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DRPLA

Synonyms: Dentatorubral-Pallidoluysian Atrophy, Naito-Oyanagi Disease
, MD, PhD
Department of Neurology
University of Tokyo Graduate School of Medicine
Tokyo, Japan

Initial Posting: ; Last Update: June 1, 2010.

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 progressive intellectual deterioration, 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 trinucleotide/polyglutamine tract in ATN1 (DRPLA). The CAG repeat length in individuals with DRPLA ranges from 48 to 93.

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. The risk to the offspring 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. Prenatal testing for pregnancies at increased risk is possible using molecular genetic testing if the diagnosis in the family has been confirmed.

Diagnosis

Clinical Diagnosis

The diagnosis of dentatorubral-pallidoluysian atrophy (DRPLA) is established in individuals with disease-causing CAG trinucleotide expansions in ATN1 (DRPLA) 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

Gene. ATN1 (known previously as DRPLA) is the only gene known to be associated with DRPLA.

Allele sizes

Clinical testing

  • Targeted mutation analysis. 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) is indicated to detect a highly expanded allele in individuals who are apparent homozygotes by PCR analysis. 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. Summary of Molecular Genetic Testing Used in DRPLA

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
ATN1 Targeted mutation analysisCAG trinucleotide expansion 100%

1. The ability of the test method used to detect a mutation that is present in the indicated gene

Testing Strategy

To establish the diagnosis in a proband requires identification of a full-penetrance allele in an affected individual.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

The onset of DRPLA ranges from childhood to late adulthood (range: 1-62 years; mean: 30 years) [Ikeuchi et al 1995b]. 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 ataxia, intellectual disability, behavioral changes, myoclonus, and epilepsy [Naito & Oyanagi 1982, Ikeuchi et al 1995b].

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

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 et al 1995b].

Myoclonic epilepsy and absence or 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].

Neuroimaging. Atrophic changes in the cerebellum and brain stem, 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 DRPLA (ATN1) 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 explain the brain atrophy and neuronal dysfunctions in this disease [Sakai et al 2006, Sato et al 2009].

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 Size
RangeMedian
<21 years63-7968
21-40 years61-6964
>40 years48-6763

Because onset before age 20 years is associated with the progressive myoclonus epilepsy (PME) phenotype and an 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 allele with an extreme ATN1 CAG expansion with 90-93 CAG repeats [c.1462CAG(90_93)] has been reported [Shimojo et al 2001].

Homozygotes. A dosage effect is observed. Individuals who are homozygous for an expanded ATN1 CAG repeat allele are more severely affected than those who are heterozygous for an expanded ATN1 CAG repeat of the same size [Sato et al 1995, Squitieri et al 2003, Zühlke et al 2003, Toyoshima et al 2004].

Penetrance

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

Anticipation

The marked expansion of the CAG repeat during transmission of mutant ATN1 alleles from parent to child results in prominent 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 et al 1994, Ikeuchi et al 1995a, Ikeuchi et al 1995b, Ikeuchi et al 1995c, Vinton et al 2005].

Nomenclature

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

Prevalence

The prevalence of DRPLA in the Japanese population is estimated at 0.48:100,000 based on the nation-wide study [Tsuji et al 2008]. Analysis of the distribution of normal ATN1 alleles by size has demonstrated that CAG repeats larger than 17 repeats are significantly more frequent in the Japanese population than in populations of European origin, which is in accordance with the observation that DRPLA is relatively more common among the Japanese than other ethnic populations [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 European and North American [Burke et al 1994b, 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 et al 1994a, Burke et al 1994b] and in a second African American family [Licht & Lynch 2002].

Differential Diagnosis

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 and Huntington disease-like phenotypes including Huntington disease-like 1 (see Genetic Prion Diseases) and Huntington disease-like 2. 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 brain stem (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 Huntington disease, Huntington disease-like phenotypes, and DRPLA in individuals with unexplained progressive dementia and involuntary movements.

Ataxia. Individuals with DRPLA who have mildly expanded CAG repeats [c.1462CAG(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 including the dominantly inherited ataxias in which the causative genes are known (e.g., SCA1, SCA2, Machado-Joseph disease [SCA3], SCA6, SCA7, SCA17) and other dominant SCAs in which the causative genes are unknown (see Ataxia Overview).

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to adult-onset DRPLA, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

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

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to juvenile-onset DRPLA, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with dentatorubral-pallidoluysian atrophy (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

The following are appropriate:

  • 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

Surveillance

Surveillance is individualized based on disease progression.

Evaluation 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. 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, 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. —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 et al 1995b].
    • 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 et al 1995b], 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 on 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 on 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 on 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 maternity (e.g., with assisted reproduction) 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.
  • 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.

Testing of asymptomatic at-risk adults. Testing of at-risk asymptomatic adults for DRPLA is possible using the 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 molecular 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 such testing 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 position statement on genetic testing of minors for adult-onset conditions 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.

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.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 an option for some families in which the disease-causing mutation has been identified.

Resources

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.

