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Keywords:

  • CAG repeat;
  • dentatorubral-pallidoluysian atrophy;
  • polyglutamine

Abstract

  1. Top of page
  2. Abstract
  3. HISTRICAL ANNOTATIONS
  4. CLINICAL FEATURES
  5. NEUROPATHOLOGIC FEATURES
  6. IDENTIFICATION OF THE GENE FOR DRPLA
  7. DEVELOPMENT OF MOLECULAR NEUROPATHOLOGY IN DRPLA
  8. EXPERIMENTAL MODELS
  9. CONCLUSION
  10. ACKNOWLEDGMENTS
  11. REFERENCES

Dentatorubral-pallidoluysian atrophy (DRPLA) is a hereditary spinocerebellar degeneration. Despite the establishment of this disease in 1982, it has been pointed out that DRPLA has an unexplained aspect concerning its clinicopathological features; that is, the discrepancy between the variety of clinical manifestations and the uniformity of the brain lesions. The discovery of a causative gene mutation (abnormal expansion of the CAG repeat in DRPLA gene) triggered the development of novel neuropathology in DRPLA, which has suggested that polyglutamine-related pathogenesis involves a wide range of central nervous system regions far beyond the systems previously reported to be affected. It is now likely that DRPLA has an aspect of neuronal storage disorder and has multiple system degeneration, the lesion distribution of which varies depending on the CAG repeat sizes in the causative gene.


HISTRICAL ANNOTATIONS

  1. Top of page
  2. Abstract
  3. HISTRICAL ANNOTATIONS
  4. CLINICAL FEATURES
  5. NEUROPATHOLOGIC FEATURES
  6. IDENTIFICATION OF THE GENE FOR DRPLA
  7. DEVELOPMENT OF MOLECULAR NEUROPATHOLOGY IN DRPLA
  8. EXPERIMENTAL MODELS
  9. CONCLUSION
  10. ACKNOWLEDGMENTS
  11. REFERENCES

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder and is now also known as one of the CAG repeat (polyglutamine) diseases. According to a review article of DRPLA by Kanazawa,1 the first case of hereditary DRPLA was reported by Titica and Bogaert in 1946,2 who described two patients in a single family. Their clinical features included progressive hemiballism with choreoathetosis cerebellar ataxia and dementia. Neuropathology of the one case disclosed a combined degeneration of the pallidoluysian and dentatorubral systems. In 1958, Smith et al. reported a sporadic case of DRPLA without a family history, who showed cerebellar ataxia with combined degeneration of the dentato-rubral and pallido-Luysian systems.3 The study which laid special emphasis on the heritability of DRPLA was started by Naito et al. in 1972.4 The authors reported two families suffering from progressive myoclonus epilepsy (PME) with autosomal dominant transmission. In 1976, Oyanagi et al. reported autopsy findings of eight patients with degenerative PME, and confirmed the combined degeneration of the two systems as the pathology responsible for PME and other neurological symptoms.5 It is interesting that the two sporadic patients in the study were later reclassified as myoclonus epilepsy with ragged-red fiber and essential myoclonus and epilepsy. In 1982, Naito and Oyanagi proposed the name “hereditary dentatorubral-pallidoluysian atrophy” for the disease conditions characterized by the following features: (i) myoclonus epilepsy syndrome with or without cerebellar ataxia or choreoathetosis or both; (ii) dentatorubral-pallidoluysian atrophy; and (iii) autosomal dominant heredity.6

CLINICAL FEATURES

  1. Top of page
  2. Abstract
  3. HISTRICAL ANNOTATIONS
  4. CLINICAL FEATURES
  5. NEUROPATHOLOGIC FEATURES
  6. IDENTIFICATION OF THE GENE FOR DRPLA
  7. DEVELOPMENT OF MOLECULAR NEUROPATHOLOGY IN DRPLA
  8. EXPERIMENTAL MODELS
  9. CONCLUSION
  10. ACKNOWLEDGMENTS
  11. REFERENCES

Dentatorubral-pallidoluysian atrophy patients show various symptoms, such as myoclonus, epilepsy, ataxia, choreoathetosis and dementia, and the combinations of these symptoms are determined by the age at onset.7 Patients with earlier onset (generally below the age of 20 years) show progressive myoclonus, epilepsy and mental retardation (juvenile type). Epileptic seizures are a feature in all patients with onset before the age of 20, and the frequency of seizures decreases with age after 20. Patients with late onset (over the age of 40 years) predominantly show cerebellar ataxia and dementia (late-adult type). Patients in whom the disease appears between the third and fifth decades belong to an intermediate type, and usually show ataxia and choreoathetosis (early-adult type).

