Trinucleotide repeat length instability and age of onset in Huntington's disease.

The initial observation of an expanded and unstable trinucleotide repeat in the Huntington's disease gene has now been confirmed and extended in 150 independent Huntington's disease families. HD chromosomes contained 37-86 repeat units, whereas normal chromosomes displayed 11-34 repeats. The HD repeat length was inversely correlated with the age of onset of the disorder. The HD repeat was unstable in more than 80% of meiotic transmissions showing both increases and decreases in size with the largest increases occurring in paternal transmissions. The targeting of spermatogenesis as a particular source of repeat instability is reflected in the repeat distribution of HD sperm DNA. The analysis of the length and instability of individual repeats in members of these families has profound implications for presymptomatic diagnosis.

Huntington's disease: two families with differing clinical features show linkage to the G8 probe.

To test the hypothesis that interfamily variability in Huntington's Disease (HD) is due to mutation at different loci, linkage analysis was undertaken in two large HD kindreds that differed in ethnicity, age-at-onset, and neurologic and psychiatric features. Both families showed linkage of the HD locus to the G8 probe. Several recombinants were documented in each family, and the best estimate of the recombination fraction for the two families was 6 percent with a 95 percent confidence interval of 0 to 12 percent. Although the data support the existence of a single HD locus, use of the G8 probe for presymptomatic testing in these kindreds would have resulted in a 12 percent error rate in genotype assignment at the HD locus.

Early loss of neostriatal striosome neurons in Huntington's disease.

During the first years of symptomatic Huntington's disease (HD), no readily apparent pathology is seen in the neostriatum at autopsy. To investigate the pathological correlates of chorea and other early clinical signs, we examined the evolution of neuronal loss and accompanying astrocytosis in neostriatal tissue from autopsy cases of early HD. We found scattered islands of astrocytosis and neuronal loss that were present before the previously described ventrally progressive wave of generalized neuronal loss. Histological demonstration of these islands, which are apparently specific to HD, is very helpful in the pathological differential diagnosis of this disease. Immunocytochemical stains for glial fibrillary acidic protein and for markers of the neostriatal striosome-matrix system showed that these islands correspond to the striosome compartment. Striosomal neuronal loss was present throughout the dorsoventral extent of the caudate nucleus and putamen during the early phase of symptomatic disease, and this loss extended to the most ventral region of the nucleus accumbens in later stages. Analysis of the functional circuitry of the basal ganglia suggests that early degeneration of striosomal neurons may produce hyperactivity of the nigrostriatal dopaminergic pathway, causing chorea and other early clinical manifestations of HD.

Magnetic resonance imaging in autism: measurement of the cerebellum, pons, and fourth ventricle.

Magnetic resonance imaging (MRI) research has suggested that autistic individuals have hypoplasia of cerebellar lobules VI and VII, the pons, and enlargement of the fourth ventricle. Using MRI we measured the mid-sagittal area of these structures in 15 high-functioning autistic males; 15 age- and IQ-comparable male volunteers (control group I); and 15 male volunteers comparable to cases on age and parental socioeconomic status (SES) (control group II). Using ratio measures, cerebellar lobules VI-VII were found to be smaller in autistic subjects than controls in group II but not those in group I. No differences were found after multivariate analysis adjusting for mid-sagittal brain area (MSBA), age, and IQ. The size of the pons and fourth ventricle did not differ between cases and controls, although autistic subjects were noted to have a significantly larger MSBA than subjects in either control group.

Assessment of lineality in bipolar I linkage studies.

OBJECTIVE: To assess lineality in families of bipolar I probands, the authors used direct interviews of family members to reclassify families initially categorized as unilineal by family history. METHOD: The families of 1,800 treated bipolar I probands were screened by the family history method with multiple informants. If the proband had one or more affected sibs and one apparently unaffected parent, the parents (and then other available first- and second-degree relatives) were directly interviewed by psychiatrists. RESULTS: Of the 1,800 families screened, 56 were apparently suitable unilineal families with multiple affected members; 46 families were interviewed directly. After interviews with the parents, 12 families (26.1%) were found to be bilineal. Direct interviews of all available relatives in the 34 remaining families revealed that only 22 (47.8% of the 46 interviewed families) were unilineal or probably unilineal and 12 were probably bilineal. The probably bilineal families had a significantly higher proportion of siblings with unipolar disorder. In addition, the affected sibs from the probably bilineal families tended to have earlier onsets but had significantly fewer symptoms in the most severe depressive episode. CONCLUSIONS: Fewer than 50% of bipolar I families appearing unilineal according to family history were found to be unilineal by direct interviews. The phenotypic differences between the affected sibs from the probably bilineal families and those from the unilineal and probably unilineal families suggest differences in genetic mechanisms. These findings highlight the need to systematically assess lineality in all families considered for bipolar I linkage studies and support the preferential inclusion of unilineal families in linkage studies.

