In 5 families, Naito and Oyanagi (1982) reported a syndrome of myoclonic epilepsy, dementia, ataxia, and choreoathetosis. At autopsy, major neuropathologic changes consisted of combined degeneration of the dentatorubral and pallidoluysian systems. Inheritance was autosomal dominant. Onset was ... In 5 families, Naito and Oyanagi (1982) reported a syndrome of myoclonic epilepsy, dementia, ataxia, and choreoathetosis. At autopsy, major neuropathologic changes consisted of combined degeneration of the dentatorubral and pallidoluysian systems. Inheritance was autosomal dominant. Onset was usually in the twenties and death in the forties. Although this condition was perhaps first described by Smith et al. (1958) and several sporadic cases have been reported from Western countries, this disorder seems to be very rare except in Japan where other hereditary cases have been described (Iizuka et al., 1984; Iwabuchi et al., 1985; Takahashi et al., 1988). Hirayama et al. (1981) classified 3 clinical forms of DRPLA: the ataxo-choreoathetoid form, the pseudo-Huntington form, and the myoclonic epilepsy form. Tomoda et al. (1991) described a Japanese family with 12 affected individuals in 3 generations. They emphasized that patients with onset in childhood usually have the progressive myoclonic epilepsy (PME) syndrome (254800). Warner et al. (1994) described 1 family in the United Kingdom in which the DRPLA repeat expansion was demonstrated in 3 affected sibs. In the course of studying Huntington disease (HD; 143100) in Wessex in the U.K., Connarty et al. (1996) found a second family with DRPLA. A father and daughter were affected. In a single Japanese family, Saitoh et al. (1998) observed 5 different clinical types of DRPLA. Two sibs and their paternal uncle manifested the juvenile type, the father of the sibs had the late-adult type, and another paternal uncle had the early-adult type. Gene analysis confirmed the diagnosis for the proband and her sib. By following the clinical courses and electroencephalographic changes, they found that the types of epileptic seizures and the EEGs of the juvenile DRPLA patients changed as the course progressed. The sibs exhibited different levels of clinical severity despite the similar DNA expansion detected in their lymphocytes (see GENOTYPE/PHENOTYPE CORRELATIONS). Shimojo et al. (2001) reported 2 unrelated patients with infantile DRPLA. Both patients developed normally until about 6 months of age, when motor signs, such as difficulty controlling the head, choreoathetosis, hyperkinetic movements, involuntary movements, and seizures developed. MRI of both patients showed cerebral atrophy and delayed myelination. CAG repeat sizes were 93 and 90, representing extreme repeat expansion. Although the parents refused DNA analysis, Shimojo et al. (2001) suggested that the early onset and severe clinical courses were related to the long repeats. - Haw River Syndrome Farmer et al. (1989) described a family, with ancestors born in Haw River, North Carolina, that contained members in 5 generations with an autosomal dominant neurologic disorder. It was characterized by the development between 15 and 30 years of age of ataxia, seizures, choreiform movements, progressive dementia, and death after 15 to 25 years of illness. Neuropathologic findings in 2 deceased family members demonstrated remarkably similar findings, including marked neuronal loss of the dentate nucleus, microcalcification of the globus pallidus, neuroaxonal dystrophy of the nucleus gracilis, and demyelination of the centrum semiovale. The clinical and pathologic findings were closely correlated: ataxia and chorea were related to severe neuronal loss in the dentate nucleus with calcification in the globus pallidus. Dementia occurred from progressive demyelination of the centrum semiovale, and loss of posterior column function occurred from neuroaxonal dystrophy of the nucleus gracilis and nucleus cuneatus. Burke et al. (1994) noted that the phenotypic differences between Haw River syndrome and DRPLA include the absence of myoclonic seizures in HRS as well as the presence of extensive demyelinization of the subcortical white matter, basal ganglia calcifications, and neuroaxonal dystrophy which are not seen in DRPLA.
