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Synonym: Dentatorubral-Pallidoluysian Atrophy

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Initial Posting: ; Last Update: September 21, 2023.

Estimated reading time: 36 minutes


Clinical characteristics.

DRPLA (dentatorubral-pallidoluysian atrophy) is a progressive neurologic disorder characterized by five cardinal features (irrespective of the age of onset): ataxia, cognitive decline, myoclonus, chorea, epilepsy, and psychiatric manifestations. Onset ranges from infancy to late adulthood (range: age 0-72 years; mean: age 31.5 years). The clinical presentation varies by age of onset: individuals with juvenile onset (before age 20 years) have myoclonus, epilepsy, and progressive intellectual deterioration, whereas individuals with adult onset (after age 20 years) have ataxia, choreoathetosis, and dementia or neuropsychiatric changes. Disease duration is on average eight years (range: 0-35 years) and age at death is on average 49 years (range: age 18-80 years).


The diagnosis of DRPLA is established in a proband with suggestive clinical findings and a heterozygous pathogenic CAG trinucleotide expansion in ATN1 identified by molecular genetic testing.


Treatment of manifestations: Standard anti-seizure medications (ASMs) for seizures; appropriate psychotropic medications for psychiatric manifestations; symptomatic treatment of ataxia with riluzole and rehabilitation therapy; adaptation of environment and care to the level of dementia; appropriate educational programs for children.

Agents/circumstances to avoid: General anesthesia can increase the risk of intra- and postoperative seizures.

Pregnancy management: Because the use of ASMs during pregnancy may have an effect on the fetus, discussion of the risks and benefits of using an ASM during pregnancy should ideally occur prior to conception when transition to a lower-risk medication may be possible. The use of riluzole during pregnancy has not been well studied in humans.

Genetic counseling.

DRPLA is inherited in an autosomal dominant manner. The risk to the children of an affected individual of inheriting an expanded CAG repeat is 50%. The size of the repeat transmitted to the offspring depends on the size of the parent's repeat and the sex of the transmitting parent. Once an abnormal CAG repeat expansion in ATN1 has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.


No consensus clinical diagnostic criteria for DRPLA (dentatorubral-pallidoluysian atrophy) have been published.

Suggestive Findings

DRPLA should be suspected in a proband with the following clinical features by age, brain MRI findings, and family history.

Clinical features (by age)

  • Juvenile onset (before age 20 years). Ataxia, myoclonus, seizures, progressive intellectual deterioration
  • Adult onset (after age 20 years). Ataxia, choreoathetosis, dementia, psychiatric disturbance

Brain MRI findings. Cerebellar and brain stem atrophy; white matter lesions [Tsuji 2012, Sugiyama et al 2020]

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations) and Japanese familial origin. DRPLA is extremely rare outside of Japanese populations [Tsuji 2012]. Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of DRPLA is established in a proband with a heterozygous abnormal CAG repeat expansion in ATN1 identified by molecular genetic testing (see Table 1).

Note: Pathogenic CAG repeat expansions in ATN1 cannot be reliably detected by standard next-generation sequencing-based methods, including multigene panels or exome sequencing.

Repeat sizes

Molecular genetic testing has traditionally relied on targeted analysis to characterize the number of ATN1 CAG repeats. However, genome sequencing-based tools for the detection of nucleotide repeat expansions have been developed [Ibañez et al 2022]. Such testing may be able to detect an expanded ATN1 CAG repeat but may not be able to accurately determine the number of repeats, depending on the method and analytical tools used by the genetic testing laboratory.

Table 1.

Molecular Genetic Testing Used in DRPLA

Gene 1Method 2, 3Proportion of Probands with a Pathogenic Variant Detectable by Method
ATN1 Targeted analysis for CAG expansions100%

See Molecular Genetics, ATN1 technical considerations, for specific methods to characterize the number of CAG repeats in ATN1.


Note: To date, standard sequence-based multigene panels and exome sequencing cannot reliably detect pathogenic CAG repeat expansions in this gene.

