Familial parkinsonism and dementia with cortical and subcortical Lewy bodies is uncommon, and no genetic defect has been reported in the previously described sibships. We present a Spanish family with autosomal dominant parkinsonism, dementia, and visual hallucinations of variable severity. The postmortem examination showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to alpha-synuclein and ubiquitin in cortical and subcortical areas. Sequencing of the alpha-synuclein gene showed a novel, nonconservative E46K mutation in heterozygosis. The E46K mutation was present in all affected family members and in three young asymptomatic subjects, but it was absent in healthy and pathological controls. The novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a much conserved area of the protein, is likely to produce severe disturbance of protein function. Our data show that, in addition to the previously described hereditary alpha-synucleinopathies, dementia with Lewy bodies is related to mutation of alpha-synuclein.

Huntington's disease (HD) is characterized by the presence of hyperkinesias, but bradykinesia is also present in most patients. We studied the motor performance of 18 patients with genetically proven HD (age, 38.5 +/- 10 y; clinical stage, 1.7 +/- 1.7; (CAG) triplet length, 49.2 +/- 6.8 triplets; all but three patients were free from neuroleptics) and compared with a control group (n = 18) and with a typical Parkinson's disease (PD) group (n = 20). Motor study included the four timed tests commonly used for PD: Pronation-supination (PS), finger dexterity (FD), movement between two points (MTP) and walking test (WT). Tests were done at 9 AM. The PD group was studied in "off" condition, with no medication given for 12 hours. The HD group was slower than the controls on all tasks (all tests significant, p < 0.01, Mann-Whitney U test) and even slower than PD group (for FD, p < 0.05). A significant correlation was found between each test and clinical stage (for PS, r = 0.84; for FD, r = 0.75; for MTP, r = 087, and for WT, r = 0.77, Pearson). Severe bradykinesia was present in HD, and motor impairment is related to clinical stage.

Huntington's disease (HD) is characterized by the presence of movement disorders, cognitive decline and psychiatric disturbances. Recently, the gene responsible for HD has been found. As a result, a more direct test for HD is available. This may lead to a comprehensive approach to HD, since it is now possible to study HD patients without uncertainties in diagnosis. We carried out a clinical-genetic study on 45 patients with HD. We performed molecular analysis on 39 patients. All had an abnormal expansion of (CAG)n ranging from 41 to 90 triplets (mean 50.8 ± 11.5 S.D.). There was a strong inverse correlation between (CAG)n expansion and age at onset Gender of the affected parent influenced age at onset (p < 0.001) and number of triplets (p < 0.001). A significant impairment of akinesia (p < 0.001), chorea (p < 0.005), MMSE (p < 0.01) and Rey scores (p < 0.05) occurred across successive stages of functional disability. Hooper Visual Organization Test (HVOT) scores did not change significantly across stages, but this test was extremely useful to discriminate between patients at an early stage and controls. A significant correlation was found between functional disability and motor-cognitive decline; correlation was stronger for motor (akinesia, r = 0.77; chorea, r = 0.61) than for cognitive aspects (MMSE, r = - 0.54; Rey, r = - 0.51; HVOT, r = -0.35).

Oculomotor abnormalities have long been recognized in Huntington's disease (HD). The precise correlation between them and other clinical findings has not yet been determined. Using videonystagmography, we studied reflexive, visually guided horizontal saccades in 32 patients with genetically confirmed HD: nine female and 23 male patients, including six with young onset HD (YOHD), 19 with adult onset HD (AOD), and seven with late onset HD (LOHD). Huntington's patients exhibited increased saccade latency (P < 0.05), decreased saccade velocity (P < 0.0005), and impaired saccade accuracy (P < 0.01). A significant difference between the different groups of patients could be determined, and YOHD was characterized by normal latency and decreased saccade velocity while LOHD showed increased saccade latency but normal velocity. Furthermore, we found a significant difference between the genetic data (length of CAG-repeats) and saccadic abnormalities, with higher repeat numbers corresponding to shorter latency and decreased velocity, as in YOHD. The study of saccade parameters might be useful as an objective method for testing the effectiveness of future therapies.