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DRPLA

[Dentatorubral-Pallidoluysian Atrophy, Naito-Oyanagi Disease]

Summary

Disease characteristics.  Dentatorubral-Pallidoluysian atrophy (DRPLA) is a progressive disorder of ataxia, choreoathetosis, and dementia or character changes in adults and ataxia, myoclonus, epilepsy, and progressive intellectual deterioration in children. The age of onset is from one to 62 years with a mean age of onset of 30 years. The clinical presentation varies depending on the age of onset. The cardinal features in adults are ataxia, choreoathetosis, and dementia. Cardinal features in children are mental retardation, behavioral changes, myoclonus, and epilepsy.

Diagnosis/testing.  The diagnosis of DRPLA rests on positive family history, characteristic clinical findings, and the detection of an expansion of a CAG/polyglutamine tract in the ATN1 (DRPLA) gene. The CAG repeat length in individuals with DRPLA ranges from 48 to 93. Molecular genetic testing is clinically available.

Management.  Treatment of manifestations: standard antiepileptic drugs (AEDs) for seizures; appropriate psychotropic medications for psychiatric manifestations; adaptation of environment and care to the level of dementia; appropriate educational programs for children.

Genetic counseling.  DRPLA is inherited in an autosomal dominant manner. Offspring of an individual with a mutant allele have a 50% chance of inheriting the disease-causing allele. DRPLA exhibits significant anticipation: 28 years/generation with paternal transmission and 15 years/generation with maternal transmission. Prenatal testing using molecular genetic testing is available for fetuses at 50% risk.

Diagnosis

Clinical Diagnosis

The diagnosis of Dentatorubral-pallidoluysian atrophy (DRPLA) is established in individuals with disease-causing CAG trinucleotide expansions in the ATN1 (DRPLA) gene who are:

• Under age 20 years and have ataxia, myoclonus, seizures, and progressive intellectual deterioration;
• Over age 20 years and have ataxia, choreoathetosis, dementia, and psychiatric disturbance.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene.   ATN1 (DRPLA) is the only gene associated with DRPLA.

Allele sizes

• Normal alleles: 6-35 CAG repeats

• Mutable normal alleles: Mutable normal alleles are not associated with symptoms but are unstable and can expand on transmission resulting in occurrence of symptoms in the next generation. Mutable normal alleles may exist; Takano et al (1998) have shown that the normal Japanese population has a greater number of individuals with 20-35 CAG repeats than are found in Caucasian populations.

• Full penetrance alleles: ≥48 CAG repeats [Koide et al 1994 ; Nagafuchi, Yanagisawa, Sato et al 1994 ; Ikeuchi, Koide, Onodera et al 1995 ; Ikeuchi, Koide, Tanaka et al 1995 ; Ikeuchi, Onodera et al 1995 , Alford et al 1997 , Shimojo et al 2001]. The largest full penetrance allele reported to date is 93.

Clinical uses

• Diagnosis
• Predictive testing
• Prenatal testing

Clinical testing

• Targeted mutation analysis.  Testing is typically performed by PCR amplification of the ATN1 trinucleotide repeat region followed by gel 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 (such as Southern blot analysis) is indicated to detect a highly expanded allele in individuals with a single allele size detected by PCR. However, the largest ATN1 allele reported to date, a 93 CAG repeat in a symptomatic 12 month old child, was detected by the PCR-based assay [Shimojo et al 2001].

Table 1. Molecular Genetic Testing Used in DRPLA

Test Method	Mutations Detected	Mutation Detection Frequency by Test Method	Test Availability
Targeted mutation analysis	CAG expansion in ATN1 gene	100%	Clinical

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations in the ATN1 gene.

Clinical Description

Natural History

The onset of DRPLA ranges from childhood to late adulthood (range: 1-62 years; mean: 30 years) [Ikeuchi, Koide, Tanaka et al 1995]. The clinical presentation varies depending on the age of onset. The cardinal features in adults are ataxia, choreoathetosis, and dementia; cardinal features in children are mental retardation, behavioral changes, myoclonus, and epilepsy [Naito & Oyanagi 1982 ; Ikeuchi, Koide, Tanaka et al 1995].

Studies have shown that ataxia and dementia are cardinal features irrespective of the age of onset [Ikeuchi, Koide, Tanaka et al 1995].

Epileptic seizures occur in all individuals with onset before age 20 years. Various forms of generalized seizures including tonic, clonic, or tonic-clonic seizures are observed. Progressive myoclonus epilepsy (PME phenotype) characterized by myoclonus, seizures, ataxia, and progressive intellectual deterioration, is common [Naito & Oyanagi 1982 ; Ikeuchi, Koide, Tanaka et al 1995].