Magnetic resonance imaging evidence for a defect of cerebral cortical development in autism.

Magnetic resonance imaging (MRI) scans were performed on 13 high-functioning male autistic subjects and 13 male nonautistic control subjects comparable in age and nonverbal IQ. Scans were rated for the presence of cerebral cortical malformations. Five autistic subjects had polymicrogyria, one had schizencephaly and macrogyria, and one had macrogyria. None of the control subjects had abnormalities of this type. These abnormalities result from a defect in the migration of neurons to the cerebral cortex during the first 6 months of gestation. The detection of these malformations by MRI, their pathogenesis, and the implications regarding the pathogenesis of autism are discussed.

Bipolar II: the most common bipolar phenotype?

OBJECTIVE: The purpose of this study was to compare the pattern of affective psychopathology in families ascertained for genetic linkage studies through bipolar I probands to that in families ascertained through bipolar II probands. METHOD: All available first-degree relatives (N = 266) of 48 bipolar I and eight bipolar II probands were interviewed with the Schedule for Affective Disorders and Schizophrenia--Lifetime Version by one of two psychiatrists who had attained high interrater reliability for bipolar II disorder and other diagnoses. RESULTS: Bipolar II disorder was the most common affective disorder in both family sets. Forty percent of the 47 first-degree relatives of the bipolar II probands and 22% of the 219 first-degree relatives of the bipolar I probands were diagnosed with bipolar II disorder. On the other hand, only one bipolar I relative was found in the bipolar II families. CONCLUSIONS: Bipolar II disorder was the most prevalent affected phenotype in both bipolar I and bipolar II families and was the only expressed phenotype in half of the bipolar II families. This suggests that bipolar II disorder is genetically related to but less complex than bipolar I disorder. Accurate diagnosis of bipolar II disorder may be crucial in finding the genetic loci underlying bipolar disorders generally.

Trial of d-alpha-tocopherol in Huntington's disease.

OBJECTIVE: Evidence suggests that the neuropathology of Huntington's disease, a neuropsychiatric disorder due to a mutation on chromosome 4, results from excessive activation of glutamate-gated ion channels, which kills neurons by oxidative stress. Therefore, the authors hypothesized that alpha-tocopherol, which reduces oxyradical damage to cell membranes, might slow the course of Huntington's disease. METHOD: A prospective, double-blind; placebo-controlled study of high-dose d-alpha-tocopherol treatment was carried out with a cohort of 73 patients with Huntington's disease who were randomly assigned to either d-alpha-tocopherol or placebo. Patients were monitored for changes in neurologic and neuropsychologic symptoms. RESULTS: Treatment with d-alpha-tocopherol had no effect on neurologic and neuropsychiatric symptoms in the treatment group overall. However, post hoc analysis revealed a significant selective therapeutic effect on neurologic symptoms for patients early in the course of the disorder. CONCLUSIONS: Antioxidant therapy may slow the rate of motor decline early in the course of Huntington's disease.

Unimpaired verbal memory and oculomotor control in asymptomatic adults with the genetic marker for Huntington's disease.

OBJECTIVE: To determine whether asymptomatic individuals at very high genetic risk for Huntington's disease (HD) have demonstrable cognitive or oculomotor abnormalities. DESIGN: A case-control study was employed. Presence of the chromosome-4 DNA marker linked to the HD phenotype was the criterion for HD risk. SETTING: The Baltimore Huntington's Disease Project Presymptomatic Testing Program at The Johns Hopkins University School of Medicine, Baltimore, Md. PARTICIPANTS: Seventy-six asymptomatic adults at risk for HD, voluntarily enrolled for genetic testing, and determined by clinical examination to be free of major psychiatric disorder or evidence of HD. Twenty were determined to be at greater than or equal to 95% risk for HD; 56 were at less than or equal to 5% risk [corrected]. MEASURES: The Hopkins Verbal Learning Test was used to assess verbal learning and memory. Oculomotor functioning was assessed using Novel-Stimulus, Mirror-Stimulus, and Predictive-Saccade paradigms. Outcome measures included number of correctly recalled words, recognition accuracy, and response bias, as well as saccade latency and number of errors on the Mirror-Stimulus Test. RESULTS: With one exception, all participants performed within the normal range on the Hopkins Verbal Learning Test. In a blind follow-up examination of the individual who performed aberrantly on the Hopkins Verbal Learning Test, she exhibited neurologic and psychiatric changes sufficient for a clinical diagnosis of HD. There were no group differences on the tests of oculomotor functioning. CONCLUSIONS: Young, asymptomatic adults at very high genetic risk for HD are unimpaired in tests of verbal learning and memory and oculomotor functioning.

Locus coeruleus involvement in Huntington's disease.