Clinical Characteristics

Clinical Description

DRPLA (dentatorubral-pallidoluysian atrophy) is a progressive neurologic disorder characterized by five cardinal features (irrespective of the age of onset): ataxia, cognitive decline, myoclonus, chorea, epilepsy, and psychiatric manifestations [Ikeuchi et al 1995b, Kanazawa 1998]. Clinical manifestations vary by age of onset, which is inversely related to ATN1 CAG repeat size [Ikeuchi et al 1995b, Komure et al 1995].

Onset ranges from infancy to late adulthood (range: age 0-72 years; mean: age 31.5 years). Juvenile onset (before age 20 years) is characterized by myoclonus, epilepsy, and progressive intellectual deterioration, whereas adult onset (after age 20 years) is characterized by ataxia, choreoathetosis, and dementia or neuropsychiatric changes. Disease duration is on average eight years (range: 0-35 years) and age at death is on average 49 years (range: age 18-80 years) [Hasegawa et al 2010].

Juvenile Onset (Before Age 20 Years)

Juvenile-onset (also referred to as childhood- or early-onset) DRPLA is generally associated with ≥65 CAG repeats. Juvenile onset is typically characterized by developmental delay, progressive intellectual disability, myoclonus, and epilepsy, often referred to as a progressive myoclonic epilepsy (PME) phenotype [Kanazawa 1998, Hasegawa et al 2010, Maruyama et al 2012, Carroll et al 2018].

Developmental delay and intellectual disability are the most common initial manifestations, with a mean age of onset of 7.1 ± 4.8 (range: 2-18) years [Egawa et al 2008, Maruyama et al 2012]. Variable findings are developmental regression, attention-deficit/hyperactivity disorder, autism spectrum disorder, and microcephaly [Licht & Lynch 2002, Shahwan et al 2005].

Seizure types vary and are frequently resistant to anti-seizure medication [Koide et al 1994, Ikeuchi et al 1995b, Egawa et al 2008]. Clinical-electrographic focal-onset seizures with altered alertness are frequently seen, with higher prevalence when epilepsy onset is before age 10 years [Egawa et al 2008]. Seizure types may evolve over time. Partial seizures and brief generalized seizures (atypical absence and myoclonic seizures) may be seen earlier and generalized tonic-clonic seizures later in the disease course [Egawa et al 2008]. Common findings are photosensitivity with reflex seizures triggered by visual stimuli and EEG photoparoxysmal response to intermittent photic stimulation.

Ataxia may occur early in the disease course or develop later. Eventually, chorea and psychiatric manifestations may also develop [Hasegawa et al 2010, Maruyama et al 2012].

Adult Onset (After Age 20 Years)

Adult-onset (also referred to as late-onset) DRPLA is generally associated with <65 CAG repeats. In one series, the mean age of onset was 48 years [Hasegawa et al 2010]. The most prominent clinical features are ataxia and/or choreoathetosis, combined with personality changes with or without cognitive decline [Kanazawa 1998]. In some individuals, involuntary movements and dementia may mask the presence of ataxia.

Behavioral impairment is characterized by delusions, hallucinations, depressed mood, apathy, loss of inhibitory control, poor judgment, impulsivity, irritability, and aggression [Adachi et al 2001, Grimaldi et al 2019]. This clinical picture may cause psychiatric hospitalization and complicate the differential diagnosis, particularly in younger adults. Cognitive decline is characterized by deterioration of attention and executive functions, semantic fluency, and visuoconstructive abilities; memory is relatively preserved in all its components [Lindsay & Storey 2017, Grimaldi et al 2019].

Rarely, seizures may be present in individuals with disease onset between ages 20 and 40 years. Older individuals (especially those older than age 60 years in one series) may present with isolated ataxia and/or ataxia combined with dementia [Sugiyama et al 2018].

The severity and frequency of sleep disturbances in DRPLA are probably underestimated. Insomnia, excessive daytime sleepiness, and circadian rhythm disturbance can occur. In a case report by Kim et al [2018], a family with DRPLA presented with REM sleep behavior disorders (RBD) in the absence of more common sleep-related respiratory issues such as sleep apnea or hypopnea. In some members of this family, RBD appeared before the classic clinical manifestations of DRPLA.

