Dentatorubral–pallidoluysian atrophy

Dentatorubral–pallidoluysian atrophy​ (DRPLA) is a clinically heterogenous autosomal dominant CAG repeat expansion disorder that is particularly prevalent within the Japanese population.

Epidemiology

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 dentatorubral–pallidoluysian atrophy​ as 0.25% in this cohort ². 

Clinical presentation

In both Asian and non-Asian populations, the natural history and symptomatology of dentatorubral–pallidoluysian atrophy​ is similar ³. With that being said, between individual patients the presentation 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, although there is a wide range present from infancy to age 72 years ^4-6.

Pathology

Etiology

Dentatorubral–pallidoluysian atrophy occurs when there are >47 CAG repeat expansions within one allele of the ​atrophin 1 (ATN1) gene on chromosome 12p ^6,7. This mutation is inherited in an autosomal dominant fashion and demonstrates anticipation ⁵.

Microscopic appearance

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 dentatorubral–pallidoluysian atrophy its name ⁶. Degeneration of white matter tracts is also frequent ⁶. 

Radiographic features

MRI

• T2: 

  • 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.