Dentatorubral‐pallidoluysian atrophy: Clinical features are closely related to unstable expansions of trinucleotide (CAG) repeat

Abstract

Dentatorubral-pallidoluysian atrophy is an autosomal dominant neurodegenerative disease characterized by various combinations of ataxia, choreoathetosis, myoclonus, epilepsy, and dementia as well as a wide range of ages at onset. A specific unstable trinucleotide repeat expansion in a gene on the short arm of chromosome 12 was recently identified as the pathogenic mutation for this disease. We investigated how the degree of expansion of the CAG repeat effects the clinical manifestations of dentatorubral-pallidoluysian atrophy. The size of the expanded alleles was well correlated with the age at onset (r = -0.696, p < 0.001). Patients with the progressive myoclonus epilepsy phenotype had larger expansions (62-79 repeats) and an earlier age at onset (onset before age 21). Furthermore, most of the patients with the progressive myoclonus epilepsy phenotype inherited their expanded alleles from their affected fathers. On the other hand, patients with the non-progressive myoclonus epilepsy phenotype showed smaller expansions (54-67 repeats) and a later age at onset (onset at or after age 21). Detailed analyses of clinical features demonstrated that ataxia, involuntary movement of either myoclonus or choreoathetosis, and intellectual decline are cardinal features of dentatorubral-pallidoluysian atrophy, with myoclonus and epilepsy being observed more frequently in patients with an earlier age at onset. Thus the wide variation in clinical manifestations of dentatorubral-pallidoluysian atrophy can now be clearly explained based on the degree of CAG repeat expansion, which strongly indicates that the expanded alleles are intimately involved in the neuronal degeneration in dentatofugal and pallidofugal systems.

Autosomal dominant cerebellar ataxias in the Kinki area of Japan

“…To date, only six families with DRPEA have been reported in non-Japanese populations (Burke et al, 1994;Potter et al, 1995;Warner et al, 1995). In contrast, six families in the Kinki area (this study) and 40 families in other areas of Japan (Ikeuchi et al, 1995;Komure et al, 1995) were positive for the DRPLA repeat expansion. Thus, the DRPLA mutation seems to be common only in the Japanese.…”

Unstable expansion of triplet repeats as a new disease mechanism for neurodegenerative diseases

“…ataxia, dementia or mental retardation, myoclonus, epilepsy, choreoathetosis and psychiatric changes including character changes, delusion or hallucinations (Ikeuchi et al, 1995a). We found that ataxia and dementia are cardinal features irrespective of age at onset.…”

“…patients with no family history of similar cases, has been extremely difficult, since a high penetrance in these diseases makes diagnosis of such cases difficult unless the disease is proven to be transmitted as an autosomal dominant trait. We have so far encountered 6 sporadic cases of DRPLA, in only one of which we had the opportunity to analyze genomic DNA of both parents (Ikeuchi et al, 1995a). The patient had generalized epilepsy at the age of 26, and began exhibiting ataxia and involuntary movements such as choreoathetosis at the age of 37.…”

Clinical Reasoning: A case of ataxia, seizure, and choreoathetosis in a 34-year-old woman

“…A much larger intergenerational increase was observed for paternal transmission (5.8 6 0.9 repeat units/generation) compared to maternal transmission (1.3 6 1.6 repeat units/generation). [5][6][7][8] More prominent genetic anticipation (26-29 years/ generation) due to paternal transmission was revealed, compared to maternal transmission (14-15 years/ generation). 1 If any family member is known to have DRPLA, genetic analysis for the disease could be part of the necessary prenatal testing in pregnancy.…”