Other clinical manifestations that may be present in adult-onset DRPLA irrespective of the actual age of onset include choreoathetosis, dystonia, myoclonus, oculomotor impairments, postural instability, corneal endothelial degeneration, and optic atrophy [Warner et al 1995, Destée et al 2000, Ito et al 2002, Hatano et al 2003, Wardle et al 2008, Vale et al 2010, Silver et al 2015, Grimaldi et al 2019].

Dysphagia is frequently seen in the late stages of disease [Hasegawa et al 2010].

Other clinical manifestations rarely reported include parkinsonism, tremors, hyperreflexia, and posterior column sensory loss [Shimojo et al 2001, Licht & Lynch 2002, Rajput 2011].

All Ages

Neuroimaging. Typical MRI findings include atrophic changes in the cerebellum and brain stem, in particular the pontine tegmentum. Quantitative analyses reveal that both the age at MRI and the size of the expanded CAG repeat correlate with the atrophic changes.

Cerebellar white matter lesions are also described in individuals with late adult-onset and elderly-onset disease, often in the paravermal areas (medial part of the cerebellar hemispheres adjacent to the vermis) and present as high-intensity signals in MRI FLAIR images. Although paravermal lesions are considered typical of DRPLA and lacking in other autosomal dominant spinocerebellar ataxias, they are not specific to DRPLA and can be present in adult-onset neuronal intranuclear inclusion disease and fragile X-associated tremor/ataxia syndrome [Sugiyama et al 2018, Sugiyama et al 2020].

Diffuse high-intensity areas deep in the white matter are often observed on T2-weighted MRI in individuals with adult-onset DRPLA of long duration [Koide et al 1997].

Using 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET), bistriatal glucose hypometabolism was reported in two affected individuals with juvenile-onset DRPLA; this was not present in individuals with adult onset [Sone et al 2016].

Neuropathology. The major neuropathologic changes are combined degeneration of the dentatorubral and pallidoluysian systems. Also described are cerebral white matter damage, including diffuse myelin pallor, axonal preservation, and reactive astrogliosis with only mild atherosclerotic changes [Muñoz et al 2004].

Histologically, as in other polyglutamine diseases, neurons show intranuclear inclusions [Mori et al 2012a, Mori et al 2012b].

Genotype-Phenotype Correlations

Heterozygotes. In general, an inverse correlation exists between the age at onset and the size of the expanded ATN1 CAG repeat [Koide et al 1994, Ikeuchi et al 1995b] (see Table 2).

Note: ATN1 CAG repeat ranges overlap and the distinctions are not clearly defined.

Table 2.

Correlation between Age at Onset and Size of ATN1 Repeat

Age at OnsetATN1 CAG Repeat Range
<21 years63-79
21-40 years61-69
>40 years48-67

Because juvenile onset (before age 20 years) is associated with the progressive myoclonus epilepsy (PME) phenotype and adult onset (after age 20 years) with the non-PME phenotype, the clinical presentation is strongly correlated with the size of expanded CAG repeats. The frequency of signs and symptoms in affected individuals with <65 CAG repeats and those with ≥65 CAG repeats were summarized by Hasegawa et al [2010].

Severe infantile onset with an extreme ATN1 CAG expansion of 90-93 CAG repeats (c.1462CAG[90_93]) has been reported [Shimojo et al 2001].


  • An individual with relatively small biallelic expanded ATN1 CAG repeat expansions had symptom onset at age 14 years, indicating a possible dosage effect [Sato et al 1995].
  • An individual of Japanese ancestry homozygous for a 57-CAG repeat expansion was born to consanguineous parents. Early onset (around age 18 years) and more severe manifestations were observed [Ikeuchi et al 1995b].


Pathogenic (full-penetrance) CAG repeats (i.e., 48-93 CAG repeats) are fully penetrant, except for one individual with 51 CAG repeats who was asymptomatic at age 81 years [Hattori et al 1999].