Burke et al. (1994) suggested that the difference in racial frequency of DRPLA is probably due to differences in the repeat size. The frequency of the repeat allele of intermediate size was very low in Europeans, somewhat higher ... Burke et al. (1994) suggested that the difference in racial frequency of DRPLA is probably due to differences in the repeat size. The frequency of the repeat allele of intermediate size was very low in Europeans, somewhat higher in African Americans, and relatively high (5-10%) in Japanese. This is a situation comparable to the virtual absence of myotonic dystrophy (DM; 160900) in South African blacks, in whom the frequency of large-length CTG repeats is much lower than in white and Japanese populations (Goldman et al., 1994). See the graphs of the distribution of CAG trinucleotide repeat frequencies in 3 populations presented by Burke et al. (1994), including Japanese colleagues. - Genetic Anticipation Koide et al. (1994) found a good correlation between the size of the (CAG)n repeat expansion and the age of onset. Patients with earlier onset tended to have a phenotype of progressive myoclonic epilepsy and larger expansions. They proposed that the wide variety of clinical manifestations of DRPLA can be explained by the variable unstable expansion of the CAG repeat. Although only 5 cases of paternal transmission and 2 cases of maternal transmission were analyzed, the length of the repeat unit was altered in all cases: the average change in repeat length for paternal transmission was an increase of 4.2 repeats, while that of maternal transmission was a decrease of 1.0 repeat. Nagafuchi et al. (1994) found that the repeat size varied from 7 to 23 in normal individuals. In patients, one allele was expanded to between 49 and 75 repeats or occasionally even more. Expansion was usually associated with paternal transmission. Like Koide et al. (1994), they found that repeat size correlated closely with age of onset of symptoms and with disease severity. Komure et al. (1995) analyzed CAG trinucleotide repeats in 71 individuals from 12 Japanese DRPLA pedigrees that included 38 affected individuals. Normal alleles varied from 7 to 23 repeats, whereas affected individuals had from 53 to 88 repeats. Like Koide et al. (1994) and Nagafuchi et al. (1994), they found a significant negative correlation between CAG repeat length and age of onset. In 80% of the paternal transmissions, there was an increase of more than 5 repeats, whereas all the maternal transmissions showed either a decrease or an increase of fewer than 5 repeats. Aoki et al. (1994) demonstrated that anticipation with expansion of the CAG repeat can occur through mothers as well as through fathers. They investigated 2 families in which offspring showed progressive myoclonic epilepsy with onset in childhood. In 1 family, patients of the first generation showed mild cerebellar ataxia with onset at 52 to 60 years. A patient of the second generation, the mother, showed severe ataxia with onset in the early thirties. The offspring in the third generation showed mental retardation, convulsions and myoclonus beginning at age 8. Sano et al. (1994) studied 4 families and also demonstrated anticipation. Older-onset patients suffered from cerebellar ataxia with or without dementia, whereas younger-onset patients presented as progressive myoclonus epilepsy syndrome, consisting of mental retardation, dementia, and cerebellar ataxia as well as epilepsy and myoclonus. Anticipation with paternal transmission was significantly greater than with maternal transmission. Sato et al. (1995) reported homozygosity for a modest (57-repeat) triplet repeat in a man with early onset of DRPLA at age 17. His parents were first cousins and were neurologically normal at ages 73 and 71, in spite of having 57 CAG repeats in heterozygous state. Four of the proband's sibs died at age 12 with the phenotype of progressive myoclonic epilepsy. These findings supported the hypothesis that the clinical features of DRPLA, like those of Machado-Joseph disease, are influenced by the dosage of expansion of triplet repeats, unlike Huntington disease, in which the homozygous state does not appear to be different