Numbers and areas of neuronal profiles from sections of brain stem at specific anatomic levels of the locus coeruleus and the dorsal raphe nucleus were measured in 33 patients with Huntington's disease and in 23 age-matched control subjects. Results from the Huntington's disease cases were correlated with severity of neostriatal atrophy and with systematically collected quantitative clinical data. Among the patients with Huntington's disease, lower locus coeruleus neuronal counts, reduced neuronal areas, and reduced locus coeruleus length (distance between rostral and caudal levels) were associated with features of advanced disease, including severity of neostriatal atrophy, severity of dementia, duration of illness, and severity of motor impairment and activities of daily living impairment. By contrast, there was no evidence of neuronal pathology within the dorsal raphe nucleus in Huntington's disease. Pathologic changes in the locus coeruleus may relate to some of the clinical manifestations of Huntington's disease.

Single photon emission computed tomographic blood flow and magnetic resonance volume imaging of basal ganglia in Huntington's disease.

OBJECTIVE: To examine basal ganglia dysfunction and atrophy in patients with mild to moderate Huntington's disease, with correlation of imaging measures with clinical and neuropsychological measures. DESIGN: Survey study in patients with Huntington's disease and matched controls, with imaging measures being evaluated by investigators unaware of the diagnosis. SETTING: Baltimore Huntington's Disease Project, The Johns Hopkins Hospital, Baltimore, Md. PATIENTS AND OTHER PARTICIPANTS: Subjects included 10 patients with mild to moderate Huntington's disease and nine healthy age-matched control subjects. MAIN OUTCOME MEASURES: Imaging measures included single photon emission computed tomographic regional cerebral blood flow in caudate, putamen, and thalamus, and magnetic resonance imaging measures of caudate and putamen volumes and bicaudate ratios. Patients underwent neurologic and mental status examinations and neuropsychological tests. RESULTS: The measure with the greatest difference between patients and control subjects was mean putamen volume, reduced 54.3% in patients, with no overlap between groups (P<.001). Of the cerebral blood flow measures, caudate showed the greatest difference (21.5% decrease; P<.001). Quantitative neurologic indexes of disease severity correlated with both putamen measures (P<.03), while Mini-Mental State Examination scores correlated with caudate volume (P<.02). Bicaudate ratio correlated with both clinical measures and was the best index of neurologic deterioration (r=.95; P<.001), while global atrophy (measured by cerebrospinal fluid percentage) was the best correlate of several neuropsychological tests, such as the Trail Making Test (r=93; P<.001). CONCLUSIONS: Volumetric measurement of putamen best discriminated patients with Huntington's disease from healthy subjects. Measures of caudate atrophy or single photon emission computed tomographic measures performed less well. Neurologic decline correlated best with subcortical atrophy measured by the bicaudate ratio, but neuropsychological performance best corresponded to cerebrospinal fluid percentage, a measure of global atrophy.

Postural stability in patients with Huntington's disease.

We characterized postural stability in patients with Huntington's disease (HD) by examining their ability to use different sensory cues to maintain balance and by recording their automatic postural responses to externally applied perturbations. Our HD patients, like normal subjects, depended more on proprioceptive than on visual cues to maintain balance. HD patients, however, developed more sway than normal subjects when proprioceptive cues, or when proprioceptive cues and vision, were altered. Thus, HD patients showed a defect in using vestibular information alone to maintain normal postural stability. The onset of compensatory motor responses in the lower extremities following sudden translations of the support surface was delayed by 30 to 60 msec in HD patients as compared with normal subjects. HD patients also had more sway and falls during unexpected rotations of the support surface, although they could appropriately reduce their motor responses on the next trial.

Saccades in Huntington's disease: slowing and dysmetria.

Eye movements were recorded from 20 mildly affected patients with Huntington's disease (HD) who were divided into two groups, 10 patients with onset of symptoms before age 30 and 10 with onset of symptoms after age 30. In the younger onset group (HD less than 30), peak saccade velocities were low (less than 255 deg/sec for 20-deg saccades) in six of the 10 patients, whereas none of the 10 patients in the older onset group (HD greater than 30) had peak saccade velocities lower than 300 deg/sec. Latencies for volitional saccades were greater than normal in the HD greater than 30 group, but were normal for the HD less than 30 group. The ability to maintain steady fixation in the face of a distracting visual stimulus was decreased, to the same degree, in both groups of HD patients. In addition, 70% of the HD less than 30 group had an affected father, while 70% of the HD greater than 30 group had an affected mother. These findings suggest that the pathophysiology of the slow saccades, initiation deficit, and excessive distractibility in HD are different.

Abnormal ocular motor control in Huntington's disease.

