DRPLA

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).

Diagnosis/testing.

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.

Management.

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.

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

• Normal. 6 to 35 CAG repeats [Koide et al 1994, Nagafuchi et al 1994, Ikeuchi et al 1995a, Ikeuchi et al 1995c]
• Intermediate. 35 to 47 CAG repeats are incompletely penetrant and are usually associated with a milder clinical phenotype [Chaudhry et al 2021]. Intermediate alleles are unstable and can expand on transmission, resulting in full-penetrance alleles in the next generation; this is a very rare event. The unaffected Japanese population has a greater number of individuals with 20-35 CAG repeats than populations of European and African origin [Yanagisawa et al 1996, Takano et al 1998]. There is a report of a normal expanded allele with 42 CAG repeats in a family of Italian ancestry [Grimaldi et al 2019].
• Pathogenic (full penetrance). 48 to 93 CAG repeats [Shimojo et al 2001, Maruyama et al 2012]. For exceptions see Penetrance.

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

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].

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

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].

Homozygotes

• 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].

Penetrance

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].

Anticipation

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].

Nomenclature

DRPLA may also be referred to as:

• Naito-Oyanagi disease [Kanazawa 1998];
• Haw River syndrome [Burke et al 1994a, Burke et al 1994b];
• ATN1-related dentatorubral-pallidoluysian atrophy (based on the dyadic naming approach proposed by Biesecker et al [2021] to delineate mendelian genetic disorders).

Prevalence

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:

• Brazil: 0.2%-0.92% [Braga-Neto et al 2017, Pinto et al 2021]
• China: 1% [Lee et al 2001]
• France: 0.25% [Le Ber et al 2003]
• Italy: 1% [Filla et al 2000]. A study of the largest northern European DRPLA pedigree, originating in Italy in the 1500s with a founder couple, demonstrated that DRPLA can be observed over time in certain geographic areas [Grimaldi et al 2019], suggesting that prevalence could be higher than expected in non-Asian populations.
• Korea: 3.4% [Jin et al 1999]
• Portugal: 2%-11.2% [Silveira et al 2002, Vale et al 2010]. In the Portuguese population, the prevalence of DRPLA was estimated at 0.33 in 100,000 people, ranking as the second most frequent autosomal dominant ataxia [Coutinho et al 2013]. The prevalence in Portugal is almost comparable to Japan, and is higher than that described for the rest of Europe. The Portuguese families with DRPLA share the same haplotype as in Japan [Martins et al 2003], which could explain the higher prevalence in this country.
• Singapore: 3.4% [Zhao et al 2002]
• South Wales: 11.4% [Wardle et al 2008]. In South Wales the theory of a founder effect only accounted for some but not all of the high prevalence of DRPLA, as the Japanese haplotype was only detected in three out of four families [Wardle et al 2008]. These findings suggested that DRPLA prevalence can also be influenced by spontaneous repeat expansions in families with high-normal repeats.
• Spain: 1.4%-3.3% [Pujana et al 1999, Infante et al 2005]
• Venezuela: 3.1% [Paradisi et al 2016]

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.

Table 5.

DRPLA: Recommended Evaluations Following Initial Diagnosis by Age of Onset

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

Table 7.

Adult-Onset DRPLA: Treatment of Manifestations

Surveillance

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.

Table 8.

Juvenile-Onset DRPLA: Recommended Surveillance

Table 9.

Adult-Onset DRPLA: Recommended Surveillance

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.

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:

• If a parent of the proband has an abnormal ATN1 CAG expansion, the risk to the sibs of inheriting an expansion is 50%. The clinical features expected in the sib depend on the size of the repeat transmitted to the sib, which in turn depends on the size of the parent's repeat and the sex of the transmitting parent.
• 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].
• In general, an inverse correlation exists between the age at onset and the size of the expanded ATN1 CAG repeat (see Genotype-Phenotype Correlations).

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.

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

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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