Continuing Education Activity

Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive, autosomal dominant disorder with symptoms and severity that vary with the age of onset. Identifying cardinal features of adult and juvenile DRPLA can guide a neurologist towards diagnosis and supportive treatment of symptoms. Given the autosomal dominant inheritance, genetic counseling is important given the level of functional impairment caused by this disorder. This activity will highlight the importance of the interprofessional team in the evaluation and management of DRPLA, including post-diagnosis counseling and symptomatic management.

Objectives:

• Identify the etiology of dentatorubral-pallidoluysian atrophy.
• Describe the history and physical findings in patients with dentatorubral-pallidoluysian atrophy.
• Review the management options available for dentatorubral-pallidoluysian atrophy.
• Summarize the role of the interprofessional team in managing patients suffering from DRPLA.

Introduction

Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive autosomal dominant disorder characterized by myoclonic epilepsy, ataxia, choreoathetosis/dystonia, cognitive impairment/dementia, and psychiatric disturbances.[1][2][3][4][5][4][3][1] Rarely, corneal endothelial degeneration, head tremor, or optic atrophy may be present.[6][7][8][7][6] The presentation varies with the age of onset. The disorder was first described in 1946, and the name was given in1958.[9][10][9]

Etiology

Dentatorubral-pallidoluysian atrophy is a cytosine, adenine, and guanine (CAG) trinucleotide repeat expansion in the atrophin-1 (ATN1) gene, in exon 5.[3][11] This gene on chromosome 12p13.31, encodes a transcriptional co-repressor expressed in the central nervous system (CNS) and other organs in the body.[12] Normal CAG repeats range between 6-35. Pathogenic CAG repeat length can range from 48 to 93, with higher repeat length correlated with worse disease severity, in most cases.[13][14]

Some exceptions are reported in rare cases of asymptomatic patients with high CAG repeats. Complete penetrance of the condition is more than 48 tandem copies, which have a typical clinical presentation. Incomplete penetrance phenotypes are found in patients with alleles of 35 to 47 repeat length, associated with a milder clinical phenotype. Japanese patients have a higher number of baseline CAG repeats, 20 to 35, compared to people of European descent.[15][16] The clinical-genetic phenomenology of non-Asian DRPLA is similar to the Asian DRPLA.[17]

Epidemiology

Dentatorubral-pallidoluysian atrophy has a median age of onset of 31 years of age. It mainly affects Asian populations, in particular, the Japanese population. The incidence is approximately 2 to 7 per million people in the Japanese population.[12][18] The prevalence of DRPLA in Japanese people has been estimated to be 0.2 to 0.4 per 100,000.[19] Although DRPLA was initially recognized in Asian populations, wider genetic testing has increased diagnosis in other ethnic groups/families.[17][20][21][22][23][24] 

When worldwide DRPLA cases are counted for among the spinocerebellar ataxia (SCA), the rate in the Japanese population is 7 to 20%, with lower rates in other Asian populations (Singapore, 6%; Korea, 3%), Portuguese families 2 to 4%, other European descent 0.25 to 1%, and Latin-American families 0.14 to 3.1%.[15] It equally affects men and women. Juveline-onset disease or progressive myoclonic epilepsy (PME) phenotype patients (less than 20 years of age), typically present with seizures and some form of neurodevelopment disorder. Genotypically, they have longer CAG repeat lengths ( more than 65), and they have generalized seizures and myoclonus with progressive intellectual disability.[15] Adult-onset or without PME phenotype (more than 20 years of age), on the other hand, has symptoms that include ataxia, choreoathetosis, cognitive impairment, dementia, and psychiatric features. Additionally, they have shorter CAG repeat lengths (less than 65), with seizures being a rare symptom.