Myoclonic epilepsy and absence of atonic seizures are occasionally observed in individuals with onset before age 20 years.

Seizures are less frequent in individuals with onset between ages 20 and 40 years. Seizures are rare in individuals with onset after age 40 years.

Individuals with onset of DRPLA after age 20 years tend to develop cerebellar ataxia, choreoathetosis, dementia, and psychiatric disturbances (non-PME phenotype). In some individuals, involuntary movements and dementia mask the presence of ataxia. Psychosis may sometimes be a presenting feature [Adachi et al 2001].

Cervical dystonia was the presenting feature in one family [Hatano et al 2003].

Corneal endothelial degeneration has been described [Ito et al 2002].

Neuroimaging.  Atrophic changes in the cerebellum and brainstem, in particular the pontine tegmentum, are the typical MRI findings of DRPLA. Quantitative analyses revealed that both the age at MRI and the size of the expanded CAG repeat correlate with the atrophic changes.

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].

Neuropathology.  In contrast to the broad clinical features of DRPLA, the major neuropathologic changes detected by conventional neuropathologic observations are relatively simple and consist of combined degeneration of the dentatorubral and pallidoluysian systems of the central nervous system.

Discovery of pathogenic mutations in the DRPLA (ATN1) gene led to identification of neuronal intranuclear inclusions (NIIs) in the brains of individuals with DRPLA [Hayashi et al 1998 , Igarashi et al 1998]. Accumulation of mutant DRPLA protein (atrophin-1) in the neuronal nuclei is the predominant neuropathologic finding, detected as diffuse nuclear staining by the antibody specifically detecting expanded polyglutamine stretches. Of note, the diffuse nuclear staining involves central nervous system regions far beyond the systems previously reported to be affected on conventional neuropathologic findings. It has been suggested that the diffuse nuclear staining is responsible for clinical features such as dementia and epilepsy [Yamada et al 2000 , Yamada et al 2001 , Yamada et al 2002].

In addition to the combined degeneration of the dentatorubral and pallidoluysian systems, cerebral white matter damage has been described. Autopsy study of the white matter lesions showed diffuse myelin pallor, axonal preservation, and reactive astrogliosis in the cerebral white matter, with only mild atherosclerotic changes [Munoz et al 2004].

Detailed neuropathologic studies of a transgenic mouse model for DRPLA did not demonstrate neuronal loss in the brain. Interestingly, however, detailed morphometric studies demonstrated several abnormalities in individual neurons including reductions in the number and size of spines as well as in the area of perikarya and diameter of dendrites. These abnormalities probably explaine the brain atrophy and neuronal dysfunctions in this disease [Sakai et al 2006].

Genotype-Phenotype Correlations

Heterozygotes.   An inverse correlation exists between the age at onset and the size of the expanded CAG repeat [Ikeuchi, Koide, Tanaka et al 1995] (see Table 2).

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

Because onset before age 20 years is associated with the PME phenotype and older age of onset with the non-PME phenotype, the clinical presentation is strongly correlated with the size of expanded CAG repeats.

Severe infantile onset with an extreme CAG expansion (90 to 93 repeats) has been reported [Shimojo et al 2001].

Homozygotes.  Gene dosage effect is observed. Individuals who are homozygous for expanded CAG repeats are more severely affected than those who are heterozygous for the expanded CAG repeats [Sato et al 1995].

Penetrance

Most mutant alleles are fully penetrant except for rare cases with mildly expanded CAG repeats (<60 repeats).

Anticipation

The marked CAG repeat expansion occurring in the transmission of mutant ATN1 (DRPLA) alleles from parent to child results in anticipation. Affected offspring typically have symptoms 26 to 29 years earlier than affected fathers and 14 to 15 years earlier than affected mothers [Koide et al 1994 ; Nagafuchi, Yanagisawa, Sato et al 1994 ; Ikeuchi, Koide, Onodera et al 1995 ; Ikeuchi, Koide, Tanaka et al 1995 ; Ikeuchi, Onodera et al 1995 , Vinton et al 2005].

Nomenclature

DRPLA in a large African-American family in North Carolina was referred to as Haw River syndrome [Burke, Ikeuchi et al 1994].

Prevalence

The prevalence of DRPLA in the Japanese population is estimated to be 0.2-0.7 in 100,000. Analysis of the distribution of normal DRPLA (ATN1) alleles by size has demonstrated that CAG repeats larger than 17 repeats are significantly more frequent in the Japanese population than in Caucasian populations, which is in accordance with the observation that DRPLA is relatively more common among Japanese than other ethnic populations [Burke, Ikeuchi et al 1994 ; Takano et al 1998].

