Dentatorubral–pallidoluysian atrophy

Signs and symptoms

DRPLA can be juvenile-onset (40 years). Late adult-onset DRPLA is characterized by ataxia, choreoathetosis and dementia. Early adult-onset DRPLA also includes seizures and myoclonus. Juvenile-onset DRPLA presents with ataxia and symptoms consistent with progressive myoclonus epilepsy{{ cite journal (myoclonus, multiple seizure types and dementia). Other symptoms that have been described include cervical dystonia,{{ cite journal |display-authors=etal}} corneal endothelial degeneration,{{ cite journal |display-authors=etal|doi-access= cite journal

Genetics

The human genome contains two atrophin genes; DRPLA has been correlated to the expansion of the polyglutamine region of the atrophin-1 gene on chromosome 12p13.3.{{ cite journal |display-authors=etal}} A normal number of CAG repeats in the atrophin-1 gene is 7–34, affected individuals display 49–93 repeats. DRPLA displays anticipation (earlier age of onset for subsequent generations) and an inverse correlation between the size of the expanded CAG repeat and the age of symptom onset. Paternal transmission results in more prominent anticipation (26–29 years) than maternal transmission (14–15 years).

Atrophin-1

Atrophin-1 (ATN1) encodes a hydrophilic 1184 amino acid protein with several repetitive motifs including a serine-rich region, a variable length polyglutamine tract, a polyproline tract, and a region of alternating acidic and basic residues. It contains a putative nuclear localization signal in the N-terminus of the protein and a putative nuclear export signal in the C-terminus.{{ cite journal |display-authors=etal|doi-access= free cite journal |display-authors=etal|doi-access= free cite journal |display-authors=etal|doi-access= free

Transgenic mouse models

Mouse models of DRPLA have been successfully generated, which demonstrate the same intergenerational instability and severe phenotype as human DRPLA.{{ cite journal |display-authors=etal|doi-access= free cite journal |display-authors=etal}}{{ cite journal |display-authors=etal|doi-access= free cite journal |display-authors=etal}}{{ cite journal |display-authors=etal|url= https://kanazawa-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=38500&item_no=1&attribute_id=26&file_no=1 |doi-access= free |hdl-access= free

Pathology

DRPLA is characterized by marked, generalized brain atrophy and the accumulation of atrophin-1 with expanded glutamine stretches. Mutant atrophin-1 proteins have been found in neuronal intranuclear inclusions and diffusely accumulated in the neuronal nuclei. While the role of neuronal intranuclear inclusions (pathologic or protective) is unclear, the diffuse accumulation of mutant protein is regarded as toxic.

Brain atrophy

There is significant reduction in CNS tissue throughout the brain and spinal cord, with brain weights of DRPLA patients often becoming less than 1000g.{{ cite journal

Transgenic DRPLA mice demonstrated several neuronal abnormalities including a reduction in the number and size of dendritic spines as well as in the area of perikarya and diameter of dendrites.

Morphometric analysis of DRPLA mouse brains has shown a loss of normal inter-microtubule spacing in neuronal axons. The microtubules were relatively compacted, suggesting abnormalities in protein transport may play a role in neuronal degeneration. In humans, atrophin-1 interacts with IRSp53, which interacts with Rho GTPases to regulate the organization of the actin cytoskeleton and the pathways that regulate lamellipodia and filopodia.{{ cite journal |doi-access= free

Neuronal intranuclear inclusions

Neuronal intranuclear inclusions are not exclusive to DRPLA; they have been found in a variety of neurodegenerative disorders. In DRPLA, neuronal intranuclear inclusions have been demonstrated in both neurons and glial cells in the striatum, pontine nuclei, inferior olive, cerebellar cortex and dentate nucleus,{{ cite journal |display-authors=etal}} though the incidence of neurons with NIIs is low, roughly 1–3%.

In DRPLA, the neuronal intranuclear inclusions are spherical, eosinophilic structures of various sizes. They are non-membrane-bound and are composed of both granular and filamentous structures. They are ubiquitinated and may be paired or in doublet form within the nucleus.{{ cite journal |display-authors=etal}}

Neuronal intranuclear inclusions are immunopositive for several transcription factors such as TATA binding protein (TBP), TBP-associated factor (TAFII130), Sp1, camp-responsive element-binding protein (CREB) and CREB-binding protein (CBP).{{ cite journal |display-authors=etal}}{{ cite journal |display-authors=etal}} It has been proposed that recruitment of transcription factors into neuronal intranuclear inclusions may induce transcriptional abnormalities that contribute to progressive neuronal degeneration. Other polyQ disorders, such as Huntington's and spinocerebellar ataxia (types 3 and 7), have been demonstrated to sequester some of the same transcriptions factors. That different gene products sequester the same transcription factors may contribute to the overlapping symptoms of genetically different diseases.{{ cite journal

Neuronal intranuclear inclusions have also been demonstrated to alter the distribution of the intranuclear structures, such as promyelocytic leukemia protein (PML) nuclear bodies. Although the role of PML bodies is unclear, they are believed to be involved in apoptosis. In neurons with inclusions, PML bodies in DRPLA patients form a shell or ring around the ubiquitinated core. In similar polyQ diseases, the association of this PML shell has been shown to be size-dependent with larger inclusions being PML negative.{{ cite journal |display-authors=etal}}{{ cite journal |display-authors=etal|doi-access= free

