DRPLA is one of the polyglutamine (PolyQ) diseases. It occurs when the ATN1 gene allele inherited from one of the parents contains a mutation with an abnormally high number of CAG (cytosine–adenine–guanine) trinucleotide repeats — typically more than 48. These CAG repeats encode the amino acid glutamine (Q) in the atrophin-1 protein produced by the gene. As a result, the encoded protein has an abnormal structure with excessive glutamine repeats, which makes it prone to accumulating and forming aggregates, especially within the nuclei of nerve cells (neurons).

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Nature has protective mechanisms to “clean up” cells by breaking down faulty or unnecessary proteins. However, these mechanisms do not work effectively on polyglutamine aggregates, which are insoluble by natural means. As a result, these abnormal proteins become toxic, disrupting critical cellular processes such as autophagy, DNA transcription, axonal transport, and protein homeostasis, ultimately leading to neuron degeneration and death, especially in the cerebellum and other parts of the nervous system. The loss of neurons leads to the development of ataxia symptoms.

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Additional Notes on PolyQ Disorders

(Adapted from "Pathogenesis of SCA3 and implications for other polyglutamine diseases", Hayley S. McLoughlin et al., 2020)

 

1. Currently, nine PolyQ diseases are known, including:

• Huntington’s disease (HD)

• Dentatorubral-pallidoluysian atrophy (DRPLA)

• Spinal and bulbar muscular atrophy (SBMA)

• Six types of spinocerebellar ataxias (SCAs): SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17

All of these diseases are caused by expanded CAG repeats in the coding regions of their respective genes, and they share common features:

• Autosomal dominant inheritance (except SBMA, which is X-linked)

• They primarily affect the central nervous system (CNS), though peripheral nerves and muscles can also be involved

• They follow a progressive course over several years

• In all PolyQ diseases, there is an inverse correlation between the number of CAG repeats and the age of symptom onset and severity — the greater the number of repeats, the earlier and more severe the symptoms. This is related to the phenomenon of anticipation.

 

2. In PolyQ diseases, the misfolded proteins with expanded glutamine tracts tend to aggregate, primarily in the nuclei of neurons, although cytoplasmic aggregates and even distal aggregates in axons can also occur.

The significance of these nuclear protein aggregates is not fully understood. One hypothesis suggests that early aggregation may be neuroprotective, but over time the process becomes toxic to nerve cells. These aggregates may:

• Sequester essential proteins (e.g., transcription factors)

• Damage mitochondria

• Disrupt the chaperone system (which helps proteins fold correctly)

• Interfere with the ubiquitin–proteasome system (UPS) (which regulates protein degradation)

• Impair autophagy, a key protein “quality control” process

• Hinder DNA repair in the nucleus

All these dysfunctions compromise the normal function of neurons and may lead to neuronal death.

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3. In addition to neurons, other types of cells — especially glial cells (astrocytes, microglia, and oligodendrocytes) — may play an important role in the pathogenesis of spinocerebellar ataxias and other PolyQ diseases.

For example:

• In SCA7, Bergmann glia have been shown to play a role in cerebellar degeneration

• Glial cell abnormalities have also been observed in SCA1 and Huntington’s disease animal models, suggesting a common feature in PolyQ conditions

 

Diagnosis - DRPLA can be diagnosed using molecular genetic testing (DNA test) to detect mutations in the ATN1 gene. Testing is especially recommended when there is a positive family history of DRPLA. Before ordering genetic testing, neurologists typically perform clinical neurological exams, including assessments of symptoms, reflexes, eye movement abnormalities, and family history. Brain imaging may also be requested to check for cerebellar atrophy, for example.

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Differential Diagnosis - Huntington’s disease (HD) can present with symptoms similar to DRPLA, but the presence of ataxia, which is common in DRPLA and not in HD, can help differentiate the two. A genetic test confirming a pathogenic CAG expansion in the ATN1 gene provides definitive diagnosis. A similar clinical syndrome may also occur in genetic prion diseases, such as Creutzfeldt-Jakob disease. Again, genetic testing for pathogenic variants in ATN1 can confirm DRPLA in positive cases [1].

 

Note: Although genetic testing can be challenging, time-consuming, and costly, it is crucial for:

• Providing accurate genetic counseling to family members (regarding inheritance and future risk)

• Ensuring better disease management, with a confirmed diagnosis

• Allowing patient participation in clinical trials for treatments targeting specific ataxias.