Plasma progranulin levels in cortical dementia phenotypes with asymmetric perisylvian atrophy.

BACKGROUND AND PURPOSE: Decreased plasma progranulin levels are a very specific marker for the diagnosis of frontotemporal lobar degeneration (FTLD) caused by mutations in the progranulin gene (GRN). A frequent neuroimaging pattern in this type of dementia is asymmetric cortical atrophy. The aim of this study was to screen for GRN-linked FTLD in cases with different cortical dementia phenotypes and asymmetric perisylvian atrophy. METHODS: Progranulin plasma levels were analyzed in a variety of FTLD phenotypes (n = 71), dementia of the Alzheimer type (DAT) (n = 22) and probable Lewy body dementia (n = 8), both latter groups presented with asymmetric perisylvian atrophy. A group of elderly controls (n = 29) and DAT cases with symmetric atrophy (n = 33) were also analyzed. The GRN gene was sequenced in cases with lower plasma levels. RESULTS: Four cases with clinical FTLD phenotypes and plasma levels below 70 ng/ml were found to carry different GRN mutations: M1?, C139R, a point mutation in the splice donor site of intron 3 (A89VfsX41), and a deletion in exon 9 (A303AfsX57), this latter one being a new mutation. Thirteen cases with levels between 72 and 85 ng/ml did not show pathogenic changes in the GRN gene. None of the cases with asymmetric atrophy and clinical phenotypes other than FTLD had GRN mutations. CONCLUSIONS: Asymmetric perisylvian atrophy is not likely to predict progranulin-linked FTLD unless it is associated with a consistent FTLD clinical phenotype.

Alpha-synuclein immunoreactivity is present in axonal swellings in neuroaxonal dystrophy and acute traumatic brain injury.

The primary neuroaxonal dystrophies (NAD), which include infantile NAD and Hallervorden-Spatz syndrome (HSS), are characterized by dystrophic terminal axons and axonal swellings. Lewy bodies have been found in some cases. In Parkinson disease (PD) and dementia with Lewy bodies (DLB), Lewy bodies and neurites display prominent alpha-synuclein immunoreactivity. We examined 2 cases of HSS and 4 cases of infantile NAD with alpha-synuclein immunohistochemistry to test the hypothesis that these disorders with similar morphological findings might share a biochemical phenotype. Furthermore, we compared them to 8 cases of secondary or physiologic NAD of various causes and 2 cases of recent traumatic head injury. Alpha-synuclein positive neuronal cytoplasmic inclusions, including Lewy bodies, and neurites were numerous in 1 HSS and 1 infantile NAD case. In addition, axonal spheroids were immunostained in all 6 cases of primary NAD, 5 cases of secondary NAD, and 2 cases of recent head injury. Axonal spheroids were faintly stained in the 3 physiologic NAD cases. Alpha-synuclein positive axonal swellings may suggest a mechanism, such as axonal injury, leading to the neuronal cytoplasmic accumulation of alpha-synuclein in NAD and other disorders.

An investigation of clinical correlates of Lewy bodies in autopsy-proven Alzheimer disease.

BACKGROUND: Studies of patients meeting clinical and pathologic criteria for Alzheimer disease (AD) have not consistently found associations between the presence of Lewy bodies (LBs) at postmortem examination and a higher frequency during life of the clinical features of dementia with LBs. OBJECTIVE: To evaluate the clinical correlates of LBs in patients with AD. DESIGN AND METHODS: Fifty-one patients were diagnosed as having probable AD during life and met pathologic criteria for AD. Semiquantitative ratings for LBs were obtained in 4 brain regions: substantia nigra, cingulate, insular cortex, and hippocampus. The patients had been followed up semiannually for up to 9.9 years before death, and clinical features associated with dementia with LBs, including extrapyramidal signs and visual hallucinations, were assessed at each study visit. Logistic regression analyses determined whether patients who had LBs were more likely than those without LBs to express specific clinical signs during follow-up. Cox analyses determined whether patients with LBs developed clinical signs or died earlier. Generalized estimating equations were used to compare rates of cognitive or functional change. RESULTS: Nineteen of the 51 patients had at least 1 LB in one of the studied regions. In no case was a significant relation noted between LBs and the presence of a measured clinical sign. No LB measure was associated with an increased risk of developing any of the evaluated clinical signs earlier in the disease. There was no association between the presence of LBs and more rapid mortality or more rapid disease progression. CONCLUSIONS: In patients diagnosed as having AD during life, we did not observe a relation of LBs noted during postmortem examination with the presence of any clinical feature that we assessed or with the rapidity of disease progression. The relation between LBs and specific clinical manifestations may be tenuous in these patients.

