally less severe than that in SCAl (Figure 3; see also 44). The mechanism of cell death in SCAl is unknown, but there is evidence to support a role for apoptosis. A recent study using the TUNEL method yielded evidence that some nigral neurons are vulnerable to apoptosis in SCA 1 brains, compared to controls ( 1 14).

The role of anterograde trans-synaptic degeneration and of retrograde degeneration in SCAl should also be considered. In other settings, the inferior olive appears to manifest histologic patterns which distinguish anterograde trans-synaptic degeneration due to lesions in afferents from the dentato-rubro-olivary pathway, from retrograde degeneration due to lesions of the cerebellar cortex (104). On the other hand, trans-synaptic de, oener- ation of the dentate nucleus has never been observed following selective deafferentation of olivo-cerebellar tracts. Since such trans-synaptic effects can take a long

time to develop, it is plausible that the severe Purkinje cell damage, combined with the long dui-ution of disease in SCAI, is partly responsible for degeneration of the dentate nucleus. An intrinsic vulnerability of dentate neurons, however, probably plays an important, and perhaps the major, role.

Sporadic cases of OPCA are often seen in association with striatonigral degeneration or autonomic dysfunc- tion (Shy-Drager). This "hybrid" degeneration is referred to as multi-system atrophy (MSA). Argyrophilic neuronal and oligodendroglial cytoplasmic inclusions have been identified i n such cases, immunoreactive for ubiquitin (27, 151). We found no such inclusions in our cases of SCAl (OPCA 1). However, there is a recent report of a family with the SCAl mutation, in which autopsy of one member showed lesions typical of MSA, including glial inclusions immunoreactive for tau and ubiquitin (62).

Spinocerebellar ataxia type 2 (SCA2) SCA2 is another subset of Harding's (76) ADCA I

group which has been distinguished from other ADCA 1 subsets by linkage analysis (63, 113). I t corresponds to OPCA 2, or spinocerebellar atrophy, Cuban type (23). Patients usually present with cerebellar findings. Slow saccades and sensorimotor neuropathy are particularly common in SCA2 when compared to SCAl and SCA3 (18, 43, 53, 156, Martha Nance this symposium). As with SCAl and SCA3, Parkinsonian features have been all but nonexistent according to most reports. although we have seen mild dystonic posturing and Parkinsonian features in some members of an SCA2 kindred from Austria (Lopes-Cendres per30nal observations). Corticospinal tract signs are less common than in SCA 1 but may occur (43). Dementia is also occasional, not characteristic (43). The mean age of onset is in the second to fourth decade and the disease duration a little over ten years. Intergenerational anticipation is recognized in SCA2 (162).

Large SCA2 kindreds likely due to a founder effect, have been well documented in the Holguin province of Cuba (150). Families have also been recognized in Europe, North America, and Japan (17, 53, 56, 162, 176). The gene maps to chromosome 12q24 (133). After its identification as a CAG-repeat disorder candidate (217), the gene was cloned, and the CAG repeat with expansions in SCA2 patients confirmed. The gene was designated ataxin-2. The protein is cytoplasmic, with an apparent molecular weight of 150kD (92, 161, 176).

The SCA2 mutation may be associated with the most devastating effects on cerebellar afferents. When suh-

- .. . ~ -. ~. . .... . . . . . . .


Figure 4. DRPLA. The neuropathology of DRPLA is quite variable, but typically is most severe in the dentate nucleus of the cerebellum (A,B) as in this case of a man who presented with ataxia at age 40, developed chorea, apathy, irritability, and halluci nations, and died at age 59. Low (A) and high (B) magnification of the dentate nucleus show typical neuronal loss and marked disruption of the dentate ribbon. The well-populated caudate nucleus (C) has mild astrocytosis ori GFAP stain (D). Many subthala mic neurons are present (E) among reactive astrocytes. The inferior olivary complex (F,G) has vawolated neurons (arrows) and bizarre reactive astrocytes ("olivary hypertrophy") seen best by GFAP (G). GFAP also reveals mild corona radiata astrocytosis ( H). A-C,E,F = H&E; D.G,H = GFAP; Bars: B,D,G = 25 mm, A,C,E,F = 50 mm, H = 100 mm.