The marked expansion of the ATN1 CAG repeat on transmission to offspring results in onset of manifestations 26 to 29 years earlier than affected fathers and 14 to 15 years earlier than affected mothers [Koide et al 1994, Nagafuchi et al 1994, Ikeuchi et al 1995a, Ikeuchi et al 1995b, Ikeuchi et al 1995c, Hattori et al 1999, Vinton et al 2005].


DRPLA may also be referred to as:


DRPLA is more prevalent in populations of Japanese ancestry, where it affects 0.2-0.7 in 100,000 people [Takano et al 1998, Tsuji et al 2008]. The Japanese population has a greater number of individuals with 20-35 CAG repeats than populations of European origin [Takano et al 1998]. A nationwide epidemiologic study showed that DRPLA is the third most common autosomal dominant ataxia, accounting for 9.7% of cases in Japan [Tsuji et al 2008]. In another Japanese study, DRPLA was the most common cause of childhood-onset cerebellar ataxia [Ono et al 2019].

DRPLA is thought to occur at much lower rates in non-Japanese populations; however, it has also been reported in North America, South America, Europe, and Australia (for a summary of all cases reported see Chaudhry et al [2021]). The frequency of DRPLA has been estimated in cohorts with mostly cerebellar ataxia of unknown cause, typically with a pattern of autosomal dominant inheritance, in the following countries/regions:

Differential Diagnosis

Adult onset. For individuals with adult-onset DRPLA (dentatorubral-pallidoluysian atrophy) who exhibit ataxia, dementia, or choreoathetosis (the non-PME phenotype), the differential diagnosis includes the autosomal dominant disorders summarized in Table 3.

Table 3.

Selected Genes in the Differential Diagnosis of Adult-Onset DRPLA

HTT Huntington disease (HD)The presence of ataxia is important for differentiating DRPLA from HD. Some persons w/the non-PME phenotype of DRPLA may initially be diagnosed as having HD, as the main clinical features in these persons are involuntary movements & dementia, symptoms that often mask the presence of ataxia. The history of ataxia as an early symptom as well as atrophy of the cerebellum and brain stem (particularly pontine tegmentum) on imaging study is important in the differential diagnosis. Atrophy of the caudate nucleus favors the diagnosis of HD. It is frequently necessary to do molecular genetic testing for Huntington disease, Huntington disease-like phenotypes, and DRPLA in persons w/unexplained progressive dementia & involuntary movements.
JPH3 Huntington disease-like 2
PRNP Genetic prion disease
~40 genes incl:
Autosomal dominant cerebellar ataxias (See Hereditary Ataxia Overview.)Persons w/DRPLA who have mildly expanded CAG repeats (c.1462CAG[49_55]) tend to exhibit, particularly in early stages, pure cerebellar symptoms such as ataxia w/o dementia, choreoathetosis, or character changes, making the clinical diagnosis of DRPLA difficult. Such persons need to be distinguished from those w/ataxia of other etiologies.

Juvenile onset. For those with early-onset DRPLA (age <20 years) who exhibit progressive intellectual deterioration, myoclonus, and epilepsy (the PME phenotype), the differential diagnosis includes the disorders summarized in Table 4 (see also Malek et al [2015]).

Table 4.

Selected Genes in the Differential Diagnosis of Early-Onset DRPLA

Neuronal ceroid lipofuscinosis (OMIM PS256730)AR
(AD) 1
Benign adult familial myoclonus epilepsy (OMIM PS601068)AD
CSTB EPM1 (Unverricht-Lundborg disease)AR
Progressive myoclonus epilepsy, Lafora type AR
FTL Neuroferritinopathy AD
GBA1 (GBA)Gaucher disease type 3 (primary neurologic disease)AR
GOSR2 EPM6 (OMIM 614018)AR
HEXA Late-onset Tay-Sachs disease (See HEXA Disorders.)AR
MERRF (myoclonus epilepsy associated with ragged red fibers)Mat
NEU1 Neuraminidase deficiency (OMIM 256550)AR
PANK2 Pantothenate kinase-associated neurodegeneration AR
PLA2G6 Infantile neuroaxonal dystrophy (See PLA2G6-Associated Neurodegeneration.)AR
PRICKLE1 Progressive myoclonic epilepsy with ataxia (EPM1B) (See PRICKLE1-Related Disorders.)AR
SCARB2 SCARB2-related action myoclonus – renal failure syndrome (EPM4)AR