  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    9 Winchester House
    Kennington Park
    London SW9 6EJ
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: marco.meinders@euro-ataxia.eu
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • Spanish Ataxia Federation (FEDAES)
    Spain
    Phone: 34 983 278 029; 34 985 097 152; 34 634 597 503
    Email: sede.valladolid@fedaes.org; sede.gijon@fedaes.org; sede.bilbao@fedaes.org
  • CoRDS Registry for the National Ataxia Foundation
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423
    Email: Cords@sanfordhealth.org

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

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
ATN112p13​.31Atrophin-1ATN1 databaseATN1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for DRPLA (View All in OMIM)

125370DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY; DRPLA
607462ATROPHIN 1; ATN1

Normal allelic variants. Human ATN1 (DRPLA) spans approximately 20 kb and consists of ten exons. The CAG repeat in ATN1 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 et al 1994, Ikeuchi et al 1995a, Ikeuchi et al 1995c].

Mutable normal alleles. 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 populations of European origin. 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.

Pathologic allelic variants. The CAG repeats in individuals with DRPLA range from 48 to 93 repeat units [Koide et al 1994, Nagafuchi et al 1994, Ikeuchi et al 1995a, Ikeuchi et al 1995b, Ikeuchi et al 1995c, Alford et al 1997, Shimojo et al 2001] (for more information, see Table A).

Table 3. Selected ATN1 Allelic Variants

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
Normalc.1462CAG(6_35)
(CAG 6-35 repeats)
See footnote 2NM_001007026​.1
NP_001007027​.1
Pathologicc.1462CAG(49_55) 3See footnote 3
c.1462CAG(48_93)
(CAG 48-93 repeats)
See footnote 2
c.1462CAG(90_93) 4
(CAG 90-93 repeats)
See footnote 2

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

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

1. Variant designation that does not conform to current naming conventions

2. Each CAG repeat results in the addition of a glutamine residue to the polymorphic polyglutamine repeat.

3. See Differential Diagnosis.

4. See Genotype-Phenotype Correlations.

Normal gene product. The ATN1 cDNA is predicted to code for 1,190 amino acids. Atrophin-1 is a nuclear protein with putative nuclear localizing signals [Sato et al 1999a, Nucifora et al 2003]. Recent studies have suggested that the Drosophila ortholog of atrophin-1 (DRPLA protein) functions as a transcriptional co-regulator in diverse developmental processes [Wood et al 2000, Zhang et al 2002, Charroux et al 2006, Shen et al 2007].

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].

Animal models. Studies of mouse models suggest that neuronal dysfunctions without neuronal death are the essential pathophysiologic process and that the age-dependent neuronal intranuclear accumulation (NIA) leading to transcriptional dysregulation underlies the neuronal dysfunctions in DRPLA.

Mouse models for DRPLA have been created by inserting a full-length mutant human ATN1 carrying expanded CAG repeats [Sato et al 1999b, Sato et al 2009]. Although mice with 76 CAG repeats exhibited intergenerational instability of CAG repeats (as similarly observed in DRPLA families), these mice did not show obvious neurologic phenotypes. Mice with 129 CAG repeats exhibited devastating progressive neurologic phenotypes similar to individuals with juvenile-onset DRPLA. Electrophysiologic studies of these mice demonstrated age-dependent and region-specific presynaptic dysfunctions in the globus pallidus (GP) and cerebellum. Progressive shrinkage of distal dendrites of Purkinje cells (PCs) and decreased currents through AMPA and GABAA receptors in CA1 neurons were also observed. Neuropathologic studies of the mice with 129 CAG repeats revealed progressive brain atrophy, but no obvious neuronal loss, associated with massive NIA of mutant proteins with expanded polyglutamine (polyQ) stretches starting on postnatal day 4 (P4), while NIA in the mice with 76 CAG repeats appeared later with regional specificity to the vulnerable regions of DRPLA.

References

Published Guidelines/Consensus Statements

  1. 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. Available online. 1995. Accessed 9-18-12. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 9-18-12.

Literature Cited

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  2. Alford RL, Margolis RL, Ross CA, Richards CS. Southern analysis for detection of CAG repeat expansions associated with dentatorubral pallidoluysian atrophy. Hum Genet. 1997;99:354–6. [PubMed: 9050922]
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Suggested Reading

  1. Nagafuchi S, Yanagisawa H, Ohsaki E, Shirayama T, Tadokoro K, Inoue T, Yamada M. Structure and expression of the gene responsible for the triplet repeat disorder, dentatorubral and pallidoluysian atrophy (DRPLA). Nat Genet. 1994;8:177–82. [PubMed: 7842016]
  2. Yamada M, Shimohata M, Sato T, Tsuji S, Takahashi H. Polyglutamine disease: recent advances in the neuropathology of dentatorubral-pallidoluysian atrophy. Neuropathology. 2006;26:346–51. [PubMed: 16961072]
  3. Zoghbi HY, Orr HT. Spinocerebellar ataxias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 226. Available online. Accessed 9-18-12.

Chapter Notes

Revision History

  • 1 June 2010 (me) Comprehensive update posted live
  • 22 December 2006 (me) Comprehensive update posted to live Web site
  • 15 June 2004 (me) Comprehensive update posted to live Web site
  • 24 May 2002 (me) Comprehensive update posted to live Web site
  • 6 August 1999 (pb) Review posted to live Web site
  • 15 February 1999 (st) Original submission
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