Although DRPLA has been reported to occur predominantly in the Japanese, individuals with molecularly confirmed DRPLA have been identified in other populations including Europe and North America [Burke, Wingfield et al 1994 ; Warner, Lennox et al 1994 ; Warner, Williams et al 1994 ; Norremolle et al 1995 ; Connarty et al 1996 ; Potter 1996 ; Le Ber et al 2003 ; Martins et al 2003].

Although rare in the US, DRPLA has been discovered in a large African-American family in North Carolina [Burke, Ikeuchi et al 1994 ; Burke, Wingfield et al 1994] and in a second African-American family [Licht & Lynch 2002].

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

For individuals with adult-onset Dentatorubral-Pallidoluysian atrophy (DRPLA) who exhibit ataxia, dementia, or choreoathetosis (the non-PME phenotype), the differential diagnosis includes the following:

Huntington disease .  The presence of ataxia is important for differentiating DRPLA from Huntington disease. Some affected individuals with the non-PME phenotype of DRPLA may initially be diagnosed as having Huntington disease, as the main clinical features in these individuals are involuntary movements and 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 brainstem (particularly pontine tegmentum) on imaging study is important in the differential diagnosis. Atrophy of the caudate nucleus favors the diagnosis of Huntington disease. It is frequently necessary to do molecular genetic testing for both Huntington disease and DRPLA in individuals with unexplained progressive dementia and involuntary movements.

Ataxia.  Individuals with DRPLA who have mildly expanded CAG repeats (49-55) tend to exhibit, particularly in early stages, pure cerebellar symptoms such as ataxia without dementia, choreoathetosis, or character changes, making the clinical diagnosis of DRPLA difficult. Such individuals need to be distinguished from those with ataxia of other etiologies, such as the dominantly inherited ataxias in which the causative genes are known [e.g., SCA1 , SCA2 , Machado-Joseph disease (SCA3), SCA6 , SCA7] and other dominant SCAs in which the causative genes are unknown (see Ataxia Overview).

Progressive intellectual deterioration, myoclonus, and epilepsy.  For those with early-onset DRPLA before age 20 years, the differential diagnosis includes:

• Lafora disease
• Unverricht-Lundborg disease
• Neuronal ceroid-lipofuscinosis
• MERRF (myoclonus epilepsy associated with ragged-red fibers)
• Sialidosis
• Galactosialidosis
• Gaucher disease
• Neuroaxonal dystrophy
• Pantothenate kinase associatedneurodegeneration
• Benign adult familial myoclonus epilepsy (BAFME, also called familial essential myoclonus and epilepsy [FEME]) [Delgado-Escueta et al 2001]

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with DRPLA, the following evaluations are recommended:

• EEG in the presence of seizures
• MRI
• Neuropsychological testing to seek evidence of dementia and psychiatric disturbance

Treatment of Manifestations

• Treatment of seizures with antiepileptic drugs (AEDs) in a standard manner
• Treatment of psychiatric problems with appropriate psychotropic medications
• Adaptation of environment and care to the level of dementia
• For affected children, adaptation of educational programming to abilities

Testing of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

DRPLA is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with DRPLA have an affected parent.
• It is appropriate to evaluate both parents of an affected individual with molecular genetic testing even if they are asymptomatic .
• Examples of delayed onset of expression in individuals with relatively small, abnormal repeat sizes include:
  • A parent of an individual with no family history of DRPLA who had 59 CAG repeats and no symptoms at age 65 years [Ikeuchi, Koide, Tanaka et al 1995];
  • A 50-year-old asymptomatic parent of an individual with no family history of DRPLA who had 56 CAG repeats.

Note: Although most individuals diagnosed with DRPLA have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members [Ikeuchi, Koide, Tanaka et al 1995 ; Yoshimoto et al 1995 ; Shimizu et al 1996], early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. In some cases, the asymptomatic fathers of the affected individuals have mildly expanded CAG repeats and paternal transmission resulted in intergenerational increase in the size of the expanded CAG repeats.

Sibs of a proband

• The risk to the sibs of the proband depends upon the genetic status of the parents.
• If a parent of the proband is affected and has a full penetrance allele, the risk to the sibs of inheriting the allele is 50%. The clinical features expected in the sib depend on the size of the repeat transmitted to the sib, which depends on the size of the parent's repeat and the gender of the transmitting parent.
• If a parent of the proband has a mutable normal allele, the risk to the sibs of inheriting an abnormal allele is 50%. The likelihood of the sib developing symptoms depends upon the size of the expansion.

