Dentatorubral pallidoluysian atrophy (DRPLA)

DRPLA is a progressive multisystem neurodegenerative disorder affecting the cerebellum, brain stem, basal ganglia, and cerebral cortex. Onset ranges from infancy to late adulthood (range: 0–72 years; mean: 31.5 years), and the clinical phenotype varies markedly with age of onset. Juvenile-onset disease (before age 20) typically presents with developmental delay, progressive intellectual disability, myoclonus, and epilepsy. Adult-onset disease usually presents with ataxia and/or choreoathetosis combined with personality changes and cognitive decline. Clinical features such as ataxia, chorea, myoclonus, and dementia may co-occur in the same individual, and inter-individual variability of presentation is marked, including within families.

DRPLA is more prevalent in populations of Japanese ancestry, where it affects 0.2-0.7 in 100,000 people (Tsuji et al., 2008). DRPLA is thought to occur at much lower rates in non-Japanese populations, with variable frequencies estimated in different countries/regions of the world.

DRPLA is caused by a heterozygous germline expansion of the CAG trinucleotide repeat in ATN1 (locus 12p13.31), which encodes atrophin-1. The disease mechanism is a toxic gain of function: expanded polyglutamine atrophin-1 fragments accumulate in neuronal intranuclear inclusions and trigger apoptotic cell death, with predominant degeneration of the dentatorubral and pallidoluysian systems.

DRPLA is inherited in an autosomal dominant manner; each child of an affected individual has a 50% risk of inheriting the pathogenic ATN1 expansion. DRPLA exhibits marked anticipation: the CAG repeat tends to expand on intergenerational transmission, with onset 26 to 29 years earlier in offspring of affected fathers and 14 to 15 years earlier in offspring of affected mothers.

In the absence of established clinical diagnostic criteria, the diagnosis of DRPLA is established by molecular detection of a pathogenic CAG repeat expansion (48-93 repeats) in ATN1. Brain MRI typically demonstrates atrophy of the cerebellum and brain stem, particularly the pontine tegmentum, with paravermal white matter lesions on FLAIR; these findings are supportive but not specific to DRPLA.

Main differential diagnoses include:

• Huntington disease: chorea and dementia without ataxia; caudate atrophy predominates; HTT.
• Autosomal dominant cerebellar ataxias (): pure cerebellar ataxia overlapping with mildly expanded ATN1 alleles; ATXN1, ATXN2, ATXN3, CACNA1A and others.
• Progressive myoclonus epilepsy, Lafora type: juvenile PME with dementia, autosomal recessive, Lafora bodies on biopsy; EPM2A, NHLRC1.

• Establishing the diagnosis: molecular genetic testing confirms the clinical suspicion, ends the diagnostic odyssey, and enables informed counselling of the affected individual and their family.
• Specific and individualised surveillance: a confirmed molecular diagnosis is a prerequisite for targeted medical care and enables condition-specific surveillance and supportive care; the choice of surveillance lies with the treating physicians in consultation with the affected individual.
• Family member testing: identification of the familial pathogenic variant enables predictive genetic testing of at-risk relatives, supporting informed reproductive and life decisions.

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• Chaudhry A, Anthanasiou-Fragkouli A, Houlden H. DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder. J Neurol. 2021;268(8):3031-41. doi:10.1007/s00415-020-10218-6. PMID:; PMCID: PMC8289787.
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