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jects with SCAl, SCA2, and SCA3 were compared by MRI for sizes of brainstem, middle cerebellar peduncle, and cerebellum, i t was SCA2 which emerged with the most severe reductions (18). Autopsy studies are in accord with the MRI findings. Weights of the brainstem and of the cerebellum are severely reduced. The nuclei basis pontis are devastated, with degeneration of trans- verse pontine fibers, middle and inferior cerebellar peduncles, and subcortical fibers of the cerebellum. The olives undergo severe neuronal loss and gliosis (Figure 1B). Cerebellar Purkinje cells are markedly depleted (Figure 2B), whereas the dentate is much less affected (Figure 3B; see also 43, 150).

The absence of Parkinsonism is remarkable, since the substantia nigra shows rather marked loss of neurons in most reported autopsies. The locus coeruleus remains well populated (43, 150). The cerebral hemispheres can undergo marked atrophy with prominent ventricu- lomegaly in the occasional demented subject (43) and weight of the cerebral hemispheres is somewhat reduced (150). Subtler changes may extend to the pallidurn and the dentatorubral system (43). Our findings in a proband from a large SCA2 French Canadian kindred (120), who died in the end-stage of the disease, are in accord with previous reports of the Holguin cases. There was marked nigral degeneration and relative sparing of the locus coeruleus, as well as absence of structural lesions in cerebral cortex and basal ganglia.

MRI has shown reduction in cervical spinal cord volume in SCA2, as well as in SCAl and SCA3 (18). An axonopathy may affect both descending motor pathways and sensory fibres, but we have not found reports to clearly distinguish between "dying back" and a primary neuronopathy in these systems. The posterior columns show degenerative changes involving tractus gracilis more than tractus cuneatus. Spinocerebellar tracts are also affected, and neurons of the dorsal column of Clarke are reportedly atrophic and reduced in number. Atrophy and depletion of lower motor neurons of the spinal anterior horn and pallor of ventral as well as dorsal roots are also reported (150). Sural nerve biopsies have shown moderate loss of large myelinated fibers (53).

Spinocerebellar ataxia type 3 (SCA3) and Machado- Joseph disease (MJD)

After loci for SCAl and SCA2 were established, various groups made efforts to determine whether ADCA I families were linked to either locus. This effort yielded evidence for a third locus (63) which was soon confirmed (199). Simultaneously, studies of Machado-

Joseph disease located the site of the mutation on chromosome 14q (210) and implicated a CAG repeat cxpan- sion in a gene at that site (100).

A series of studies then led to demonstration that the "third locus" (SCA3) for ADCA I disorders was in the same gene mutated in MJD at 14q24.3-q31 (182, 198). The size of the responsible CAG-repeat expansions have been shown to influence age of onset, seventy of certain clinical features, and age at death. Severity of some clinical features correlated better with diseasc duration than with CAG repeat expansion size (44). Although MJD was originally described in Portuguese families, it was documented in diverse ethnic groups, probably on the basis of multiple independent mutations at the same genetic site (69, 182, 207, 211).

MJD had been studied for almost 25 years (10, 28) when the allelic identity of SCA3 with MJD was discovered. SCA3MJD is perhaps the most heterogeneous and common of the autosomal dominant ataxias (96, 100, 165, 18 1, 203). Progressive cerebellar ataxia associated with pyramidal tract involvement and oculomotor abnormalities is characteristic; extrapyramidal and peripheral nerve signs may also occur. Onset is typically between 30 and SO years of age, but the disease may begin before 20. In one report of two brothers firs' affected at 8 and 7 years, the authors suggested homozygosity for the MJD gene to account for the earlier onset and somewhat greater pathologic severity (29, 192). There is recent evidence that age at death has a stronger inverse correlation with CAG repeat amplitudes than age of onset and disease duration not only in SCA3 kindreds, but in SCAl and SCA2 kindreds as well (1 22 and personal observations). As with SCAI, mosaicism in the CNS does not seem to account for selective vulnerability of neuronal populations (123)

Neuropathologically, SCA3/MJD shows much less effect on the inferior olives (Figure 1C) and the Purkinje cells (Figure 2C) than seen in SCAl and SCA2 (44, 171, 21 1). There are significant degenerative changes in the substantia nigra, dentate nucleus (Figure 3C), nuclei basis pontis, lower motor neurons, and neurons of Clarke's column. The internal globus pallidus is more affected than the external globus pallidus (the inverse of the pattern seen in DRPLA), and the subthalamic nucleus can be markedly af fected (44, 21 1).