AD = autosomal dominant; AR = autosomal recessive; EPM = epilepsy, progressive myoclonic; Mat = maternal; MOI = mode of inheritance


Neuronal ceroid lipofuscinosis (NCL) is inherited in an autosomal recessive manner with the exception of DNAJC5-related NCL, which is inherited in an autosomal dominant manner.


No clinical practice guidelines for DRPLA (dentatorubral-pallidoluysian atrophy) have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DRPLA, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for DRPLA.

Few publications regarding symptomatic treatment for DRPLA are available in the literature. Thus, many manifestations of DRPLA are treated in a standard way in clinical practice.

The supportive care for individuals with juvenile-onset (before age 20 years) DRPLA is summarized in Table 6 and for individuals with adult-onset (after age 20 years) DRPLA in Table 7.

Table 6.

Juvenile-Onset DRPLA: Treatment of Manifestations

Myoclonus Pharmacologic treatment
  • Carbamazepine, phenytoin 1
  • Levetiracetam 2
  • All standard drugs
OtherAvoid extreme stimuli (lights, noises, stress).
Epilepsy ASM
  • Generalized seizures: sodium valproate, perampanel, zonisamide 1
  • Standard medications
Cerebellar ataxia PT & OT
  • PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function 3
  • OT to optimize ADL (incl use of adaptive devices, e.g., weighted eating utensils & dressing hooks)
  • Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs).
  • Inpatient rehab w/OT/PT may improve ataxia & functional abilities in affected persons w/degenerative ataxias. 4
  • Weight control to avoid obesity
  • Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs)
  • Although neither exercise nor PT slows progression of incoordination or muscle weakness, affected persons should maintain activity.
  • Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs).
  • Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs)
Developmental delay /
Intellectual disability
See Developmental Delay / Intellectual Disability Management Issues.
Dysarthria Speech & language therapyConsider alternative communication methods as needed (e.g., writing pads & digital devices).
Dysphagia Feeding therapy programs to improve nutrition & dysphagia & reduce aspiration risk
  • Video esophagram may help define best food consistency.
  • Education re strategies to mitigate aspiration
  • PEG tube in advanced cases
Psychiatric comorbidity Pharmacologic & psychological therapyUse psychotropic medications in standard manner.
Weight Nutrition assessment
  • Consider nutritional & vitamin supplementation to meet dietary needs.
  • Avoid obesity, which can exacerbate difficulties w/ambulation & mobility.
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing

ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PEG = percutaneous endoscopic gastrostomy; PT = physical therapy


Table 7.

Adult-Onset DRPLA: Treatment of Manifestations

Cerebellar ataxia
  • PT & OT
  • Self-directed exercise
  • PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function 1
  • OT to optimize ADL (incl use of adaptive devices, e.g., weighted eating utensils & dressing hooks)
  • Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs)
  • Inpatient rehab w/OT/PT may improve ataxia & functional abilities in affected persons w/degenerative ataxias. 2, 3
  • Weight control to avoid obesity
  • Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs)
  • Although neither exercise nor PT slows progression of incoordination or muscle weakness, affected persons should maintain activity.
Pharmacologic treatmentRiluzole 2 may be beneficial for ataxia
Choreoathetoid & dystonic movements Pharmacologic treatmentTetrabenazine, risperidone, bromazepam, gabapentin 4
Dystonia Pharmacologic treatmentUse standard medications
Dysarthria Therapy by SLPConsider alternative communication methods as needed (e.g., writing pads & digital devices).
Dysphagia Feeding therapy programs to improve nutrition & dysphagia & reduce aspiration risk
  • Video esophagram may help define best food consistency.
  • Education re strategies to mitigate aspiration
Weight Nutrition assessment
  • Consider nutritional & vitamin supplementation to meet dietary needs.
  • Avoid obesity, which can exacerbate difficulties w/ambulation & mobility.
Pharmacologic treatment
  • Use standard treatments for psychiatric manifestations.
  • Quetiapine may be beneficial for psychosis. 5
Psychotherapy / neuropsychological rehabConsider cognitive & behavioral therapy. 6
  • Ensure appropriate social work involvement to connect families or care providers w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing

