Dentatorubral–pallidoluysian atrophy (DRPLA) is a clinically heterogenous autosomal dominant CAG repeat expansion disorder that is particularly prevalent within the Japanese population.
The majority of case reports are in patients of Japanese origin, where disease prevalence is 1 in 200,000. The worldwide prevalence is unknown. A large case series of Caucasian patients with cerebellar ataxia identified the frequency of DRPLA as 0.25% in this cohort 2.
In both Asian and non-Asian populations, the natural history and symptomatology of DRPLA is similar 3. With that being said, between individual patients the presentation of DRPLA is highly heterogeneous and varies with age of onset 4. Specifically, younger patients - less than 20 years - tend to present with myoclonic epilepsy and older patients - onset over 40 years - with choreoathetosis, cerebellar ataxia and dementia 4. Median age of onset is 31 years, ranging from infancy to age 72 years 4-6. Of note, one of the most striking features of DRPLA is its strong heritability and genetic anticipation 5.
DRPLA occurs when there are 47 to 93 CAG repeat expansions within one allele of the atrophin 1 (ATN1) gene on chromosome 12p 6,7. Histopathology reveals widespread intranuclear granular and filamentous inclusion bodies within deep brain nuclei and the cerebellar cortex, particularly affecting neurons 8. The finding of combined degeneration of the dentatorubral and pallidoluysian systems gives DRPLA its name 6. Degeneration of white matter tracts is also frequent 6.
- symmetrical, diffuse white matter hyperintensities in the cerebrum, deep brain structures, namely the thalamus and globus pallidus, although the midbrain and pons may be involved in elderly patients 6,9
- spreading of white matter changes through the corona radiata and centrum semiovale has been reported at follow-up 10
Additionally, atrophy of the cerebellum and pontine tegmentum are typical, with the extent of atrophy correlating with the extent of CAG expansion 6. Generalized atrophy is reported in most patients.
Treatment and prognosis
Treatment focuses on symptom control. Death generally occurs 8 years following symptom onset, at a mean age of 49 years 6.
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- 2. Le Ber I, Camuzat A, Castelnovo G, Azulay J-P, Genton P, Gastaut J-L, Broglin D, Labauge P, Brice A, Dürr A. Prevalence of Dentatorubral-Pallidoluysian Atrophy in a Large Series of White Patients With Cerebellar Ataxia. (2003) Archives of Neurology. 60 (8): 1097. doi:10.1001/archneur.60.8.1097
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- 7. Komure O, Sano A, Nishino N, Yamauchi N, Ueno S, Kondoh K, Sano N, Takahashi M, Murayama N, Kondo I. DNA analysis in hereditary dentatorubral-pallidoluysian atrophy: correlation between CAG repeat length and phenotypic variation and the molecular basis of anticipation. (1995) Neurology. 45 (1): 143-9. Pubmed
- 8. Hayashi Y, Kakita A, Yamada M, Koide R, Igarashi S, Takano H, Ikeuchi T, Wakabayashi K, Egawa S, Tsuji S, Takahashi H. Hereditary dentatorubral-pallidoluysian atrophy: detection of widespread ubiquitinated neuronal and glial intranuclear inclusions in the brain. (1998) Acta neuropathologica. 96 (6): 547-52. Pubmed
- 9. Uyama E, Kondo I, Uchino M, Fukushima T, Murayama N, Kuwano A, Inokuchi N, Ohtani Y, Ando M. Dentatorubral-pallidoluysian atrophy (DRPLA): clinical, genetic, and neuroradiologic studies in a family. (1995) Journal of the neurological sciences. 130 (2): 146-53. Pubmed
- 10. Esteban Muñoz, Jaume Campdelacreu, Isidre Ferrer, María J. Rey, Adriana Cardozo, Beatriz Gómez, Eduardo Tolosa. Severe Cerebral White Matter Involvement in a Case of Dentatorubropallidoluysian Atrophy Studied at Autopsy. (2004) Archives of Neurology. 61 (6): 946. doi:10.1001/archneur.61.6.946