Cranial nerve nuclei which may be affected include 111, IV, VT, VII, VII (vestibular portion), XII, the nucleus ambiguus, and the dorsal nucleus of the vagus nerve (44, 172, 173, 231). In one of the cases thought to be homozygous, there was also involvement of the nuclei gracilis and cuneatus, the medial lemniscus. the inter-

908 Robitaille et al: Re, 'ew and Update of Molecular and Genetic Features

Figure 5. DRPLA. Moderate dentate nucleus neuronal loss (A) with severe degeneration of the dentate hilus (B) and marked depopulation of the globus pallidus (C,D) are within the spectrum of DRPIA as found in this woman who presented at age 20 with ataxi a followed by a seizure disorder, dementia, and mild chorea until her death at 31 years of age. Globus pallidus neuronal loss and astrocytosis are less severe in the internal segment (C) than in the external segment (D). The caudate nucleus (E) is intac t although prominent astrocytes are present in the red nucleus (F). There is extensive neuroaxonal dystrophy in the nucleus gracilis (G) , one of the classic findings in the Haw River Syndrome phenotype of DRPIA. Arrows = asrocytes. A,E = H8E; 8-D,F,G = H8E-Luxol Fast Blue; Bars: F = 25 mm, C-E,G = 50 mm, A = 100 mm, B = 1 mm.

~ -~ ~- -. _- Robitaille et al: Review and Update of Molecular and Genetic Features 909

mediolateral columns of the cord, and the dorsal root ganglia (29). A recent clinical and pathologic study ind- cates that SCA3hlJD could be distinguished on clinical criteria from SCA2, but'not from SCAI; whereas the pathologic features of SCA3/MJD and SCAl were distinct (44), in agreement with our studies (171).

Evidence of polyglutamine tract involvement was demonstrated by Western blots and immunocytochemical methods, which revealed a major 68K band, and 2 minor 74K and 87K bands in lymphoblastoid cell extracts of SCA3 subjects. They are integrated within the mutated version of the protein, ataxin 3, encoded by the SCA3MJD gene. The protein has an intracytoplas- mic distribution in normal controls. It was immunocyto- chemically detected as dot-like structures within neuronal nuclei of basis pontis, which is severely degener- ated (155). In cultured cells transfected with the SCA3 mutation, apoptosis was triggered only when the mutant gene fragment was translated into polyglutamine residues (90).

SCA sites not yet shown to be associated with CAG repeat mutations (SCA4, SCA5, SCAB)

Three other loci, which are associated with inherited ataxias, but to date have not been shown to be CAG repeat expansion sites, are mentioned here for the sake of clarity regarding the SCA numbering system currently in use. Two (SCA4 and SCA5) are from families that fit ADCA I criteria. Intergenerational anticipation sug- gests a trinucleotide repeat expansion for both disorders (121, 166). SCA4 has been mapped to chromosome 16q22.1. Clinically it is a late-onset ataxia associated with a proximal axonal sensory neuropathy. SCAS maps to l l p l l - q l l (57, 135, 166). The neuropathological features remain to be defined. The recently reported SCA8 locus is associated with an infantile onset, recessively inherited ataxia (107, 145).

Spinocerebellar ataxia type 6 (SCA6) SCA6 has emerged as a separate autosomal dominant

ataxia as the result of using polymorphic CAG repeats to screen DNA from patients with late onset neurodegenerative disease. Using this approach, Zhuchenko and colleagues (234) identified a CAG repeat in a gene which proved to encode the human (Y 1 A voltage-dependent calcium channel subunit. The gene was independently mapped to chromosome 1 9 ~ 1 3 (37) and the full- length sequence published (149). Zhuchenko and colleagues further screened DNA from controls and from I33 patients with progressive cerebellar ataxia for CAG repeat polymorphisrns in this calcium channel gene, and

found eight unrelated patients with a CAG repeat expar.- sion. The a 1 A voltage-dependent calcium channel subunit is expressed in cerebellar Purkinje cells. The authors argue that the polyglutamine tract expansion in SCA6 interferes with normal function of this calcium channel.