MRI findings of DRPLA are characterized by atrophic changes in the cerebellum, pons, brain stem and cerebrum (Fig. 1a,b). High-signal lesions in the cerebral white matter, globus pallidus, thalamus, midbrain and pons on T2-weighted MRI have been often found in adult patients with long disease durations (Fig. 1c).8

image

Figure 1. MRI findings of a brain with dentatorubral-pallidoluysian atrophy (DRPLA). T1-weighted MRIs from a patient with juvenile type (a,b) show a diffuse atrophy of the cerebrum, brain stem and cerebellum. T2-weighted MRI from a patient with late-adult type (c) shows high-signal lesions in the cerebral white matter.

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NEUROPATHOLOGIC FEATURES

  1. Top of page
  2. Abstract
  3. HISTRICAL ANNOTATIONS
  4. CLINICAL FEATURES
  5. NEUROPATHOLOGIC FEATURES
  6. IDENTIFICATION OF THE GENE FOR DRPLA
  7. DEVELOPMENT OF MOLECULAR NEUROPATHOLOGY IN DRPLA
  8. EXPERIMENTAL MODELS
  9. CONCLUSION
  10. ACKNOWLEDGMENTS
  11. REFERENCES

At autopsy, the thickening of the skull is a significant feature of DRPLA. Macroscopically, the brain is generally small. The cerebrum, brain stem and cerebellum are relatively well proportioned in external appearance. The spinal cord is proportionately small in size. There is no correlation between brain weight and clinical factors such as age at onset, age at death and disease duration, and between brain weight and CAG repeat size. On cut surface, the brain reveals atrophy and brownish-tan discoloration of the globus pallidus (Fig. 2), subthalamic nucleus (Luys body), and dentate nucleus. The atrophy of the brain stem tegmentum, being more marked in the pontine tegmentum, is also remarkable. The cerebral cortical atrophy is slight or negligible. However, almost every case shows mild to moderate dilatation of the lateral ventricle.

image

Figure 2. Gross findings of a brain with dentatorubral-pallidoluysian atrophy (DRPLA). Atrophy of the globus pallidus, especially its lateral segment (arrow), and subthalamic nucleus (arrowhead) are observed on a coronal brain section through the mammillary body (a), as well as on its KB staining preparation (b).

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Combined degeneration of the dentatorubral and pallidoluysian systems is the major pathological feature of DRPLA. The globus pallidus, especially the lateral segment (Fig. 3a), and the dentate nucleus are consistently involved, showing loss of neurons and astrocytosis. The subthalamic nucleus also shows loss of neurons (Fig. 3b). The loss of neurons is always milder than that of the lateral segment of the globus pallidus. In the dentate nucleus, the remaining neurons are often swollen or shrunken with so-called “grumose degeneration”: numerous eosinophilic and argytophilic granular materials, which represent the secondary change of the axon terminals of Purkinje cells, accumulating around the somata and dendrites. In the red nucleus, definite astrocytosis is seen, but loss of neurons is usually not evident. In general, pallidoluysian degeneration is more marked than dentatorubral degeneration in the juvenile-type DRPLA, and the reverse is often seen in the late-adult type. The population of cerebral cortical neurons appears to be mildly or slightly decreased. In some cases, especially in the adult-onset cases, diffuse myelin pallor with slight gliosis is also evident in the white matter. In DRPLA, various other brain regions may be affected mildly or moderately, but it is also important to note that the substantia nigra, the locus ceruleus, the pontine nuclei and the cranial nerve nuclei, with the exception of vestibular nuclei, are well preserved.

image

Figure 3. Microscopic findings of a brain with dentatorubral-pallidoluysian atrophy (DRPLA). Severe loss of neurons with astrocytic gliosis is observed in the lateral segment of the globus pallidus (a) and subthalamic nucleus (b). Intranuclear inclusions (arrows) are seen in dentate nucleus neurons (c,d). Diffuse intranuclear accumulation of expanded polyglutamine stretches (arrowhead) is seen in neurons of the pontine nuclei (e), subthalamic nucleus (f), and cerebral cortex (g). A skein-like inclusion is seen in the cytoplasm of a neuron in the cerebellar dentate nucleus (h). HE stain, (a,b); immunohistochemistry for ubiquitin (c,h) and expanded polyglutamine stretches with 1C2 monoclonal antibody (d–g). Scale bars = 20 µm.

