Test ID: DRPL    
Dentatorubral-Pallidoluysian Atrophy (DRPLA) Gene Analysis, Varies

Molecular confirmation of a diagnosis of dentatorubral-pallidoluysian atrophy (DRPLA) for symptomatic patients

Predictive testing for individuals with a family history of DRPLA and a documented expansion in the ATN1 gene in an affected family member

Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder characterized by ataxia, choreoathetosis, dementia, and psychiatric disturbance in adults and ataxia, myoclonus, seizures, and progressive intellectual deterioration in children. Characteristic neuropathologic observations include degeneration of the dentatorubral and pallidoluysian systems of the central nervous system.

The prevalence of DRPLA depends on the geographic and ethnic origin of the population being studied. DRPLA was first described in a European individual without a family history; however, it is predominantly found as an inherited condition and is most prevalent in Japan (0.2-0.7 per 100,000). Although rare, DRPLA has been identified in other populations including Europe and North America.

DRPLA is caused by an expansion of the CAG trinucleotide repeat in the ATN1 (DRPLA) gene. This trinucleotide repeat is polymorphic in the general population, with the number of repeats ranging from 7 to 35. In affected individuals the CAG expansion ranges from 48 to 93 repeats. As with other trinucleotide repeat disorders, anticipation is frequently observed, and larger CAG expansions are associated with earlier onset and a more severe and rapid clinical course. In DRPLA, the observed anticipation appears to be significantly greater in paternal transmissions.

Normal alleles: 7-35 CAG repeats

Abnormal alleles: 49-93 CAG repeats

An interpretive report will be provided.

An interpretive report will be provided.

For predictive testing, it is important to first document the presence of CAG-repeat amplification in the ATN1 gene in an affected family member to confirm that molecular expansion is the underlying mechanism of disease in the family.

We strongly recommend that patients undergoing predictive testing receive genetic counseling both prior to testing and after results are available.

Predictive testing of an asymptomatic child is not recommended.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.

The absence of an expansion in the ATN1 gene does not eliminate the diagnosis of other inherited neurodegenerative disorders that have overlapping clinical features with DRPLA, such as Huntington disease or spinocerebellar ataxias.

Method validation involved comparative studies with other laboratories and testing 50 individuals from the general population (anonymous blood donors) and 48 patients with cerebellar ataxia. In each case, the distribution of observed repeat sizes closely correlated with previously reported values (ie, similar range and frequencies of specific repeat sizes). Sequencing of 2 specimens confirmed accuracy of CAG repeat numbers compared with estimations based on the size of polymerase chain reaction products.

1. Ikeuchi T, Onodera O, Oyake M, et al: Dentatorubral-pallidoluysian atrophy (DRPLA): close correlation of CAG repeat expansions with the wide spectrum of clinical presentations and prominent anticipation. Semin Cell Biol 1995;6:37-44

2. Tsuji S: Dentatorubral-pallidoluysian atrophy: clinical aspects and molecular genetics. Ad Neurol 2002;89:231-239

3. Oyanagi S: Hereditary dentatorubral-pallidoluysian atrophy. Neuropathology 2000 20 Suppl:S42-6

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