Neuropathologic studies on two patients from one family with this mutation have revealed severe loss of hrkinje cells as the salient neuropathologic finding. Grossly there was some evidence of cerebellar atrophy and suggestive evidence of brainstem atrophy. Milder neuronal loss of cerebellar granule cells and dentate nucleus neurons, and neurons of the inferior olive, was also described; the nuclei basis pontis and other areas examined, including the spinal cord, showed either normal findings or changes not obviously related to the disease (204). Findings were similar in one French- Canadian kindred in whom the SCA6 mutation had been detected: neuropathology in a single proband revealed a predominantly cerebello-olivary degeneration without involvement of cerebral hemispheres, basal ganglia, basis pontis, dentate nucleus, or motor neurons (personal observations).

Clinical findings in SCA6, however, include not only mild, slowly progressive cerebellar ataxia, dysarthria and nystagmus, but also vibratory and proprioceptive sensory loss and hypo- or areflexia. Hence involvement of peripheral and sensory pathways sh ould be sought in future neuropathologic studies. The disorder progresses over 20 to 30 years, leading to a wheelchair-bound state. CAG repeat expansion size seemed to correlate inversely with age of onset, but the sample size was small (234).

The mutated gene in SCA6 is of extraordinary inter- est currently, being associated with a function from which a highly plausible pathogenetic mechanism can be conceived. Remarkably, a group who independently cloned the a 1 A voltage-dependent calcium channe I gene found that missense mutations which truncate the protein were associated with familial hemiplegic migraine and episodic ataxia type 2 (149 ). Episodic ataxia type 2 is a distinct cerebellar disorder but has some overlapping features with SCA6 (8, 234). Importantly, the patients with the episodic ataxia type 2 mutations did not have CAG repeat expansions in the same gene (149; see discussion in 234).

Spinocerebellar ataxia type 7 (SCA7) ADCA I1 is associated with retinal degeneration (68,

75). In several families which fit the ADCA II proto- type, linkage studies placed the responsible locus

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91 0 Robitaille et al: Review and Update of Molecular and Genetic Features

(SCA7) at chromosome 3p14-21.1 (30, 68, 69, 119). Using a monoclonal antibody which detects polyglutamine tract expansions, Trottier and colleagues found such expansions in probands of several large European kindreds with ADCA and HD. In ADCA 11, a 130 K glu- tarnine-rich protein was observed on Western blots of lymphoblastoid cell lines, conspicuously in the nuclear fraction, providing evidence for a CAG repeat expansion as the responsible mutation in SCA7 (217). To our knowledge, the neuropathological phenotype remains unascertained.

Dentatorubropallidoluysian atrophy (DRPLA) and the Haw River Sydrome (HRS)

DRPLA is an autosomal dominant degenerative disease, mapped to chromosome 12~13.31 (209,219). The identified gene has now been shown to harbor a CAG repeat which is expanded in affected subjects (91, 105, 137). It encodes a protein (atrophin) carrying a polyglu- tarnine tract (130, 136, 179). HRS has clinical and pathologic similarities to DRPLA. Identified in an African-American family with an ancestor from Haw kve r , North Carolina (47), it was traced to a CAG- repeat expansion in the DWLA-associated gene (19) within 5 years of its original description. DWLA and H R S are currently considered variants of the same disorder.

- The atrophin transcript is expressed in many tissues including brain. In DRPLA subjects, both expanded and normal alleles are transcribed with similar efficiency, and regional mosaicism is detectable in brain, with cerebellar transcripts having slightly smaller CAG repeat regions than transcripts from other brain regions (148). There is evidence for mitotic instability of CAG repeat size in nonneuronal cells of the CNS (208). Both the normal and the expanded versions of atrophin are also detectable in DRPLA brain, about 190 and 205 kDa. respectively. Atrophin has been immunocytochem- ically localized to somatic and somato-dendritic compartments of cortical cerebral and cerebellar neurons, mainly within Purkinje cells as well as in dentate nucleus neurons (232).

The clinical phenotype for DRPLA shows extreme heterogeneity both within and between involved kindreds (88, 89, 106). In Europe, familial cases with psy- chiatric disturbances and chorea have repeatedly been misdiagnosed as Huntington's disease (222). Adult onset cases often present with ataxia, chorea, and dementia, and childhood to early adult onset cases with progressive myoclonus epilepsy and dementia (see review by Martha Nance in this symposium).