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IDENTIFICATION OF THE GENE FOR DRPLA

  1. Top of page
  2. Abstract
  3. HISTRICAL ANNOTATIONS
  4. CLINICAL FEATURES
  5. NEUROPATHOLOGIC FEATURES
  6. IDENTIFICATION OF THE GENE FOR DRPLA
  7. DEVELOPMENT OF MOLECULAR NEUROPATHOLOGY IN DRPLA
  8. EXPERIMENTAL MODELS
  9. CONCLUSION
  10. ACKNOWLEDGMENTS
  11. REFERENCES

The gene for DRPLA was identified in 1994,9,10 and mapped to 12p13.31 by in situ hybridization.11 The human DRPLA gene spans approximately 20 kbp and consists of 10 exons, with the CAG repeats located in exon 5.12 The number of CAG repeats in normal chromosomes and DRPLA patients range from 6 to 35 and from 54 to 79, respectively.13

It is characteristic that there is anticipation in DRPLA.9,10,14 Paternal transmission results in more prominent anticipation (26–29 years/generation) than does maternal transmission (14–15 years/generation). There is an inverse correlation between the size of expanded CAG repeats and age at onset, and also a correlation between clinical features and the repeat size.13 DRPLA patients with longer CAG repeats show a more early onset and severer phenotypes. The physiological functions of DRPLA protein remain to be elucidated. It is generally accepted that mutant DRPLA proteins with expanded polyglutamine stretches are toxic to neuronal cells (“gain of toxic functions”).

DEVELOPMENT OF MOLECULAR NEUROPATHOLOGY IN DRPLA

  1. Top of page
  2. Abstract
  3. HISTRICAL ANNOTATIONS
  4. CLINICAL FEATURES
  5. NEUROPATHOLOGIC FEATURES
  6. IDENTIFICATION OF THE GENE FOR DRPLA
  7. DEVELOPMENT OF MOLECULAR NEUROPATHOLOGY IN DRPLA
  8. EXPERIMENTAL MODELS
  9. CONCLUSION
  10. ACKNOWLEDGMENTS
  11. REFERENCES

The discovery of neuronal intranuclear inclusions (NIIs) in transgenic mice for Huntington's disease15 triggered new development of neuropathology in polyglutamine diseases, including DRPLA. NIIs are eosinophilic round structures, and easily detectable by ubiquitin immunohistochemistry (Fig. 3c). In DRPLA, they are also immunoreactive for expanded polyglutamine stretches (Fig. 3d) as well as for atrophin-1, the DRPLA gene product.16,17 Ultrastructurally, NIIs are non-membrane bound, heterogeneous in composition, and contain a mixture of granular and filamentous structures, approximately 10–20 nm in diameter. NIIs were initially thought to be toxic structures responsible for neuronal cell death in affected brain regions; however, subsequent investigations raised the possibility that NII formation itself might be a cellular reaction designed to reduce the acute toxic effect of the mutant proteins.18–20 In DRPLA, NIIs were detectable in multiple brain regions far beyond the dentatorubral and pallidoluysian systems, suggesting that neurons are affected much more widely than was recognized previously, although the incidences of NIIs were very low even in the affected regions.21 In 2001, it became apparent that diffuse intranuclear accumulation of the mutant DRPLA protein affects many neurons in wide area of the CNS, including the cerebral cortex (Fig. 3e–g), and that the prevalence of this pathology changes dynamically in relation to CAG repeat size. The results suggest that the novel lesion distribution revealed by the diffuse nuclear labeling may be responsible for a variety of clinical features, such as dementia and epilepsy in DRPLA.22 In addition to NIIs, skein-like inclusions were also detectable in DRPLA brains, although their appearances were restricted in the cerebellar dentate nucleus (Fig. 3h).23

