Repeat instability in the 27-39 CAG range of the HD gene in the Venezuelan kindreds: Counseling implications.

The instability of the CAG repeat size of the HD gene when transmitted intergenerationally has critical implications for genetic counseling practices. In particular, CAG repeats between 27 and 35 have been the subject of debate based on small samples. To address this issue, we analyzed allelic instability in the Venezuelan HD kindreds, the largest and most informative families ascertained for HD. We identified 647 transmissions. Our results indicate that repeats in the 27-35 CAG range are highly stable. Out of 69 transmitted alleles in this range, none expand into any penetrant ranges. Contrastingly, 14% of alleles transmitted from the incompletely penetrant range (36-39 CAGs) expand into the completely penetrant range, characterized by alleles with 40 or more CAG repeats. At least 12 of the 534 transmissions from the completely penetrant range contract into the incompletely penetrant range of 36-39 CAG repeats. In these kindreds, none of the individuals with 27-39 CAGs were symptomatic, even though they ranged in age from 11 to 82 years. We expect these findings to be helpful in updating genetic counseling practices.

Autoradiographic evidence for increased dopamine uptake sites in striatum of hypoxic mice.

Ligand binding to dopamine uptake sites, D1 and D2 dopamine receptors was measured autoradiographically in brain sections of mice exposed to intermittent hypobaric hypoxia (450 Torr; 4,300 m) for 14 days and compared to sea level controls. Desipramine-insensitive [3H]mazindol, [3H]SCH23390 and [3H]YM-09151-2 were used respectively for the labeling of the three binding sites. After 14 days, the striatum of hypoxic mice showed a significant 21% increase in dopamine uptake sites, one of the loci of action of cocaine. A similar (28%) but non-significant increase was found in the ventral tegmental area. No changes were seen in the activities of D1 or D2 receptors in several areas examined including the substantia nigra and the striatum.

Huntington's disease in Venezuela: 7 years of follow-up on symptomatic and asymptomatic individuals.

Persons symptomatic and at risk for Huntington's disease (HD) from a large extended family in the state of Zulia, Venezuela, have been followed prospectively for 7 years. Between 1981 and 1988, 593 people were examined, of whom 128 had symptomatic HD and 171 persons at risk had examination abnormalities that were insufficient to meet criteria for diagnosis. The remaining 294 had normal examinations. Abnormalities of saccadic eye movement and slowness of rapid alternating movements were the most common abnormalities found in at-risk individuals. Thirty persons who did not meet criteria for diagnosis at their first examination have subsequently been diagnosed with symptomatic HD. Their average age at diagnosis was 33.5 +/- 8.3 (SD) years. The likelihood of developing symptomatic HD within 3 years was 3% for those persons with normal first examinations, 23% for those with mildly abnormal first examinations, and 60% for those with highly abnormal first examinations. The rate of disease progression in early symptomatic cases were 1.4 +/- 0.1 (SEM) points per year on the Shoulson-Fahn functional capacity scale. Paternal or maternal inheritance did not appear to affect the rate of progression in this group of individuals. The data suggest that there is not a discrete age of onset but rather a prolonged period of time during which symptoms unfold.

Huntington's disease in Venezuela: neurologic features and functional decline.

We studied 65 Huntington's disease patients and 225 at-risk individuals over the past 4 years. The rate of decline of these untreated patients from Venezuela was similar to that seen in US patients who had received neuroleptic drugs. Chorea, oculomotor dysfunction, and dysdiadochokinesis were early symptoms; parkinsonian features and dystonia came later. Juvenile patients declined nearly twice as fast as adult-onset patients. No distinctive neurologic phenotypes were seen in children of two affected parents.