Severity of cognitive impairment in juvenile and late-onset Huntington disease.

OBJECTIVES: To compare the severity of cognitive impairment among groups of patients with different age ranges at the onset of Huntington disease (HD) and to evaluate the variable influence of motor and cognitive deficits on functional disability across different ages at the onset of HD. DESIGN: Cross-sectional multidisciplinary evaluation of patients referred to our institution for care related to a possible diagnosis of HD. SETTING: The Huntington disease program in the Departments of Neurology and Genetics at the Fundación Jimenez Diaz, Madrid, Spain. PARTICIPANTS: Seventy-one patients with Huntington disease were classified into 3 groups depending on age at onset of motor symptoms: juvenile onset, 25 years of age or younger (group 1, n = 15); adult onset, from 26 to 50 years (group 2, n = 43); and late onset, 51 years or older (group 3, n = 13). Age- and education-matched controls (n=50) were included to compare cognitive performance with patients in groups 1 and 3. MEASURES: Cognitive evaluation encompassed a wide neuropsychological battery to assess global cognitive functioning and visuospatial, prefrontal, and memory functions. Clinical data included motor and functional variables measured by using the Unified Huntington's Disease Rating Scale. Genetic analysis determined the number of CAG trinucleotide repeats. RESULTS: Patients in group 1 scored 2.9 points and patients in group 3 scored 4.2 points below their respective controls on the Mini-Mental State Examination. Patients in groups 1 and 3 were similarly impaired in verbal memory. Visual function was much more impaired in patients in group 3, and prefrontal functions were slightly worse in patients in group 1. Cognitive scores were correlated only with time of evolution for patients in group 2. Functional scores were not significantly different among the 3 groups, but 11 (85%) of the patients in group 3 were in stage I or II vs 10 (67%) of the patients in group 1. Total functional capacity correlated better with the Mini-Mental State Examination score for patients in group 3 and with motor deficits (akinesia) and prefrontal dysfunction for patients in group 1. The mean+/-SD CAG repeat length decreased from 59.9+/-12.6 for patients in group 1 to 46.2+/-3.5 for patients in group 2 and 41.7+/-2.6 for patients in group 3. Longer CAG repeats in the HD study population correlated with akinetic features but not with cognitive performance. CONCLUSIONS: Despite the much greater genetic defect, cognitive status is slightly better preserved in patients with juvenile-onset HD. Cognitive impairment in patients with juvenile- and late-onset HD differs in the severity of visual and prefrontal deficits. Functional disability in patients with late-onset HD depends more on global cognitive status, while in patients with juvenile-onset HD, it is conditioned more by motor deficits and prefrontal dysfunction.

Induction of visual extinction by rapid-rate transcranial magnetic stimulation of parietal lobe.

