Dentatorubropallidoluysian Atrophy

71.1 Clinical Features

and Laboratory Investigations Dentatorubropallidoluysian atrophy (DRPLA) is a rare disease with an autosomal dominant mode of inheritance. The disease has a pronounced ethnic predilection and occurs most frequently in Japan.

However, an increasing number of American and Eu- ropean patients have been described. Although spo- radic cases have been reported, nearly all cases are fa- milial with two or more successive generations affect- ed. There is evidence of anticipation: in the next gen- eration the disease tends to have an earlier onset and be more severe.

The presenting symptoms are a variable mixture of cerebellar ataxia, myoclonus, epilepsy, choreoatheto- sis, dementia, and psychiatric abnormalities. The age at onset ranges from the first to the sixth decade, with an average age of 32 years. In the early-onset forms progressive myoclonic epilepsy and dementia are the predominant symptoms, whereas in the patients with later onset progressive cerebellar ataxia and choreo- athetosis are more prominent. Among the older pa- tients two clinical presentations can be distinguished:

a pseudo-Huntington form with prominent choreoa- thetosis, cognitive dysfunction, and psychiatric syn- dromes, and a form with progressive ataxia with less severe cognitive impairment.

In the younger group of patients, DRPLA has to be distinguished from other diseases with progressive myoclonic epilepsy, such as neuronal ceroid lipofusci- nosis, sialidosis, myoclonus epilepsy with red ragged fibers (MERRF), and Unverricht disease. In the older patients DRPLA has to be distinguished from Hunt- ington disease, which may have a very similar clinical presentation. Laboratory investigations are unreveal- ing in DRPLA, but DNA confirmation is possible.

71.2 Pathology

There are some variations in the histopathological findings between different families. Most data on histopathology in DPRLA come from Japanese pa- tients, in whom histopathological findings are the most uniform. On gross inspection there may be some atrophy of the base of the pons and the cerebel- lar vermis. The principal histopathological alter- ations consist of severe neuronal cell loss and astrocy-

tosis in the globus pallidus, subthalamic nucleus, red nucleus, and dentate nucleus. Mild changes occur in the caudate nucleus, putamen, thalamus, and inferior olives. There is only subtle involvement of the sub- stantia nigra. The superior cerebellar peduncles, con- taining the outflow tracts of the dentate nuclei, are at- rophic. The base of the pons and the tegmentum of the midbrain and pons display variable atrophy.

Unlike findings in other dementias, there is no signif- icant cell loss in the nucleus basalis of Meynert.

Immunohistochemistry demonstrates the presence of ubiquin-positive intranuclear aggregates in neu- rons and also astroglia. In addition, filamentous ubiquinated intracytoplasmic inclusions may be found in neurons of affected structures.

In younger patients patchy periventricular white matter abnormalities are found, whereas in older pa- tients the white matter abnormalities are more con- fluent and symmetrical, and affect the deep white matter of the centrum semiovale. Microscopy reveals gliosis and demyelination in the affected areas. Occa- sionally the cerebellar white matter is involved. In- tranuclear aggregates have been demonstrated in oligodendrocytes within the affected white matter.

Spinal cord involvement has been reported, with degeneration of the posterior columns, spinocerebel- lar tracts, corticospinal tracts, and anterior horn cells.

In the Haw River variant of the disease, marked neuronal loss of the dentate nuclei, microcalcification of the globus pallidus, neuroaxonal dystrophy of the nucleus gracilis, and demyelination of the centrum semiovale have been found.

71.3 Pathogenetic Considerations

DRPLA is caused by an unstable expansion of a cyto- sine-adenine-guanine (CAG) repeat in the gene DRPLA, located on chromosome 12p13.31. The prod- uct of DRPLA is atrophin-1, a protein that is widely expressed in many tissues including the brain. It shares no homology with other known proteins. Ex- pansion of the CAG repeat in the DRPLA gene in nor- mal subjects ranges from 10 to 21, in patients from 58 to 82. No overlap has been reported between nor- mal alleles and mutant alleles.

In the brain atrophin-1 is located in the cytoplasm of neurons. In DPRLA subjects both expanded and normal alleles are detectable in the brain, with re-

Dentatorubropallidoluysian Atrophy

gional variation. Atrophin-1 has been immunocyto- chemically localized to somatic and somatodendritic compartments of cortical and cerebellar neurons. In the cerebellum the protein is especially abundant in Purkinje cells and neurons of the dentate nucleus.

The unstable CAG repeat encodes for a polygluta- mine repeat. Polyglutamine repeats also occur in my- otonic dystrophy, fragile X syndromes, spinobulbar muscular atrophy (Kennedy disease), Huntington dis- ease, spinocerebellar ataxia type 1 (SCA1), spinocere- bellar ataxia type 2 (SCA2), Machado–Joseph disease (SCA3) and spinocerebellar ataxia type 7 (SCA7). The number of repeats clearly influences the phenotypic expression. As in other trinucleotide repeat syn- dromes, the number of repeats increases with succes- sive generations. This leads to an earlier onset and worsening of the phenotype in every following gener- ation, a phenomenon referred to as “anticipation.” In the patients presenting with progressive myoclonic epilepsy end dementia (early presentation) the num- ber of repeats is much higher than in the patients without the progressive myoclonic epilepsy (late pre- sentation).