Pathophysiology

Dentatorubral-pallidoluysian atrophy is one of the CAG repeat disorders that show atrophin-1 protein deposition in the nucleus of affected neurons, known as neuronal intranuclear inclusion (NII). Polyglutamine (poly-Q) expansion characterizes autosomal-dominant neurodegenerative disorders such as Huntington disease (HD), and six of the spinocerebellar ataxia (SCA) disorders, which could be an important pathogenic feature in common with DRPLA and may explain the genetic anticipation and de novo expansion.[25][26][27][28] 

Lysine-specific demethylase 1 (LSD1) and its target ATN1 may be responsible for neuronal pluripotent development of cells in the cortex.[29] Animal models suggest that NII occurs without completed apoptosis, leading to poor clearance of aggregated polyQ inclusions.[30] It is still unclear whether the inclusion is a pathogenic feature, or a failed neuroprotective process, such as seen in HD.[26][31][32]

Antibody mediated-immunohistochemistry, in DRPLA post-mortem brains, shows polyglutamine protein structures or stretches that co-deposit with a mutant and insoluble ATN1 protein as part of a diffuse intraneuronal accumulation in densely packed areas within the NII. The dominant hypothesis is that the number of NII correlates with clinical features such as dementia and epilepsy, with neuropathological studies showing reduced number and size of spines and diameter of dendrites. All these findings could explain the brain atrophy seen in neuroimaging.[15]

Histopathology

Post-mortem studies of the patients suffering from dentatorubral-pallidoluysian atrophy show interesting features including atrophy in the entire spinal cord neuraxis, neuronal apoptosis, and astrocytosis in the dentatorubral and pallidoluysian systems (globus pallidus, red nucleus, and to a lesser degree, the dentate nucleus and subthalamic nucleus). It can cause severe diffuse cortical white matter disease. Frontal lobe and pontine atrophy are present in the juvenile-onset cases, characterized by a severe clinical phenotype with cognitive deterioration and seizures. Interestingly, hippocampal regions are relatively spared. 

Chemical staining for protein structures encoded by a mutant ATN1 protein shows poly-Q deposition of diffuse intraneuronal accumulation within the nucleus of affected neurons. The latter are spherical, eosinophilic non-membrane bound structures that contain a mixture of granular and filamentous ubiquitinated structures, containing inclusions of the mutant ATN1 protein.[15][33][34]

History and Physical

Clinical diagnosis of dentatorubral-pallidoluysian atrophy is challenging, given heterogeneous phenotypes and similarities to spinocerebellar ataxias. Symptoms and neuroimaging vary according to the age of onset. Late-onset DRPLA can sometimes present as isolated cerebellar ataxia, or dementia.[15]

When it begins before the age of 20 it typically exhibits:

• Myoclonus
• Seizures of different types
• Behavioral changes
• Progressive intellectual disability and deterioration
• Ataxia

When it begins after the age of 20 years it presents with: 

• Ataxia
• Choreoathetosis or dystonia
• Psychiatric symptoms (delusions)
• Dementia
• Rarely, head tremors and visual problems

Exam findings include neurocognitive impairment on executive function, language, memory, dysmetria, cerebellar ataxia, motor weakness, upper motor neuron signs, and difficulties with gait.

Evaluation

There are no clinical diagnostic criteria for dentatorubral-pallidoluysian atrophy. Clinical symptoms, family history, and ancestry can increase the yield of the targeted molecular genetic testing.[35][36] Genetic testing consists of a polymerase chain reaction (PCR) amplification across the ATN1 CAG repeat region. To increase the sensitivity of the test in higher CAG repeats, a capillary electrophoresis-Southern Blot is used to confirm the diagnosis.

Although whole-genome sequencing technologies are promising, they lack internal and external validation for CAG expansion specific for DRPLA. An electroencephalogram (EEG) is used to guide management in the context of suspicion of seizures. Focal motor seizures with impaired awareness progressing to generalized tonic-clonic seizures are the typical semiology.[37][38] Brain magnetic resonance imaging (MRI) can show diffuse cerebellar and brainstem atrophy, diffuse periventricular white matter disease, but these are mostly non-specific.[39][40][41][42][43][44] 

Hypoalbuminemia has also been studied as a possible biological marker, given that some studies show it is inversely correlated with CAG length.[15][45] Although next-generation sequencing technologies are promising, they have not been widely used or validated for the ATN1 repeat expansion.