We studied eye movements in 50 patients with Huntington's disease. Fixation was impaired in 73% of patients; such individuals had difficulty in suppressing saccades toward novel visual stimuli. Impaired initiation of saccades was manifest by increased reaction time (89%) and inability to make a saccade without head movement (89%) or blink (35%). Saccades and quick phases of nystagmus were slowed in 62%. Smooth pursuit was abnormal in 60%, and vergence in 33%. The vestibulo-ocular reflex and the ability to hold eccentric gaze were preserved even late in the disease.

Saccades in Huntington's disease: predictive tracking and interaction between release of fixation and initiation of saccades.

We compared saccadic eye movements in 21 patients with Huntington's disease (HD) and 21 normal subjects. In a predictive tracking task, HD patients were unable to anticipate normally the timing and location of a visual target that alternated its position predictably (+/- 10 degrees, 0.5 Hz; mean latency of +170 msec in HD and -78 msec in normal subjects). HD patients and normal subjects, however, showed comparable decreases in saccade latency (110 msec in HD, 124 msec in normal subjects) when the fixation target was turned off 200 msec before (gap task) versus 200 msec after (overlap task) the appearance of an unexpected peripheral stimulus. Taken together, these findings support the idea that HD patients show greater defects in initiating internally generated than in initiating externally triggered saccades. This dichotomy is likely due to involvement of frontal lobe--basal ganglia structures in HD, with relative sparing of parietal--superior collicular pathways.

Saccades in Huntington's disease: initiation defects and distractibility.

We recorded saccadic eye movements in patients mildly affected with Huntington's disease. Most showed an increase in saccade latencies that was greater for saccades made on command than to the sudden appearance of a visual target. All patients showed excessive distractibility during attempted fixation. They had particular difficulty suppressing a saccade to a suddenly appearing visual target when simultaneously trying to initiate a saccade in the opposite direction. Our results are compatible with a posited role of the basal ganglia in both the initiation of volitional saccades and in the maintenance of fixation. Saccade abnormalities--especially distractibility--are sensitive but probably not specific indicators of Huntington's disease.

The diagnosis of Huntington's disease.

We investigated all patients in Maryland reported to have Huntington's disease (HD), and found considerable diagnostic inaccuracy. Fifteen percent of cases reported as HD actually had some other diagnosable condition; 11% of cases that met diagnostic criteria for HD had been given some other diagnosis. Diagnostic errors could be reduced by documentation of the family history by systematic interviewing of relatives and by demonstration of the characteristic disorder of voluntary movement in addition to chorea.

The nucleus basalis in Huntington's disease.

The nucleus basalis of Meynert (nbM) provides most of the cholinergic input to the cerebral cortex. The loss of cortical choline acetyltransferase (CAT) activity in Alzheimer's disease (AD) and senile dementia of the Alzheimer's type (SDAT) appears to be related to a severe depopulation of the nbM in this dementia. In Huntington's disease (HD), by contrast, there is no loss of cortical CAT activity. The present quantitative study indicates that (1) there is no significant loss of neurons from the nbM in HD, and (2) that the previously described cytologic changes in the neurons of this nucleus in HD patients do not differ significantly from controls. These findings are consistent with the working hypothesis that the types of dementia associated with reductions of neocortical CAT activity are characterized by dysfunction or death of neurons in the nbM, but dementing disorders with normal neocortical CAT activity manifest no major abnormalities in this cholinergic nucleus of the basal forebrain.

Paralimbic frontal lobe hypometabolism in depression associated with Huntington's disease.

We measured regional cerebral glucose metabolism using 2-[18F]-fluoro-2-deoxy-D-glucose and positron emission tomography in depressed and nondepressed patients with early Huntington's disease (HD), compared with appropriately matched controls. Caudate, putamen, and cingulate metabolism was significantly lower in patients with HD than in control subjects, independent of mood state. Orbital frontal-inferior prefrontal cortex hypometabolism, however, differentiated depressed patients from both nondepressed patients and normal controls. These findings implicate selective dysfunction of the paralimbic regions of the frontal lobes in the mood disorder of HD. The metabolic pattern is similar to that in depression associated with Parkinson's disease, suggesting that the integrity of pathways linking paralimbic frontal cortex and the basal ganglia may be integral to the normal regulation of mood.

EEG power spectra in Huntington's disease: clinical and neuropsychological correlates.

Quantitative power spectral analysis (PSA) was applied to frontal (F3, F4, F7, F8), temporal (T5, T6), and occipital (O1, O2) EEGs of 16 Huntington's disease (HD) patients and eight healthy control subjects. PSA revealed HD patients' EEGs to be abnormal: (i) raw and percent Alpha power were reduced; (ii) raw and percent Theta power were reduced at F3 and F4; (iii) percent Delta and percent Beta power were increased; (iii) Theta frequency was reduced by approximately 1.0 Hz. Frontal and temporal EEG power measures and decreased EEG amplitude correlated with severity of neurological and cognitive impairment.