Filementous, atrophin-1 positive, inclusions are also observed exclusively in the cytoplasm of the dentate nucleus, which are extremely similar to the inclusions observed in the motor neurons in amyotrophic lateral sclerosis.{{ cite journal |display-authors=etal}}

Diffuse accumulation in the nuclei

In DRPLA, diffuse accumulation of mutant ATN1 occurs far more extensively than neuronal intranuclear inclusion formation. The extent and frequency of neurons showing the diffuse nuclear accumulations changes depending on CAG repeat length. It is believed that the diffuse nuclear accumulations contribute to the clinical features such as dementia and epilepsy.

ATN1 contains both a nuclear localization sequence and a nuclear export sequence. Cleavage of ATN1 to an N terminal fragment relieves ATN1 of its nuclear export signal and concentrates it in the nucleus. Increased nuclear concentrations have been demonstrated via transfection assay to enhance cellular toxicity.

In both the juvenile and adult forms, regions in which more than 40% of neurons became immunoreactive to 1C2 (a monoclonal antibody against expanded polyglutamine stretches) included: the nucleus basalis of Meynert, large striatal neurons, globus pallidus, subthalamic nucleus, thalamic intralaminar nucleus, lateral geniculate body, oculomotor nucleus, red nucleus, substantia nigra, trigeminal motor nucleus, nucleus raphes pontis, pontine nuclei, vestibular nucleus, inferior olive and the cerebellar dentate nucleus. The juvenile type also shows reactivity in the cerebral cortex, hippocampal CA1 area, and the reticular formation of the brainstem. Nuclei containing accumulations of mutant atrophin-1 are deformed with nuclear membrane indentations.{{ cite journal |display-authors=etal}}

Diagnosis

Diagnosis of DRPLA rests on positive family history, clinical findings, and genetic testing. Family history can be difficult to obtain if a relative was misdiagnosed, died young, or experiences late onset of symptoms.

Other diseases in the differential diagnosis of adult-onset DRPLA include Huntington's and the spinocerebellar ataxias. For juvenile-onset disease, familial essential myoclonus and epilepsy (FEME), Lafora, Unverricht–Lundborg, Neuroaxonal dystrophy, Gaucher's disease, sialidosis, and Galactosialidosis should be considered.

Management

To quantify the extent of the disease, an MRI, EEG and neuropsychological testing are recommended. Seizures are treated with anticonvulsants and psychiatric disturbances with psychotropic medications. Physical therapy has also been recommended to maintain function as the condition progresses and occupational therapy to focus on activities of daily living.

Epidemiology

The prevalence of DRPLA in the Japanese population is believed to be between 2 and 7 in 1,000,000. It is observed relatively less frequently in other ethnic populations, and an analysis of normal ATN1 alleles has demonstrated that CAG repeat lengths greater than 17 are significantly more frequent in the Japanese population.{{ cite journal |display-authors=etal}}{{ cite journal |display-authors=etal}}

DRPLA was thought to mainly affect people of Japanese origin, but a 2007 research study, revealed a relatively high prevalence in south Wales.

References

References

1. Kanazawa I. (June 1999). "Molecular pathology of dentatorubral–pallidoluysian atrophy". Philos. Trans. R. Soc. Lond. B Biol. Sci..
2. (2001-11-01). "Dentatorubropallidoluysian Atrophy in Chinese". Archives of Neurology.
3. (2018-01-16). "Pearls & Oy-sters: Family history of Huntington disease disguised a case of dentatorubral-pallidoluysian atrophy". Neurology.
4. (2010). "Proteolytic processing regulates pathological accumulation in dentatorubral-pallidoluysian atrophy". The FEBS Journal.
5. Rowan, Alison. (December 2004). "Allies in the fight against neurodegeneration". Nature Reviews Neuroscience.
6. (2010-07-01). "The fine line between waste disposal and recycling: DRPLA fly models illustrate the importance of completing the autophagy cycle for rescuing neurodegeneration". Autophagy.
7. (2006-09-01). "Neuronal atrophy and synaptic alteration in a mouse model of dentatorubral–pallidoluysian atrophy". Brain.
8. (2001). "Widespread occurrence of intranuclear atrophin-1 accumulation in the central nervous system neurons of patients with dentatorubral-pallidoluysian atrophy". Annals of Neurology.
9. (2012-08-01). "Is cerebral white matter involvement helpful in the diagnosis of dentatorubral-pallidoluysian atrophy?". Journal of Neurology.
10. (2009-08-01). "A case of late adult-onset dentatorubral-pallidoluysian atrophy mimicking central pontine myelinolysis". Journal of Neurology.
11. (2018-10-01). "Dentatorubral-pallidoluysian Atrophy: An Update". Tremor and Other Hyperkinetic Movements.
12. Edwards, Oscar. (21 September 2025). "DRPLA: Parents fight to raise awareness of rare disease 'cluster'". BBC News.
13. (July 2008). "Dentatorubral pallidoluysian atrophy in South Wales". Journal of Neurology, Neurosurgery, and Psychiatry.