EXPERIMENTAL MODELS

  1. Top of page
  2. Abstract
  3. HISTRICAL ANNOTATIONS
  4. CLINICAL FEATURES
  5. NEUROPATHOLOGIC FEATURES
  6. IDENTIFICATION OF THE GENE FOR DRPLA
  7. DEVELOPMENT OF MOLECULAR NEUROPATHOLOGY IN DRPLA
  8. EXPERIMENTAL MODELS
  9. CONCLUSION
  10. ACKNOWLEDGMENTS
  11. REFERENCES

To elucidate the molecular mechanisms of neuronal degeneration in DRPLA, transgenic mice harboring a single copy of a full-length human mutant DRPLA gene with 76 or 129 CAG repeats have been generated.24 Q129 mice show clinical phenotypes similar to DRPLA patients, commencing myoclonic movement at 3 weeks of age. Histologically, the formation of NIIs is detectable after 9 weeks of age in the restricted CNS regions similar to those in the human DRPLA brain. Despite the strong neurological phenotype, obvious neuronal loss is not observed in any brain region. Diffuse polyglutamine accumulation in neuronal nuclei occurs in some regions, including the basal ganglia at as early as post-natal day 4 and expands to multiple brain regions by 4 weeks of age, suggesting that this nuclear pathology is responsible for the onset of clinical phenotype. Interestingly, this mouse model shows generalized brain atrophy that commences synergistically with the intranuclear accumulation of mutant proteins.

CONCLUSION

  1. Top of page
  2. Abstract
  3. HISTRICAL ANNOTATIONS
  4. CLINICAL FEATURES
  5. NEUROPATHOLOGIC FEATURES
  6. IDENTIFICATION OF THE GENE FOR DRPLA
  7. DEVELOPMENT OF MOLECULAR NEUROPATHOLOGY IN DRPLA
  8. EXPERIMENTAL MODELS
  9. CONCLUSION
  10. ACKNOWLEDGMENTS
  11. REFERENCES

It is now apparent that DRPLA brains share several polyglutamine-related changes in their neuronal nuclei, in addition to the conventional pathology characterized by neuronal depletion. The extensive involvement of CNS regions by polyglutamine pathology suggests that neurons are affected much more widely than has been recognized previously. The dynamics of the lesion distribution, which varies depending on the CAG repeat sizes in the causative gene, may be responsible for a variety of clinical phenotypes in DRPLA. It is likely that DRPLA has an aspect of neuronal storage disorders, and transcriptional and metabolic disturbances of affected neurons may play a pivotal role in the pathogenesis of the disease.25

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. HISTRICAL ANNOTATIONS
  4. CLINICAL FEATURES
  5. NEUROPATHOLOGIC FEATURES
  6. IDENTIFICATION OF THE GENE FOR DRPLA
  7. DEVELOPMENT OF MOLECULAR NEUROPATHOLOGY IN DRPLA
  8. EXPERIMENTAL MODELS
  9. CONCLUSION
  10. ACKNOWLEDGMENTS
  11. REFERENCES

The author would like to thank Dr Hitoshi Takahashi, Department of Pathology, Brain Research Institute, Niigata University, for helpful suggestions, and Dr Arika Hasegawa, Department of Neurology, National Hospital Organization, Nishi-Niigata Chuo National Hospital, for MRI. This research was supported by a grant from the Research Committee for Ataxic Diseases, and the Research Grant (19A-4) for Nervous and Mental Disorders, from the Ministry of Health, Labor and Welfare, Japan.

REFERENCES

  1. Top of page
  2. Abstract
  3. HISTRICAL ANNOTATIONS
  4. CLINICAL FEATURES
  5. NEUROPATHOLOGIC FEATURES
  6. IDENTIFICATION OF THE GENE FOR DRPLA
  7. DEVELOPMENT OF MOLECULAR NEUROPATHOLOGY IN DRPLA
  8. EXPERIMENTAL MODELS
  9. CONCLUSION
  10. ACKNOWLEDGMENTS
  11. REFERENCES
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