Familial DRPI-A may have first been described in a Belgian man (2! 15) and sporadic cases also from Europe and North America (144, 190, 191). Most sporadic and familial reports have since come from Japan, however (66, 139), where DRPLA is much more prevalent than in European populations. Nonetheless, contemporary documentation of DRPLA in the West is increasing (12, 41, 146, 158, 160, 222, 223, 224). Genetic criteria now surpass clinical and pathologic features in diagnostic specificity. "Sporadic" cases of D W L A and undiag- nosed cases a.ith dentatofugal or pallidofugal atrophy should be tested for CAG repeat expansion in the atrophin gene. Cases of DRPLA combined with other neurodegenerative disease (7 1) should become more informative w th application of genetic methods.

In DRPLA, the dentate nuclei are affected, with neuronal loss and gliosis in the nucleus and axonal degeneration in the hilum (Figures 4 and 5). This is variable from case to case, but usually severe. The cerebellar cortex is relative,y spared, but an o ccasional case shows marked invohement (206). The paper by Ross and colleagues (this symposium) compares features of the cerebellar pathology in DRPLA and juvenile onset Huntington's disease.

The superior cerebellar peduncle, which is the outflow pathway of the dentate nucleus, is atrophic, as would be expected. The middle cerebellar peduncle is relatively unaffected, again as would be expected from the fact that it!; fibers originate largely in the nuclei basis pontis, which are generally well preserved. The olivary nuclei in the medulla are moderately to severely affected (Figures 4F,G). The red nucleus undergoes variable cell loss and Sliosis (Figure 5F), and myelinated tracts of the brai nstlm tegmentum can be affected. In fact, the tectum and the tegmentum of the brainstem are often atrophic, with involvement including parts of the reticu-

The globu:; pallidus, particularly the outer segment, is characteristically ravaged by the disease (Figure SC,D); and the subthalarnic nucleus may also be involved, perhaps more conspicuously in non-Japanese cases (222, 223, 224; see Figure 4E). Substantia nigra involvement is usually subtle if present (222,223,224). The neostriatiim may be affected (206) and GABA and substance P deficits similar to those of HD have been reported in the globus pallidus externa, apparently reflecting changes in the striatopallidal projections, rather than loss of striatal neurons (99). But the neostn- atal pathology in DRPLA is mild and occasional (Figures 4C, 5E) compared to that of the globus pallidus (Figures 5C,I>). The thalamus may also be affected (12)

. lar formation (88).

Robitaille et al: Review and Update of Molecular and Genetic Features 91 1

Figure 6. The Caudate Nucleus in Huntington's Disease. The hallmark of HD, degeneration of the striaturn can be classified into different grades of severity based on the the Vonsattel (VS) system which uses both gross and microscopic features. Astrocyto sis and medium spiny neuronal loss in the caudate nucleus increase from VS grade 1 (A) which has minimal astrocytosis and an intact neuronal population, through VS grades 2 (B) and 3 (C) with increasing reactive astrocytosis and decreasing neuron numbers to VS grade 4 (D) where astrocytes are numerous and neuronal depopulation is severe. Arrows = astrocytes; arrowheads = neurons. A-D = H&E; Bars: A-D, left = 50 mrn, right = 25 mm.

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Robitarile et al: Review and Update of Molecular and Genetic Features 91 3

The distribution of lesions in DRPLA has some overlap with those of Friedreich's ataxia, noticably so in the spinal cord (87, 88). In their review, Iizuka and Hirayama tabulate spinal cord lesions in DRPLA present in 19 of 23 subjects, including degeneration of posterior columns, spinocerebellar tracts, corticospinal tracts, and anterior horn cells (88).

HRS has a pathology broadly similar to that of DWLA. Myelin pallor may be more common or severe in HRS. Involvement of the globus pallidus features mineralization and "mulberry bodies" rather than severe loss of neurons; and neuroaxonal dystrophy of the nucleus gracilis, far in excess of what would be expected for age, has been emphasized in HRS but not in DWLA. Distinction between HRS and D W L A on clinicopathologic grounds has been debated (46, 188). White matter degeneration, neuroaxonal dystrophy in nucleus gracilis (Figure 5G), and mineralization of the globus pallidus, have also been reported in D W L A (Becher et al. in press). Hence distinctions between HRS and D W L A pathology may recede as the pathologic heterogeneity of DRPLA is progressively revealed.