We used repetitive, rapid-rate transcranial magnetic stimulation (rTMS) for the noninvasive study of visual attention in humans. Six right-handed volunteers completed eight blocks of 20 single- and 10 double-visual-stimulus trials. The visual stimulus was a single asterisk on the right or left side of a computer screen or two asterisks presented simultaneously. The subject had to respond to the stimulus by pressing the right or left response key or both keys simultaneously. During six of the blocks, we applied focal rTMS in trains of five pulses at 25 Hz and 115% of the subject's motor threshold intensity to scalp positions O1, O2, P3, P4, T5, or T6. Occipital rTMS led to a large number of misses of the contralateral asterisk regardless of whether a single or double stimulus was presented. Parietal rTMS did not induce misses of single stimuli but led to a large number of misses of the contralateral asterisk in the double-stimulus condition. The effects of temporal rTMS were inconsistent. We conclude that rTMS to the occipital lobe causes a sensory detection block, whereas rTMS to the parietal lobe can induce selective extinction of contralateral visual stimuli during a simultaneous double stimulus.

Clinical and quantitative pathologic correlates of dementia with Lewy bodies.

OBJECTIVES: To examine the distribution of cortical Lewy bodies (LB) and their contribution to the clinical syndrome in dementia with LB (DLB) and to address their relationship to the pathologic markers of AD and PD. METHODS: We studied 25 cases meeting neuropathologic criteria for DLB: 13 cases without AD (Braak stage I or II) and 12 cases with concomitant AD changes (Braak stages III to V). Age at onset, disease duration, and clinical symptoms were reviewed for each case. We quantified the regional distribution of LB in substantia nigra, paralimbic areas (cingulate gyrus, insula, entorhinal cortex, and hippocampus), and neocortex (frontal and occipital association areas) using anti-alpha-synuclein immunostaining. We compared the LB pathology between groups of patients with different symptoms at onset or with specific clinical phenotypes. RESULTS: There were no significant differences in clinical symptoms or LB density between cases with or without concomitant AD. LB density showed a consistent gradient as follows: substantia nigra > entorhinal cortex > cingulate gyrus > insula > frontal cortex > hippocampus > occipital cortex. LB density in substantia nigra and neocortex was not significantly different in cases that started with parkinsonism compared with those that started with dementia. There were no significant differences in LB density in any region among patients with or without cognitive fluctuations, visual hallucinations, delusions, recurrent falls, or parkinsonism. Duration of the disease correlated with a global LB burden for each case (p = 0.02) but did not correlate with LB density in any individual area. Paralimbic and neocortical LB density were highly correlated with each other (p<0.0001), but neither of these correlated well with the number of LB in substantia nigra. LB density did not correlate with Braak stage or frequency of neuritic plaques. CONCLUSIONS: There is a consistent pattern of vulnerability to LB formation across subcortical, paralimbic, and neocortical structures that is similar for DLB cases with or without concomitant AD. Paralimbic and neocortical LB do not correlate with LB in substantia nigra, suggesting that DLB should not be considered just a severe form of PD. LB density correlates weakly with clinical symptoms and disease duration.

Clinicopathologic correlates in temporal cortex in dementia with Lewy bodies.

OBJECTIVE: To address the relationship between dementia and neuropathologic findings in dementia with Lewy bodies (DLB) in comparison with AD. METHODS: We evaluated the clinical presentation of autopsy-confirmed DLB in comparison with AD according to new Consortium on DLB criteria and compared the two conditions using quantitative neuropathologic techniques. This clinicopathologic series included 81 individuals with AD, 20 with DLB (7 "pure" DLB and 13 "DLB/AD"), and 33 controls. We counted number of LB, neurons, senile plaques (SP), and neurofibrillary tangles (NFT) in a high order association cortex, the superior temporal sulcus (STS), using stereologic counting techniques. RESULTS: The sensitivity and specificity of Consortium on DLB clinical criteria in this series for dementia, hallucinations, and parkinsonism are 53% and 83%, respectively, at the patient's initial visit and 90% and 68%, respectively, if data from all clinic visits are considered. In pathologically confirmed DLB brains, LB formation in an association cortical area does not significantly correlate with duration of illness, neuronal loss, or concomitant AD-type pathology. Unlike AD, there is no significant neuronal loss in the STS of DLB brains unless there is concomitant AD pathology (neuritic SP and NFT). CONCLUSIONS: The evaluation of new Consortium on DLB criteria in this series highlights their utility and applicability in clinicopathologic studies but suggests that sensitivity and specificity, especially at the time of the first clinical evaluation, are modest. The lack of a relationship of LB formation to the amount of Alzheimer-type changes in this series suggests that DLB is a distinct pathology rather than a variant of AD.

