Dentatorubral–pallidoluysian atrophy

Abstract

Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder clinically characterized by various combinations of cerebellar ataxia, choreoathetosis, myoclonus, epilepsy, dementia, and psychiatric symptoms. The most striking clinical features of DRPLA are the considerable heterogeneity in clinical presentation, depending on the age of onset, and the prominent genetic anticipation. DRPLA is caused by unstable expansion of CAG repeats coding for polyglutamine stretches located in exon 5 of the DRPLA gene. DRPLA is characterized by prominent anticipation, with paternal transmission resulting in more prominent anticipation than does maternal transmission, which is now understood based on the intergenerational stability of the CAG repeats. DRPLA protein (also called atrophin-1) is localized in the nucleus and functions as a transcription co-regulator. Recent immunohistochemical studies on autopsied tissues of patients with DRPLA have demonstrated that diffuse accumulation of mutant DRPLA protein (atrophin-1) in the neuronal nuclei, rather than the formation of neuronal intranuclear inclusions (NIIs), is the predominant pathologic condition and involves a wide range of central nervous system regions far beyond the systems previously reported to be affected. Thus, age-dependent and CAG repeat-dependent intranuclear accumulation of mutant DRPLA leading to nuclear dysfunctions are suggested to be the essential pathophysiologic mechanisms in DRPLA.

Introduction

Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder clinically characterized by various combinations of cerebellar ataxia, choreoathetosis, myoclonus, epilepsy, dementia, and psychiatric symptoms (MIM #125370) (Naito and Oyanagi, 1982). The term DRPLA was originally used by Smith et al. to describe a neuropathological condition associated with severe neuronal loss, particularly in the dentatorubral and pallidoluysian systems of the central nervous system, in a sporadic case without a family history ( Smith et al., 1958, Smith, 1975). The hereditary form of DRPLA was first described in 1972 by Naito and his colleagues (Naito et al., 1972). Since then, a number of reports on Japanese pedigrees with similar clinical presentations have been published (Oyanagi and Naito, 1977, Tanaka et al., 1977, Hirayama et al., 1981, Iizuka et al., 1984, Suzuki et al., 1985, Iizuka and Hirayama, 1986, Akashi et al., 1987, Iwabuchi, 1987, Iwabuchi et al., 1987, Naito et al., 1987), and DRPLA has been established as a distinct disease entity.

The gene for DRPLA was discovered in 1994 and an unstable CAG trinucleotide repeat expansion in the protein-coding region of this gene was found to be the causative mutation for DRPLA (Koide et al., 1994, Nagafuchi et al., 1994a). To date, at least nine diseases have been found as being caused by expansion of CAG repeats coding for polyglutamine stretches; these include spinal and bulbar muscular atrophy (SBMA) (La Spada et al., 1991), Huntington's disease (HD) (Huntington's Disease Collaborative Research Group, 1993), spinocerebellar ataxia type 1 (SCA1) (Orr et al., 1993), DRPLA (Koide et al., 1994, Nagafuchi et al., 1994b), Machado–Joseph disease (also called SCA3) (Kawaguchi et al., 1994), SCA2 (Imbert et al., 1996, Pulst et al., 1996, Sanpei et al., 1996), SCA6 (Zhuchenko et al., 1997), SCA7 (David et al., 1997), and SCA17 (Nakamura et al., 2001).

In this chapter, the clinical and molecular genetic aspects of DRPLA are described. Recent progress in the study of the molecular mechanisms of neurodegeneration caused by expanded polyglutamine stretches is also discussed.