Huntington's disease (HD) Huntington's disease (HD) is an entity familiar to

neurologists and geneticists alike (58). The clinical features include not only the choreic and dementing form of adult onset, but more severe forms of earlier onset, often associated with rigidity (see Martha Nance, this symposium). The gene responsible is linked to a mutation on chromosome 4 ~ 1 6 . 3 , a locus which encodes a protein now designated huntingtin. The CAG repeat expansion size of the huntingtin gene correlates inversely with age of onset of th e disease, and directly with the severity of clinical deficits.

Huntingtin harbors polyglutamine tracts and is very widely expressed (116, 117, 126, 185, 201), but with heterogeneity even in the normal neostriatum (51). Discovered as a result of genetic investigations in HD, huntingtin is of unknown function. Both mutated and normal versions of huntingtin are expressed in HD brains (157). The epitopes have been identified in perikarya, in punctate profiles presumed related to synaptic terminals, and in synaptosomes (7, 32, 36, 74, 2 16). Although polyclonal antibodies to huntingtin have immunolabeled components of the nucleus (including neuronal nuclei, 32), the evidence for a nuclear localization is in dispute (see Ross et al., this symposium). Huntingtin is ubiquitinated (98) and may interact with proteins of the ubiquitination pathway (see Ross et al,

this symposium). Huntingtin may be essential for normal cerebral

development and homeostasis. In transgenic mice whose huntingtin homologue had undergone targeted disruption, the embryonic homozygotes perished (140). These embryos had an increased rate of apoptosis, suugg esting that huntingtin operates as an apoptosis inhibitory factor (45, 233). Heterozygotes with targeted disruption show significant neurologic and neuropathologic changes, though not a precise phenocopy of HD (140). Huntingtin apparently undergoes cleavage during apoptosis, more avidly with increasing length of its polyglutamine tract (65, 141, Wellington et al. this symposium).

Apoptosis studies (159) are one part of the extensive efforts now being made to identify proteins with which huntingtin or polyglutamine tracts may interact, and to establish potential links between the normal or pathologic effects of normal or mutated huntingtin, with cell processes previously suspected in HD pathogenesis (excitotoxicity, apoptosis, free radical damage, mito- chondrial and other metabolic effects). These topics are developed in the detailed updates provided by Ross and colleagues, and by WelIington and colleagues, in this symposium.

For the classic pathologic changes in the neostriatum, Vonsattel and colleagues (221) have published a useful grading system, ranging from 0 (no changes evident on gross examination and no microscopic abnormalities by routine histologic examination, despite typical clinical course and family history) to 4 (grossly concave head of caudate, with severe neuronal loss and gliosis) (Figure 6). This grading system has been applied in several studies (134), including a recent study correlating seventy of pathology with size of the CAG repeat expansion (59).

A given HD patient may have tissue-specific differences in size of the huntingtin CAG repeat, a phenome- non known as mosaicism. The repeat size is particularly unstable in sperm (213). and meiosis, not mitosis, is probably the event most associated with instability and expansion of the repeats (1 25, 226). Nonetheless, striatum and cerebral cortex reportedly harbor larger huntingtin CAG repeat sizes than does cerebellar cortex (214). Despite small regional differences in length of CAG repeats from HD brains (33, 59), mosaicism does not seem to account for much of the selective vulnerability in HD or other CAG repeat diseases.

The pathology of Huntington's disease had been extensively studied before the genetic defect was discovered. Reviews of pathology and pathogenetic concepts are available ( I 1,72,733,75, 178). The remainder of this section gives an overview of some of the perti-


Figure 7. Huntington's Disease. The classic appearance of HD (A, left) compared to control (A, right) emphasizes the marked striatal degeneration, but atrophy of the neocortical grey and white matter are also present. Extensive astrocytosis and neuronal loss in the caudate and putarnen (6) contrasts with the lack, in most HD cases, of significant degeneration in the regions affected by other triplet repeat disorders. The neuronal populations of the globus pallidus (C) and subthalamic nucleus (D) are generally intact although varying degrees of astrocytosis are often present in the globus pallidus, as in this case, and thalamus. Arrow=astrocyte; arrowhead=neuron. B-D=H&E; Bars: B-D=25 mm

nent issues that have arisen in HD pathology, independently of huntingtin and its properties.