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 gender of the transmitting parent.
• DRPLA exhibits significant anticipation. See Anticipation .

Other family members of a proband.  The risk to other family members depends upon the genetic status of the proband's parents. If a parent is found to be affected or to have a full penetrance allele, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation.  When neither parent of a proband with DRPLA has clinical features of the disorder, a full penetrance mutation or a mutable normal allele, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or undisclosed adoption could also be explored.

Family planning.  The optimal time for determination of genetic risk and availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.

Testing of asymptomatic at-risk adults. Testing of at-risk asymptomatic adults for DRPLA is available using the same techniques described in Molecular Genetic Testing . Testing of asymptomatic at-risk adults for DRPLA in the presence of nonspecific or equivocal symptoms is predictive testing, not diagnostic testing. When testing at-risk individuals for DRPLA, it is helpful to test for the CAG expansion in an affected family member to confirm the diagnosis in the family.

At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of DRPLA, the possible impact of positive and negative test results, and neurologic status are assessed.

Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be obtained and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluation.

Testing of at-risk asymptomatic individuals during childhood. Requests from parents for testing of asymptomatic at-risk individuals during childhood require sensitive and understanding counseling. Consensus holds that individuals under age 18 at risk for adult-onset disorders should not have testing in the absence of symptoms. The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications. Individuals who are symptomatic usually benefit from having a specific diagnosis established. See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider : ethical, legal, and psychosocial implications of genetic testing in children and adolescents (Genetic Testing; pdf)

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal diagnosis for pregnancies at 50% risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see

Molecular Genetics

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.

Normal allelic variants: The human ATN1 (DRPLA) gene spans approximately 20 kbp and consists of ten exons. The CAG repeat in the ATN1 gene is located in exon 5, 1462 bp downstream from the putative methionine initiation codon, and is predicted to code for a polyglutamine stretch. The CAG repeats in normal individuals range from six to 35 repeat units [Koide et al 1994 ; Nagafuchi, Yanagisawa, Sato et al 1994 ; Ikeuchi, Koide, Onodera et al 1995 ; Ikeuchi, Onodera et al 1995].

Polyserine and polyproline stretches exist near the CAG repeats. In contrast to the length of the polyglutamine stretch, the lengths of these polyserine and polyproline stretches are not highly polymorphic [Nagafuchi, Yanagisawa, Ohsaki et al 1994 ; Onodera et al 1995].

Pathologic allelic variants: The CAG repeats in individuals with DRPLA range from 48 to 93 repeat units [Koide et al 1994 ; Nagafuchi, Yanagisawa, Sato et al 1994 ; Ikeuchi, Koide, Onodera et al 1995 ; Ikeuchi, Koide, Tanaka et al 1995 ; Ikeuchi, Onodera et al 1995 ; Alford et al 1997 ; Shimojo et al 2001]. (For more information, see Genomic Databases table above.)

Normal gene product: The ATN1 cDNA is predicted to code for 1,185 amino acids. Atrophin-1 is a nuclear protein with putative nuclear localizing signals [Sato et al 1999 , Nucifora et al 2003]. Recent studies have sugegsted that the Drosophila ortholog of the DRPLA protein functions as a transcriptional corepressor in diverse developmental processes [Zhang et al 2002 , Charroux et al 2006].

Abnormal gene product: Investigations have demonstrated that expression of truncated mutant proteins encoded by ATN1 with expanded polyglutamine stretches in COS7 cells results in frequent formation of peri- and intranuclear aggregates and apoptotic cell death, suggesting that processed mutant proteins are more toxic to cells than full-length proteins [Igarashi et al 1998 , Shimohata et al 2002]. Expanded polyglutamine stretches have been shown to interact with TATA-binding protein (TBP)-associated factors (TAFII130) or cAMP response element-binding protein (CREB)-binding protein (CBP), resulting in the suppression of CREB-dependent transcriptional activation that is vital for neuronal survival and plasticity [Shimohata et al 2000 , Nucifora et al 2001 , Shimohata et al 2005].

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

References

Published Statements and Policies Regarding Genetic Testing

• American Society of Human Genetics and American College of Medical Genetics (1995) Points to consider : ethical, legal, and psychosocial implications of genetic testing in children and adolescents (pdf; Genetic Testing).
  
  
• National Society of Genetic Counselors (1995) Resolution on prenatal and childhood testing for adult-onset disorders.

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Suggested Readings

• Zoghbi HY and Orr HT (modified 2002) Spinocerebellar ataxias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID), McGraw-Hill, New York, Chap 226. www.ommbid.com
  
  

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