Clinical Aspects of CAG Repeat Diseases

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Abstract
Seven neurodegenerative disorders are known to be caused by unstable expansions of the trinucleotide CAG within human genes, and more will be discovered in the coming years. These disorders share some clinical similarities, as well as some differences, which are summarized here. These diseases have unusual clinical genetic properties related to the dynamic nature of CAG repeat expansions, including instability of the repeat expansion in meiosis, particularly male meiosis; a strong correlation between onset age and size of the repeat expansion; anticipation (earlier disease onset in succeeding generations); new mutations arising from unstable, mutable alleles with a high‐normal CAG repeat number; and reduced penetrance for alleles in the lowaffected range. Much more remains to be learned about the molecular biology and clinical pathophysiology of this new class of genetic diseases. Summary In the last six years, seven neurodegenerative diseases have been found to be caused by expansions of intragenic CAG repeat sequences. The diseases share a variable (usually adult) age of onset, which is highly dependent on the length of the CAG repeat, and effects on multiple systems within the central and peripheral nervous systems. The cerebral cortex is not a primary site of pathology for any of the diseases, and organs other than the nervous system are not primarily affected (except for SBMA). The diseases differ in their primary site of neuropathology, and for that reason have widely varying neurologic profiles. The distributions of normal and abnormal CAG repeat sizes vary among the diseases, and suggest that different mechanisms of mutagenesis or disease pathogenesis could exist for the different disorders. The dynamic nature of trinucleotide repeat mutations has clarified a number of clinical and genetic observations in these diseases. New mutations arising from mutable normal alleles have been reported for some of the diseases. The tendency to further expansion of an expanded allele provides a molecular correlate to the clinical observation of anticipation (171). Sex‐ and disease‐dependent meiotic instability correlates with the observation of a paternal bias among juvenile onset cases for HD, SCA1 and DRPLA. Finally, reduced penetrance for alleles at the low end of the abnormal range has been observed for some (but not all) diseases in the group. Detection of CAG repeat expansions is relatively easy and inexpensive in the clinical laboratory, and molecular diagnosis has greatly improved diagnostic accuracy for this group of disorders. However, a full understanding of the biology and pathophysiology of this new class of mutations is still to come, and is awaited eagerly by clinicians and patients alike.

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