The neostriatum is preferentially involved (Figure 7), the earliest detectable change perhaps appearing in the striosomal compartment (79). However, as the matrix becomes involved, changes progress in a dorsal to ventral direction. The "small neurons" are selectively vulnerable, and are currently classified as medium spiny neurons (15). They predominantly express enkephalin and GABA. Certain classes of striatal neurons are remarkably spared (24, 50, 52). The patterns of neurotransmitter loss in HD brain tissue have been compared in rigid and choreic cases of the disease (200).

A pathophysiologic paradigm has been developed to account for the chorea on the basis of the selective neurodegeneration. The major neurotransmitters of the normal caudate inzlude glutamate (corticostriatal afferents), dopamine (nigrostriatal afferents), acetylcholine (intrinsic interneurons), and GABA (striatal projection neurons). Of these, it is the GABAergic population that is most devastated. The physiologic result in the choreic stage of the disease is a loss of striatal inhibitory input to the I ateral globus pallidus. Two important case studies of early or presymptomatic HD yield supportive evidence. Enkephalin-containing neurons which project to the external segment of globus pallidus, and substance P


containing neurons which project to substantia nigra, are affected very early in the disease (1, 4), supporting the view that it is preferential loss of striatal projections to lateral pallidum that accounts for the chorea (2, 167, 168).

The pathophysiologic paradigm then proposes that the loss of striatal inhibitory input to the lateral globus pallidus results in an increased output from the lateral globus pallidus to the subthalamic nucleus. Since that pathway (pallidoluysian) is inhibitory, the subthalamic output is suppressed (reminiscent of focal damage to the subthalamic nucleus, which produces hemiballismus). This is summarized and illustrated in (3, 34,73).

Efforts to understand pathogenesis rely on an established profile of affected and "unaffected" cell populations. Experience teaches that the list of affected populations grows as investigators devote careful attention to various parts of the brain initially overlooked or disput- ed in pathologic descriptions. Involvement of cortex, notably layers V and VI is now well documented (80, 194). Indeed, atrophy of the brain in HD involves cortex, subcortical white matter, and thalamus, as well as neostriatum and lenticular nuclei (31, 112, 129; see also Figure 7C). Careful studies reveal cell loss in parts of hippocampus and entorhinal cortex (16,97). Certain cell populations relevant to eye movement abnormalities can be affected in HD (103, 115). The lateral tuberal nucleus of the hypothalamus is severely affected (108).

Findings in the substantia nigra have been described as essentially normal (128) or showing significant neuronal loss and atrophy (152). There is massive loss of striatonigral projection terminals in the pars reticulata (64). Other nuclei which undergo detectable changes include the ventrolateral nucleus (38) and centromedi- an-parafascicular complex (8 1) of the thalamus; the subthalamic nucleus (1 12; but see Figure 7D); and the locus coeruleus (237). Evidence for involvement of cerebellar Purkinje cells is convincing (95). The nucleus basalis of Meynert, on the other hand, seems to be spared (6, 25, 205).

Ideally, involvement of a given anatomic site should be characterized as a primary or secondary (trans-synaptic) effect. A primary effect implies molecular vulnerability of that neuronal type, whereas a secondary effect implies a nonspecific degeneration, less informative in working out strategies of therapy and prevention. Studies of the earliest stages of the disease are helpful in making the distinction, as are other approaches, but the distinction is often impossible. Studies of cellular changes in surviving neurons in HD are not extensive. However, altered dendritic morpology (70, 195) and

neuronal atrophy (152) can be detected in certain populations.

In juvenile onset cases the clinical picture differs, and the pathology can be more severe, with extension to the cerebellum. Comparison of DRPLA and juvenile HD reveals some remarkable similarities, as well as differences, as reviewed and illustrated in the manuscript by Ross and colleagues (this symposium).