The molecular basis for the selective neuronal damage in dentatorubropallidoluysian atrophy is not yet fully understood. Misfolding and conformational alterations of the mutant protein due to polygluta- mine expansion may lead to aberrant protein–protein interactions and targeting of the misfolded proteins for degradation. Ubiquination of proteins in the ag- gregates indicates targeting for degradation. Protein aggregation is probably a critical molecular compo- nent of polyglutamine diseases. These aggregates are present as nuclear inclusions in the neurons selective- ly affected by the disease. Transglutaminases appear to play a role in the formation of the protein aggre- gates. Transglutaminases are a large family of pro- teins with the common capacity to catalyze cross- linking of protein substrates, resulting in the forma- tion of large protein aggregates that are insoluble to all known protein detergents. These aggregates may contribute to neuronal dysfunction and degenera- tion. It may also be that mutant proteins are most tox- ic when roaming freely and that the aggregates repre- sent the cell’s effort to convert the toxic proteins into more innocuous clumps. The differences in clinical expression and cell specificity of the affected neurons in the different polyglutamine disorders could be re- lated to different factors, including the cellular distri- bution of the polyglutamine protein, protein interac- tors, and cell specificity of certain modifying pro- teins. The latter group may include cell-specific trans- glutaminases and cysteine proteases.

Nuclear inclusions were previously considered to be a feature specific to neuronal degenerative dis-

eases, but recently histopathological studies have shown nuclear inclusions in oligodendrocytes of DRPLA patients as well. In transgenic DRPLA mice, too, oligodendrocytes demonstrated the same inclu- sions. Apparently not only neurons but also glial cells are affected in DRPLA. It is probable that oligoden- droglial involvement is responsible for the white matter abnormalities that may be observed in DRPLA patients.

71.4 Therapy

No causal treatment is available, but symptomatic care is important. Anticonvulsants should be used when seizures are present. Psychiatric problems can be treated with appropriate psychotropic medications.

71.5 Magnetic Resonance Imaging

Standard sequences usually suffice to make an inven- tory of the abnormalities in DPRLA. Sophisticated techniques as diffusion tensor imaging may be useful to identify involved tracts, as may be fiber tracking.

Gradient echo techniques may be useful in the detec- tion of calcifications.

The characteristic findings on conventional MR include atrophy of the tegmentum of the midbrain, pons, dentate nucleus, superior cerebellar peduncles, and cerebellum (Figs. 71.1 and 71.2). The lateral ventricles show moderate to severe enlargement and commonly there is moderate but clear cortical atro- phy. The globus pallidus and subthalamic nucleus are usually either normal or slightly atrophic on MRI.

High signal intensity of the globus pallidus on pro- ton-density and T

-weighted images is often present from early on (Figs. 71.1–71.3). Bilateral symmetric signal changes in the thalamus and abnormal signal intensity in the midbrain and pons are characteristic (Figs. 71.1–71.3). The red nucleus characteristically has normal signal (Fig. 71.2). In older patients there is an increase of lesions in the midbrain and thalamus.

Although not invariable, white matter abnormali- ties are characteristically present in patients with DRPLA. In younger patients patchy periventricular areas with high signal intensity may be found on T

- weighted, proton-density, and FLAIR images. Conflu- ent white matter abnormalities are found in older pa- tients with a diffuse increase in signal in the periven- tricular and deep white matter, only sparing most of the U fibers (Figs. 71.1–71.3). The pattern of cerebral white matter abnormalities in combination with sig- nal changes in the globus pallidus, thalamus, and brain stem is typical of an advanced stage of DRPLA.

71.5 Magnetic Resonance Imaging 531

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Fig. 71.1. A 73-year-old female patient with DRPLA. The mid- brain, pons, and cerebellum are atrophic. There is also some cerebral atrophy. There are diffuse signal abnormalities in the cerebral hemispheric white matter with partial sparing of the

U fibers and the corpus callosum. Note the signal abnormali-

ties in the globus pallidus, thalamus, midbrain, and pons. From

Uyama et al. (1995), with permission

71.5 Magnetic Resonance Imaging 533

Fig. 71.2. A 60-year-old female patient with DRPLA.The sagit- tal and axial FLAIR images reveal extensive signal abnormali- ties in the cerebral white matter with partial sparing of the U fibers. The inner rim of the corpus callosum shows an abnor- mal signal. There are additional signal abnormalities in the

caudate nucleus, globus pallidus, putamen, thalamus, mid- brain, tegmentum of the pons, and dorsal part of the medulla.

The red nuclei are spared. Note the atrophy of the cerebellum, pons and superior cerebellar peduncles. From Yoshii et al.

(1998), with permission

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Fig. 71.3. A 68-year-old female patient with DRPLA. Note the evident pontine and cerebellar atrophy. There are extensive cerebral white matter abnormalities, sparing the corpus callo-

sum and some of the U fibers. There are also signal abnormal-

ities in the globus pallidus, thalamus, midbrain, and pons. From

Uyama et al. (1995), with permission