Treatment / Management

Unfortunately, there is no cure for dentatorubral-pallidoluysian atrophy. Treatment is predominantly supportive. Genetic counseling of patients and their family members is essential given that the condition is autosomal dominant, with important ethical considerations before diagnosis disclosure.

When there is clinical suspicion of seizures; selecting an anti-epileptic drug (AED) could be individualized to the predominant clinical scenario of the seizures. No AED is found superior to others in randomized controlled studies. However, levetiracetam and perampanel show promise in juvenile-onset DRPLA.[38][46][47] Choreoathetoid and dystonic movements are treated with tetrabenazine, risperidone, and gabapentin.[42][48] Consensus European guidelines show that riluzole (Class B evidence) or amantadine (Class C evidence) can potentially improve ataxic symptoms.[49][50][51][52] Given unknown teratogenicity, however, they are avoided in childbearing patients or currently pregnant patients.

A neuropsychological and psychiatric assessment is instrumental for evaluating major neurocognitive deficits and associated mood disorders, for enhanced quality of life. Physical and occupational therapy is important to maintain functional activities of daily living. Structured and individualized educational programs for children with the disease is another important consideration. Involving an interprofessional team of providers can help address all the co-morbidities associated with the disorder and enhance the number of quality life years. Avoiding general anesthesia during surgical procedures can decrease the rate of breakthrough seizures.[15]

CAG repeat expansion disorder and developments in transcription silencing is a promising venue for curative treatment. This is currently used for SCA and HD with some success in animal models. Ribonucleic acid (RNA) interference of multiple alleles is possible within the CNS, although it is costly and time-consuming, and still in an experimental phase. Another promising strategy is to use targeted RNA small molecules that affect the translation of mutant ATN-1 and has the advantage of crossing the blood-brain barrier. Challenges include poor absorption and allergic reactions.[15][53][54][55][56]

Differential Diagnosis

The diagnosis of dentatorubral-pallidoluysian atrophy is challenging without a known family history of the disease. Clinical symptoms can mimic other familial degenerative or acquired ataxic disorders. An extensive metabolic and genetic workup can be helpful if the diagnosis is unclear. Advanced imaging, along with cerebrospinal fluid and serum studies, may also help rule out other disorders.[15][40][57]

Differential diagnoses for adult-onset DRPLA include:

• Huntington disease
• Spinocerebellar ataxia
• Atypical parkinsonism with cerebellar ataxia
• Alcohol
• Toxic/metabolic induced ataxias
• Ataxic paraneoplastic syndromes

Differentials for juvenile-onset DRPLA are broad and include:

• Familial essential myoclonus and epilepsy
• Progressive myoclonic epilepsy
• Lafora disease
• Unverricht-Lundborg disease
• Infantile neuroaxonal dystrophy
• Neuroferritinopathy
• Myoclonus epilepsy associated with ragged red fibers
• Heoxosaminidase A deficiency
• Neuronal ceroid-lipofuscinosis
• Gaucher disease
• Sialidosis
• Galactosialidosis

Prognosis

As there is no cure for dentatorubral-pallidoluysian atrophy, the mean age at death is 49 years (range 18–80 years); the median time from disease onset to death is 15 years.[13] The length of the CAG repeat expansion in ATN1 is positively correlated with age of onset, clinical symptoms, and longevity, with more than 48 repeats being linked to early-onset, severe disease phenotype, and a shorter lifespan. Functional impairment is also inversely correlated with CAG repeat length and lead to a poorer quality of life years and higher disability burden.[13] Unfortunately, DRPLA is classified as a microsatellite repeat disorder, which shows genetic anticipation with earlier onset and worse disease severity as it passes to the next generation of offsprings.[15]

Complications

Many complications can arise from the comorbidity that comes with dentatorubral-pallidoluysian atrophy. Following are some of the complications such patients can have:

• Progressive repetitive seizures
• Status epilepticus
• Solid/liquid dysphagia with potential aspiration pneumonia[13]

Consultations

As dentatorubral-pallidoluysian atrophy is a disorder involving the neuromuscular system of the patient it requires input from an interprofessional team. This team may comprise of the following:

• Adult or pediatric neurologists
• Epilepsy neurologists
• Geriatrics
• Pediatrics
• Geneticists
• Physical and occupational therapists
• Social workers
• Psychiatrists/psychologists
• Palliative medicine

Deterrence and Patient Education

Dentatorubral-pallidoluysian atrophy is a significant and severe disease affecting parents and children of affected parents. Exhaustive counseling is needed for both generations. It is a hereditary disorder whose symptoms vary depending on whether they begin in childhood or adulthood. A parent with the disease has a 50% chance of passing it to their children, regardless of sex or gender; therefore, genetic counseling is important. It involves excessive protein deposition in the cells of the CNS, causing dysfunction and leading to the death of brain cells. There is no cure for this disorder. Prognosis is poor, mean disease duration is about 15 years, and life expectancy 8 to 16 years from symptom onset. Early recognition of the disorder may improve patient understanding, and access to services and treatments.

Support Resources for Affected Patients and Families 

• Seek a healthcare specialist for medical advice, you can find them through advocacy organizations, academic medical centers, clinical trials, or medical peer-reviewed articles published in medical journals.
• If unable to find a specialist in your local area, contact national or international specialists.
• Global organizations supporting this disease include the National Ataxia Foundation, Ataxia UK, European Federation of Hereditary Ataxias, Epilepsy Foundation, and RareConnect.

Pearls and Other Issues

• Dentatorubral-pallidoluysian atrophy is a progressive, autosomal dominant CAG repeat disorder typically characterized by ataxia, myoclonus, epilepsy, choreoathetosis, dementia, psychiatric disturbance, and progressive intellectual deterioration.

• Juvenile onset (less than 20 years) disease presents with progressive myoclonus epilepsy disorder with ataxia and abnormal intellectual development, with recurrent severe seizures. The sudden unexpected death of someone with epilepsy (SUDEP) is the most deadly complication.

• Adult-onset (more than 20 years) disease presents with dystonias, neurocognitive and neuropsychiatric decline with ataxia, with aspiration pneumonia as the most common cause of mortality.

• DRPLA is a microsatellite CAG repeat disorder with genetic anticipation affecting the atrophin-1 (ATN1) gene, leading to the intranuclear accumulation of protein deposits in affected neurons, ultimately leading to progressive neuronal dysfunction, atrophy, and death.

• Pathogenic CAG repeat length can range from 48 to 93. Complete penetrance has 48 tandem copies, incomplete penetrance clinical phenotype has 35–47, and normal is less than 35.

• Japanese patients have a higher baseline of CAG repeats (20-35) compared to individuals from European descent, which could explain their increased susceptibility to the disease.

• Prognosis is poor, mean disease duration is about 15 years, and life expectancy is 8–16 years from symptom onset. The length of the ATN1 CAG repeat expansion is directly correlated with the age of onset, clinical phenotype, and life expectancy.

• Highly suspicious cases for DRPLA are further evaluated by targeted molecular genetic testing: PCR amplification across the ATN1 CAG repeat region; for higher CAG repeats, ancillary Southern Blot electrophoresis, is used to confirm the diagnosis.

• EEG and MRI are helpful for certain clinical scenarios, but they are mostly non-specific for the disorder.

• Treatment is predominantly supportive: symptomatic treatment of seizures, ataxias, choreoathetosis, as well as nonpharmacological interventions such as special education programs for children, neurorehabilitation, neuropsychological and neuropsychiatric, and most importantly, genetic counseling.  

• Avoiding general anesthesia during surgical procedures can decrease the rate of breakthrough seizures.

Enhancing Healthcare Team Outcomes

An interprofessional team that provides a holistic and integrated approach is important in patients with DRPLA, to reach diagnosis sooner, provide symptomatic control of co-morbidities, maximize life expectancy and the quality of life for patients with this devastating disorder.[58] Collaborative patient-centered decision-making and coordination of care between primary providers and subspecialists are essential to avoid gaps in care and improve health outcomes. Education, physiotherapy, occupational therapy, genetic counseling, and environmental adaptation may also be needed at different disease stages. Serious complications may need to be addressed in an intensive care unit. Palliative care can be considered during the late stages of the disease.[59][60][61][62][63] [Level 1]