Clinical features of early and juvenile onset in polyglutamine disorders other than Huntington’s disease: autosomal dominant cerebellar ataxias and dentatorubral pallidoluysian atrophy

André R. Troiano and Alexandra Dürr

in Juvenile Huntington's Disease

Published on behalf of Oxford University Press

Published in print January 2009 | ISBN: 9780199236121
Published online November 2012 | e-ISBN: 9780191753213 | DOI:
Clinical features of early and juvenile onset in polyglutamine disorders other than Huntington’s disease: autosomal dominant cerebellar ataxias and dentatorubral pallidoluysian atrophy

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Numerous conditions other than Huntington’s disease (HD) are currently known to arise from abnormal expansions in polyglutamine tracts, as a result of enlarged CAG repeats in the corresponding gene. These include: autosomal dominant cerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17 and dentatorubral pallidoluysian atrophy (DRPLA) (Table 8.1). The clinical presentation of these conditions is distinct from HD, with the exception of some cases of adult onset DRPLA and young onset SCA2. Most cases of SCA will present with cerebellar ataxia dominating the clinical picture, whereas in HD cerebellar signs are additional to chorea and behavioural/cognitive dysfunctions. Before the discovery of the genetic heterogeneity of autosomal dominant cerebellar ataxia, the precise classification of a SCA phenotype depended on the presence or absence of associated clinical clues, such as chorea, dystonia or parkinsonism, oculomotor disturbances, epilepsy, and visual changes. The description of the underlying mutations helped redefine the clinical aspects of each disease, besides enormously facilitatingtheir diagnosis. Furthermore, as the mutational basis of polyglutamine diseases is of a quantitative nature, it is possible to correlate the severity of symptoms with the extent of CAG repeat expansion: individuals with young disease onset almost invariably inherit long CAG repeats, with symptom onset at a younger age than the preceding generation and a more severe clinical presentation. The phenomenon, referred to as anticipation, results from meiotic instability during spermatogenesis and is therefore commonly related to paternal transmission. However, maternal transmission was shown to be associated to 25% of cases of anticipation in HD.The probability of receiving an expanded allele ultimately depends on the severity of meiotic instability during transmission, which is different for each gene. As an example, the increase of CAG repeats from one generation to another is less than one CAG repeat in SCA3/Machado–Joseph disease. On the other hand, in SCA7, there is an increase of a mean of 10 CAG repeats during transmission.

It is worth noticing that for most SCAs (with the exception of SCA6) the disease-related CAG stretch is usually between 35 and 40 repeats, indicating similar cellular mechanisms by which polyglutamine leads to degeneration. However, again as is well known for HD, the size of CAG repeat does not correlate entirely with disease severity and age at onset. The correlation of CAG repeat size vs. age at onset is weaker in SCA3—repeat size explains 45% of variance in age at onset—and stronger in SCA7—explaining 75% of variance. For SCA1, the correlation is 66% and for SCA2, 73%. This leaves room for numerous other elements that could be implicated in disease onset and progression, such as co-regulation by other genetic and environmental factors. The latter can be shared by a family or impinge randomly on at-risk individuals, thus further complicating the matter. Finally, phenotype does not depend only on the size of polyglutamine tracts but also where it is expressed and on the function of the wild-type protein, as mutated polyglutamine of similar sizes will lead to distinct topographical degeneration in HD (striatum) in comparison with the SCAs (cerebellum, brainstem, and spinal cord).

In this chapter we discuss clinical aspects of young onset polyglutamine disorders. Such presentations are often the result of unusually large CAG repeats, leading to significant biochemical changes, multisystemic disease, and atypical signs, particularly in infantile cases. Furthermore, the CAG repeat length substantially reduces the participation of other genetic and environmental factors.

It must be pointed out that there are pitfalls in detecting large expansions. An alternative method [polymerase chain reaction (PCR) blot assay] has been developed to identify CAG repeats that are too large to be detected by the usual techniques [i.e. PCR and denaturing polyacrylamide gel electrophoresis (PAGE)]. It is conceivable that this PCR blot assay applied to other very early onset SCAs could also uncover extremely large expansions, in contrast with the 200–230 CAG repeats that are detected within the limits of standard techniques. Therefore, a discussion with the laboratory undertaking molecular analysis is required in cases where there is clinical suspicion that the patient has juvenile onset of a polyglutamine repeat expansion disorder.

No specific treatment is known for any of these disorders, expect for supportive therapy, treatment of associated problems (e.g. epilepsy), and physical therapy. We will not describe SCA6 and spinal bulbar muscular atrophy (SBMA), as, to the best of our knowledge, there are no reports of young onset cases of these diseases.

Chapter.  5333 words. 

Subjects: Neurology

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