clinically from the heterozygous state. Norremolle et al. (1995) described a Danish family in which affected persons in at least 3 generations had been thought to be suffering from Huntington disease. Because analysis of the huntingtin gene revealed normal alleles and because some of the patients had seizures, they analyzed the B37 gene and found significantly elongated CAG repeats, as had been reported in cases of DRPLA. Norremolle et al. (1995) reported that affected persons with almost identical repeat lengths presented very different symptoms. Both expansion and contraction in paternal transmission was observed. Ikeuchi et al. (1996) analyzed the segregation patterns of 411 transmissions of 24 DRPLA pedigrees and 80 transmissions in 7 Machado-Joseph disease (MJD; 109150) pedigrees, with the diagnoses confirmed by molecular testing. Significant distortions in favor of transmission of the mutant alleles were found in male meiosis, where the mutant alleles were transmitted to 62% of all offspring in DRPLA (P less than 0.01) and 73% in MJD (P less than 0.01). The results were considered consistent with meiotic drive in both disorders. The authors commented that since more prominent meiotic instability of the length of the CAG trinucleotide repeats is observed in male meiosis than in female meiosis and since meiotic drive is observed only in male meiosis, these results raised the possibility that a common molecular mechanism underlies the meiotic drive and the meiotic instability in male meiosis. On the basis of studies in an extensively affected Tennessee family, Potter (1996) emphasized the intrafamilial variability and lack of close correlation between age of onset and (CAG)n repeat number in this disease. The studies were done on DNA derived from leukocytes; tissue-specific instability (somatic mosaicism) has been reported in DRPLA. Takiyama et al. (1999) determined the CAG repeat size in 427 single sperm from 2 men with DRPLA. The mean variance of the change in the CAG repeat size in sperm from the DRPLA patients (288.0) was larger than any variances of the CAG repeat size in sperm from patients with Machado-Joseph disease (38.5), Huntington disease (69.0), and spinal and bulbar muscular atrophy (16.3; 313200), which is consistent with the clinical observation that the genetic anticipation on the paternal transmission of DRPLA is the most prominent among CAG repeat diseases. The variance was different in the 2 patients (51.0 vs 524.9, P greater than 0.0001). The segregation ratio of normal to expanded allele sperm was 1:1. Vinton et al. (2005) reported a 3-generation Caucasian family of Macedonian origin with DRPLA, manifesting as very mild elderly onset, severe young-adult onset, and severe childhood onset presentations in the 3 generations, respectively. Atrophin-1 expansion sizes of 52, 57, and 66 repeats were demonstrated in the 3 patients, respectively. Vinton et al. (2005) stated that the grandparental trinucleotide expansion size of 52 repeats was the smallest overtly pathogenic mutation yet reported.
DRPLA is one of several examples of disorders related to expansion of a trinucleotide repeat. Koide et al. (1994) searched a catalog of genes identified by Li et al. (1993) that contained trinucleotide repeats expressed in human brain. ... DRPLA is one of several examples of disorders related to expansion of a trinucleotide repeat. Koide et al. (1994) searched a catalog of genes identified by Li et al. (1993) that contained trinucleotide repeats expressed in human brain. One of these cDNAs, B37 (ATN1), known to map to chromosome 12, was examined and found to show CAG repeat expansion (607462.0001) in 22 individuals with DRPLA. Fragile X syndrome (300624), myotonic dystrophy (see 160900), Kennedy disease (313200), Huntington disease, spinocerebellar ataxia-1 (SCA1; 164400), and fragile XE mental retardation (see 309548) were the previously identified disorders due to expanded trinucleotide repeats. Burke et al. (1994, 1994) demonstrated that despite their distinct cultural origins and clinical and pathologic differences, Haw River syndrome and DRPLA are is caused by the same expanded CAG repeat in the ATN1 gene (607462.0001).
