Careful comparison of symptomatic individuals with normal controls has revealed the primary biochemical abnormality in many human genetic diseases, particularly recessive disorders. This strategy has proved less successful for most human disorders which are not recessive, and where a single copy of the aberrant gene has clinically significant effects even though the normal gene product is present. An alternative approach that eliminates the impediment of a normal protein in affected individuals is to study homozygotes for the mutant allele. For virtually all dominant human disorders in which homozygotes have been described, symptoms have been significantly more severe in the homozygote than in the heterozygote. Thus, these disorders do not conform to the classical definition of dominance which states that homozygotes and heterozygotes for a defect are phenotypically indistinguishable. Instead, they display incomplete dominance, indicating that the normal allele may play a role in ameliorating the disease process. The D4S10 locus, defined by the probe G8 and linked to the gene for Huntington's disease (HD), has permitted us to identify individuals with a high probability of being homozygous for this autosomal dominant neurodegenerative disorder. These homozygotes do not differ in clinical expression or course from typical HD heterozygotes. HD appears to be the first human disease of genetically documented homozygosity that displays complete phenotypic dominance.

Fifteen drug-free patients with early to midstage Huntington's disease were evaluated with quantitative neurological examinations, scales for functional capacity, computed tomographic (CT) scans, and positron emission tomographic (PET) scans of 18F-2-fluoro-2-deoxyglucose (18F-FDG) uptake. All patients had abnormal indices of caudate metabolism on PET scanning, whereas in patients with early disease indices of putamen metabolism and CT measures of caudate atrophy were normal. Indices of caudate metabolism correlated highly with the patients' overall functional capacity (r = 0.906; p less than 0.001) and bradykinesia/rigidity (r = -0.692; p less than 0.01). Indices of putamen metabolism correlated highly with motor functions: chorea (r = -0.841; p less than 0.01), oculomotor abnormalities (r = -0.849; p less than 0.01), and fine motor coordination (r = -0.866; p less than 0.01). Indices of thalamic metabolism correlated positively with dystonia (r = 0.559; p less than 0.05). The data suggest that PET scanning with 18F-FDG is a sensitive measure of brain dysfunction in Huntington's disease and that basal ganglia metabolism is highly correlated with the overall functional capacity of individual patients and with the degree of their motor abnormalities.

Human gliomas were imaged in vivo using ligands for the peripheral-type benzodiazepine binding site ( A technique for imaging the extent and viability of a ghoma without depending on abnormal permeability of the blood-brain barrier would be of great value in the diagnosis and management of tumor. At present the diagnosis and treatment of gliomas rely primarily on x-ray computed tomography (CT) and magnetic resonance imaging (MRI). The contrast enhancement typically present in high-grade gliomas with CT or MRI and contrast agents delineates a region of increased permeability of the blood-brain barrier that correlates well with the solid tumor mass {l-61. However, CT is often unsatisfactory for demonstrating tumor regions with normal permeability of the bloodbrain barrier, including most low-grade gliomas and the infiltrating portions of high-grade gliomas 11-47.MRI reveals a more extensive abnormality than CT but cannot reliably distinguish tumor from peritumoral edema C4-77. Neither technique can accurately differentiate gliomas from other tumors such as brain metastases, and neither can distinguish viable tumor from largely necrotic tumor 17, 8).A promising approach to imaging gliomas employs radiolabeled ligands for the peripheral-type benzodiazepine binding site (PBBS), also known as the 0 3 binding site (9). The "peripheral" notation indicates that this site is normally present in highest density in certain tissues outside the central nervous system (CNS) including the adrenal gland, lung, kidney, heart, and skin {lo]. Selective ligands for the PBBS include the benzodiazepine Ro5-4864 and the isoquinoline derivative PK 11 195, while nonselective ligands including the benzodiazepine flunitrazepm bind to the PBBS but also to central benzodiazepine receptors. The PBBS is present in low density in the normal brain and is thought to be located primarily on glia rather than on neurons { 1 1-14).Several studies indicate that the PBBS is present on gliomas in high density. Specific binding to the PBBS is greatly increased in C6 rat gliomas and U87 human gliomas implanted in rat brains and studied in vitro and in vivo [lo]. In vivo accumulation of PBBS ligands in gllomas in rats can be blocked with unlabeled ligand,

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Article abstract-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. The HD population of Venezuela is unique for several reasons: (1) clinical features can be studied prospectively in a nonmobile, ascertained cohort; (2) there is a large affected kinship, with a single allelic determinant,2.3 minimizing the impact of genetic heterogeneity and providing a measure of clinical heterogeneity; (3) the disorder is seen in a nonmedicated population, not influenced by neuroleptic-induced motor or behavioral changes; and (4) there are uniform environmental influences including climate, nutrition, social milieu, and health care.As a part of a genetic linkage study? we have made a systematic and prospective clinical evaluation of the Venezuelan HD community whose members live in clusters along the western shores of Lake Maracaibo (figure 1). We believe that a single gene-canying progenitor gave rise to this family, which includes many marriages between affected and possible carriers of the HD gene. The HD population in Venezuela was originally described by Drs. Americo Negretteg and Ramon Avila-Giron.'O Methods. The HD pedigree in Venezuela includes approximately 4,000 individuals from eight generation^.^.^ Two hundred ninety individuals have been examined in detail neurologically,2 including 225 individuals immediately at risk and 65 with clear clinical features of the disease.HD patients were evaluated by four neurologists (A.B.Y., I.S., J.B.P., S.S.R.) and one psychologist (N.W.). Evaluations included standardized ratings of chorea, dystonia, parkinsonism, oculomotor dysfunction, dysdiadochokinesia, dysarthria, and hyperreflexia.11J2 Scores ranged from 0 (completely normal) to 3 to 5 (very abnormal)(table 1). Functional capacity was rated by a standardized ~y s t e m .~.~, '~ Estimated age at onset of motor features and cognitive/behavioral profiles will be the subject of a separate report.Clinical evaluations were conducted annually each March between 1981 and 1984. Forty-seven patients were evaluated on at least two occasions a year apart.Results. Between 1981 and 1984,486 neurologic examinations were performed on 290 individuals, including 65 with motor evidence of HD, 207 with at least 50% risk for HD, and 18 with 25% risk (table 2). Diagnosis was based on unequivocal extrapyramidal motor signs of chorea, dystonia, or parkins~nism.~ Sixty-five people (33 men, 32 women; 40.7 f 1.7 yrs, mean k SEM) had