ADL = activities of daily living; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist


Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for school-age individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • Individualized education plan (IEP) services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
    • Vision consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.


To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 8 (for individuals with juvenile onset) and Table 9 (for individuals with adult onset) are recommended.

Agents/Circumstances to Avoid

General anesthesia can increase the risk of intra- and postoperative seizures [Takayama et al 2002].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In general, women with epilepsy from any cause are at greater risk for mortality during pregnancy than pregnant women without epilepsy; use of anti-seizure medications (ASMs) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASMs during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

The medications carbamazepine, phenytoin, and levetiracetam, discussed in Treatment of Manifestations, Table 6, are considered ASMs, even when they are used for an indication other than seizures (such as myoclonus). Care must be taken when weighing the fetal risk of adverse effects versus the benefit to the pregnant woman when one of these medications is being taken for an indication other than for seizure control.

There is little to no human data on potential adverse fetal effects when piracetam, brivaracetam, or perampanel is taken during pregnancy.

Limited data about the use of N-acetylcysteine during human pregnancy has been reassuring, without an appreciable increased risk of fetal malformations.

The use of riluzole during pregnancy has not been well studied in humans. One woman took riluzole throughout her pregnancy and delivered a healthy term infant, whereas another woman delivered an infant with growth restriction [Kawamichi et al 2010, Scalco et al 2012].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

DRPLA (dentatorubral-pallidoluysian atrophy) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with DRPLA have an affected parent.
  • In some families, an asymptomatic father of an affected individual has a mildly expanded CAG repeat and paternal transmission results in intergenerational increase in the size of the expanded CAG repeats. Examples include:
    • A proband with no family history of DRPLA whose father had 59 CAG repeats and was asymptomatic at age 65 years [Ikeuchi et al 1995b];
    • A proband with no family history of DRPLA whose father had 51 CAG repeats and was asymptomatic at 81 years [Hattori et al 1999].
  • If neither of the parents of the proband is known to have DRPLA, recommendations for the evaluation of parents include physical examination and consideration of targeted analysis for an ATN1 CAG expansion.
  • The family history of some individuals diagnosed with DRPLA may also appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for an expanded ATN1 CAG repeat.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the parents:

Offspring of a proband

  • The risk to the children of an affected individual of inheriting an expanded CAG repeat is 50%. The size of the repeat transmitted to the offspring depends on the size of the parent's repeat and the sex of the transmitting parent.
  • DRPLA exhibits significant anticipation, particularly when transmitted paternally (see Anticipation).

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected and/or is known to have an ATN1 CAG expansion, the parent's family members are at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

  • Testing of at-risk adults for DRPLA in the presence of nonspecific or equivocal symptoms is predictive testing, not diagnostic testing.
  • Predictive testing for at-risk relatives is possible once the ATN1 CAG expansion has been identified in an affected family member.
  • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

  • Predictive testing of minors for disorders for which early treatment would have no beneficial effect on disease morbidity and mortality is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
  • For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

It is appropriate to consider testing symptomatic individuals regardless of age in a family with an established diagnosis of DRPLA.