Since DRPLA occurs almost only in Japanese, Koide et al. (1994) suggested that there may exist a founder effect. In a nationwide survey of Japanese patients, Hirayama et al. (1994) estimated the prevalence of all forms of spinocerebellar ... Since DRPLA occurs almost only in Japanese, Koide et al. (1994) suggested that there may exist a founder effect. In a nationwide survey of Japanese patients, Hirayama et al. (1994) estimated the prevalence of all forms of spinocerebellar degeneration to be 4.53 per 100,000, of which 2.5% were estimated to have DRPLA. Watanabe et al. (1998) investigated 101 kindreds with spinocerebellar ataxias from the central Honshu island of Japan, using a molecular diagnostic approach with amplification of the CAG trinucleotide repeat of the causative genes. DRPLA ranked second in prevalence, accounting for 19.8% of the cases. DRPLA has been considered to be rare in Europe. Dubourg et al. (1995) failed to find a single case in a survey of 117 French patients with cerebellar ataxia from 94 families, concluding that DRPLA is rare in the French population. Among 202 Japanese and 177 Caucasian families with autosomal dominant SCA, Takano et al. (1998) found that the prevalence of DRPLA was significantly higher in the Japanese population (20%) compared to Caucasian population (0%). This corresponded to higher frequencies of large normal ATN1 CAG alleles (greater than 17 repeats) in Japanese controls compared to Caucasian controls. The findings suggested that large normal alleles contribute to the generation of expanded alleles that lead to dominant SCA. Shimizu et al. (2004) estimated the prevalence of autosomal dominant cerebellar ataxia (ADCA) in the Nagano prefecture of Japan to be at least 22 per 100,000. Thirty-one of 86 families (36%) were positive for SCA disease-causing repeat expansions: SCA6 (183086) was the most common form (19%), followed by DRPLA (10%), SCA3 (109150) (3%), SCA1 (2%), and SCA2 (183090) (1%). The authors noted that the prevalence of SCA3 was lower compared to other regions in Japan, and that the number of genetically undetermined SCA families in Nagano was much higher than in other regions. Nagano is the central district of the main island of Japan, located in a mountainous area surrounded by the Japanese Alps. The restricted geography suggested that founder effects may have contributed to the high frequency of genetically undetermined ADCA families.
The diagnosis of dentatorubral-pallidoluysian atrophy (DRPLA) is established in individuals with disease-causing CAG trinucleotide expansions in ATN1 (DRPLA) who are:...
DiagnosisClinical DiagnosisThe 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 TestingGene. ATN1 (known previously as DRPLA) is the only gene known to be associated with DRPLA.Allele sizesNormal alleles. 6-35 CAG repeats 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; this is a very rare event. Full-penetrance alleles. ≥48 CAG repeats [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]. The largest full-penetrance allele reported to date is 93.Clinical testingTargeted 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 DRPLAView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityATN1 Targeted mutation analysisCAG trinucleotide expansion 100%Clinical1. The ability of the test method used to detect a mutation that is present in the indicated geneTesting StrategyTo 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.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in ATN1.
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]....
Natural HistoryThe 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].
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)....
Genotype-Phenotype CorrelationsHeterozygotes. 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 RepeatView in own windowAge at OnsetATN1 CAG Repeat SizeRangeMedian<21 years63-796821-40 years61-6964>40 years48-6763Because 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].
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:...
Differential DiagnosisFor 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 , 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:Progressive myoclonus epilepsy, Lafora type Unverricht-Lundborg diseaseNeuronal ceroid-lipofuscinosis Neuroferritinipathy MERRF (myoclonus epilepsy associated with ragged-red fibers) Sialidosis Galactosialidosis Gaucher diseaseInfantile neuroaxonal dystrophy Pantothenate kinase associated neurodegeneration Benign adult familial myoclonus epilepsy (BAFME, also called familial essential myoclonus and epilepsy [FEME]) [Delgado-Escueta et al 2001] Note to clinicians: For a patient-specific ‘simultaneous consult’ related to juvenile-onset DRPLA, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with dentatorubral-pallidoluysian atrophy (DRPLA), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with dentatorubral-pallidoluysian atrophy (DRPLA), the following evaluations are recommended:EEG in the presence of seizuresMRINeuropsychological testing to seek evidence of dementia and psychiatric disturbanceTreatment of ManifestationsThe following are appropriate:Treatment of seizures with antiepileptic drugs (AEDs) in a standard mannerTreatment of psychiatric problems with appropriate psychotropic medicationsAdaptation of environment and care to the level of dementiaFor affected children, adaptation of educational programming to abilitiesSurveillanceSurveillance is individualized based on disease progression.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDATN112p13.31Atrophin-1ATN1 homepage - Mendelian genesATN1Data 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) View in own window 125370DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY; DRPLA 607462ATROPHIN 1; ATN1Normal 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 View in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference SequencesNormalc.1462CAG(6_35) (CAG 6-35 repeats)See footnote 2NM_001007026.1 NP_001007027.1Pathologicc.1462CAG(49_55) 3See footnote 3c.1462CAG(48_93) (CAG 48-93 repeats)See footnote 2c.1462CAG(90_93) 4(CAG 90-93 repeats)See footnote 2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions2. 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.