Analysis of huntingtin CAG repeat polymorphism has become a valuable adjunct in selected autopsies (231). HD does have overlap with other neurodegenerative disorders, as well as residual problems of differential diagnosis. Cases in which HD and familial amyotrophic lateral sclerosis occur in the same subject ( 175) illustrate the heterogeneity on the "fringe" of these established genetic diseases. The neostriatum is involved in various neurodegenerative disorders, but the preferential pattern of involvement seen in HD is rare, Neuroacanthocytosis may approximate it (170), despite a very different pathogenetic point of departure.

For individual cases with pathologic resemblance to HD, where the genetic or nosologic classification is not clear, it will be worthwhile to rule out CAG-repeat expansions in the huntingtin gene. This should be applicable to the rare Huntington-like case with atypical pathologic features (for example, case 1 of Munoz- Garcia and Ludwin (1 32) as well as more common disorders such as the dementias lacking distinctive histologic features. Recent advances in genetics have helped resolve classification of senile chorea; reported cases did not have CAG repeat expansions in the HD range (186).

Conclusion: CAG repeats and the future of neuropathology

This review illustrates a small part of the rich interactions between molecular genetics and the neuro- sciences. Genetic advances in understanding the CAG repeat disorders drew upon the existing clinical and pathologic classifications, and refined them. Identification of genetic loci has led to more precise and meaningful comparisons of clinical and pathologic features in several of the diseases, notably the cerebellar degenerations. The molecular probes made available have enormous implications for clinical and preclinical diagnosis and genetic counseling.

For the neuropatholo,oist, the advances not only facil- itate diagnosis, but also open lines of pathogenetic investigation. It should be emphasized that not all the neuronal degeneration in these disorders is primary; some of the affected neuronal populations probably

-- - - ___ _ - ~. _. - - -


degenerate secondarily, by retrograde or anterograde trans-synaptic mechanisms identical to those which operate after focal lesions of their efferent or afferent projection systems.

That caveat aside, local effects of the mutated proteins must account for much of what we see; and the new genetic information has already given some pre- liminary answers to the questions we posed in our introduction. Although CAG repeat expansion size seems to influence age of onset and clinical and patholo,' UIC severity in several of these diseases, regional differences in size of the CAG repeat expansions do not correlate well with the neuroanatomic sites (neuronal subsets) most vulnerable to the disease. Nor have regional differences in transcript levels accounted for the selective vulnerability in any obvious way. This would suggest that pathogenetic mechanisms depend on something down- stream, somehow involving the encoded protein with the expanded polyglutamine tract. The selective vulnerability might then depend upon unique features of the affected neuronal populations, such as expression of other proteins with which the mutant protein interacts. Or receptors expressed on a given neuronal population might initiate an intracellular cascade in which the mutant protein constitutes (or strikes) a unique cellular Achilles heel. Hence the efforts, described in other papers of this symposium, to identify other proteins with which the mutated proteins interact; and to identify involvement of the mutant proteins in processes such as apoptosis, excitotoxic or other metabolic effects, which are hypothesized modes of neuronal death.

In general, the mechanisms of the CAG repeat disorders are believed to be due to a "gain of function," rather than to a simple loss or impairment of function of the protein. This is discussed elsewhere in this symposium. However, identifying the function of the normal protein seems important to sorting out the pathogenetic effect of the mutation. Of the mutated proteins, just two (the androgen receptor in SBMA and the a l A voltage- dependent calcium channel protein in SCA6) corre- spond to proteins, for which normal functions had been established before the association with mutation and neurologic disease was discovered. For the calcium channel protein, the next pathogenetic breakthrough seems a step away, since the receptor is expressed on Purkinje cells and the mutant protein is now associated with two cerebellar ataxias. Both the established and the newly discovered proteins (ataxins, atrophin, and hunt- instin) and their genes and transcripts permit approaches to the questions stated in our introduction.

Recent advances in molecular genetics have obvious

implications for the training of neuropatholgists and the practice of neuropathology. Some basic familiarity with molecular genetics and the advances in neurogenetics is essential. The approach to autopsies and biopsies is affected; there i:; a much higher premium now on freez- ing, or otherwise processing, a fragment of fresh tissue for genetic analysis. Enriched by a steady stream of new insights, questions, and methods, modem neuropathology faces impressive opportunities and challenges.

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The neuropathology of CAG repeat diseases: review and update of genetic and molecular features

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