Linkage to the Huntington's disease locus in a family with unusual clinical and pathological features

We used the anonymous DNA probe, D4S10 (G8), known to be linked to the Huntington's disease (HD) locus, to confirm inheritance at that locus in a family in whom most affected individuals had atypical clinical and pathological features. Their clinical features were similar to the Westphal variant (usually seen in juvenile-onset HD) but they had onset in adult life, and in contrast to juvenile-onset HD, their course of illness was prolonged. Most family members had been repeatedly misdiagnosed during life because of the absence of chorea and prominence of long-tract signs. In 2 patients who died, neuropathological examination at autopsy revealed prominent involvement of brainstem and spinal cord structures, and in 1, mild neostriatal atrophy relative to duration of the disease. The study demonstrates the usefulness of genetic linkage analysis as a diagnostic tool in families with atypical forms of HD. This method allows study of phenotypic variations that can be inherited at or near the HD locus and implies either multiple alleles at the locus gene, modifiers of a single allele, or another locus in the same region causing a dominantly inherited neurodegenerative disease.