Prenatal Testing and Preimplantation Genetic Testing

Once an abnormal CAG repeat expansion in ATN1 has been identified in an affected family member, prenatal and preimplantation genetic testing for DRPLA are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • CureDRPLA
    Email: info@cureDRPLA.org
  • Ataxia UK
    United Kingdom
    Phone: 0800 995 6037; +44 (0) 20 7582 1444 (from abroad)
    Email: help@ataxia.org.uk
  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    United Kingdom
    Email: lporter@ataxia.org.uk
  • National Ataxia Foundation
    Phone: 763-553-0020
    Fax: 763-553-0167
    Email: naf@ataxia.org
  • Parent to Parent
    Phone: 484-272-7368
  • Spanish Ataxia Federation (FEDAES)
    Phone: 601 037 982
    Email: info@fedaes.org
  • CoRDS Registry
    Sanford Research
    Phone: 605-312-6300
  • CureDRPLA Global Patient Registry
    Email: drplaregistry@ataxia.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

DRPLA: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ATN1 12p13​.31 Atrophin-1 ATN1 database ATN1 ATN1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for DRPLA (View All in OMIM)

607462ATROPHIN 1; ATN1

Molecular Pathogenesis

Expression of truncated proteins encoded by ATN1 with expanded polyglutamine stretches result in frequent formation of peri- and intranuclear aggregates and apoptotic cell death, suggesting that processed expanded proteins are more toxic to cells than full-length proteins [Igarashi et al 1998, Shimohata et al 2002].

As in other polyglutamine disorders, the disease-causing CAG expansion in ATN1 lead to the identification of neuronal intranuclear protein aggregates, or intranuclear inclusions (NIIs), in the brains of affected individuals [Hayashi et al 1998, Igarashi et al 1998, Mori et al 2012a, Mori et al 2012b]. Accumulation of abnormal atrophin-1, the protein encoded by ATN1, in the neuronal nuclei is the predominant neuropathologic finding. Of note, NIIs are observed in central nervous system regions far beyond the systems previously reported to be affected on conventional neuropathologic findings. It has been suggested that NIIs are responsible for clinical features such as dementia and epilepsy [Yamada et al 2000, Yamada et al 2001, Yamada et al 2002].

Mechanism of disease causation. Gain of function

ATN1 technical considerations

  • Molecular genetic testing approaches have until recently involved targeted testing. Testing is typically performed by PCR amplification of the ATN1 trinucleotide repeat region followed by gel or capillary electrophoresis. Note: In CAG repeat disorders in general, highly expanded alleles (usually >100 CAG repeats) may not be detectable by the PCR-based assay, and additional testing (e.g., Southern blot analysis or triplet repeat-primed [TP] PCR [Warner et al 1996]) is indicated to detect a highly expanded repeat in individuals who are apparently homozygotes by PCR analysis.
  • Genome sequencing-based tools have been developed for the detection of triplet repeat expansions [Ibañez et al 2022].
  • Variants detectable by sequencing have not been associated with DRPLA, but are associated with ATN1-related neurodevelopmental disorder.

Table 10.

ATN1 Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide ChangeRepeat Range
c.1462CAG[48_93]Pathogenic (full penetrance)

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Author Notes

Silvia Prades, PhD, is actively involved in managing research projects regarding individuals with DRPLA and peer support groups. She would be happy to communicate with persons who have any questions regarding diagnosis of DRPLA or other considerations.

Author History

Thomas Felton, MS, CGC (2023-present)
Marina Frontali, MD; Italian National Research Council (2016-2023)
Silvia Grimaldi, MD (2023-present)
Henry Houlden, MD, PhD (2023-present)
Claudio Melo de Gusmao, MD (2023-present)
Silvia Prades, PhD (2023-present)
Yael Shiloh-Malawsky, MD (2023-present)
Shoji Tsuji, MD, PhD; University of Tokyo Graduate School of Medicine (1999-2016)
Liana Veneziano, PhD; Italian National Research Council (2016-2023)

Revision History

  • 21 September 2023 (bp) Comprehensive update posted live
  • 9 June 2016 (ma) Comprehensive update posted live
  • 1 June 2010 (me) Comprehensive update posted live
  • 22 December 2006 (me) Comprehensive update posted live
  • 15 June 2004 (me) Comprehensive update posted live
  • 24 May 2002 (me) Comprehensive update posted live
  • 6 August 1999 (pb) Review posted live
  • 15 February 1999 (st) Original submission


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