Dementia with Lewy bodies.

In the last decade, a new degenerative dementia, probably the second most common after Alzheimer's disease (AD), has been increasingly recognized under the consensus name of dementia with Lewy bodies (DLB). This article reviews current clinical, genetic, and pathological DLB data and indicates directions for future research. DLB overlaps in clinical, pathological, and genetic features with AD and Parkinson's disease (PD). Clinically, it is characterized by progressive cognitive impairment with significant fluctuations in alertness, parkinsonism, and psychosis with recurrent hallucinations. The neuropathological hallmarks are the intracytoplasmic inclusions in substantia nigra typical of PD, known as Lewy bodies (LB) but distributed widely throughout paralimbic and neocortical regions. Most of the cases also coexist with a plaque predominant AD. It is probably the unique and differential distribution of the lesions throughout cortical and subcortical structures in each of these disorders that supports a specific clinical syndrome and may ultimately prove most useful in understanding their different etiologies. Several genes have recently been implicated in LB formation. Special interest arises from mutations in the alpha-synuclein gene, which appears to be responsible for autosomal dominant PD in several kindreds. This gene encodes a presynaptic protein, a fragment of which is present in AD plaques. Recent studies show intense and quite specific alpha-synuclein immunoreactivity in LB and related neurites, suggesting a potential role of this protein in the aggregation or precipitation of LB inclusions.

Clinical and neuropathological correlates of dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is characterized pathologically by widespread Lewy body (LB) neuronal inclusions in the brain, but the contribution of LBs to the clinical syndrome of dementia and parkinsonism is unclear. In a clinical-pathological study of 25 cases with DLB, we examined the regional neuroanatomical distribution of Lewy-related pathology using alpha-synuclein immunostaining to evaluate the relationship between LBs, neuronal loss, Alzheimer-type changes, and the clinical phenotype. Compared to traditional ubiquitin immunostaining, alpha-synuclein immunohistochemistry was more specific and slightly more sensitive, staining about 5% more intracytoplasmic structures. There was a consistent pattern of vulnerability to LB formation across subcortical, paralimbic, limbic, and neocortical structures, which was independent of concomitant Alzheimer-type changes. There were no significant differences in regional LB densities among patients with or without cognitive fluctuations, visual hallucinations, delusions, recurrent falls or parkinsonism. Duration of disease correlated weakly with LB density. There was no neuronal loss in superior temporal sulcus or entorhinal cortex in pure DLB cases compared to nondemented controls. Thus, DLB is characterized by a specific neuroanatomical vulnerability to LB pathology, distinct from AD pathology, with a complicated relationship to clinical symptoms.

Induction of a recall deficit by rapid-rate transcranial magnetic stimulation.

We used rapid-rate, repetitive transcranial magnetic stimulation (rTMS) for the noninvasive study of verbal recall. Five right-handed normal subjects were studied. Recall followed immediately after presentation of a 12-word list. Focal rTMS was applied with a figure eight coil in trains of 500 ms duration to F7, F8, T5, T6, P3, P4, or O1, O2 at latencies of 0, 250, 500, or 1000 ms during word list presentation. Recall was consistently significantly diminished only after left mid-temporal and bilateral dorsofrontal rTMS at both 0 and 250 ms latencies. We conclude that rTMS may be useful as a non-invasive tool for the study of verbal memory processes.

Visual processing disorders in patients with Huntington's disease and asymptomatic carriers.

Deficits in visual processing are early cognitive abnormalities in patients with Huntington's disease (HD) and may be found in presymptomatic gene carriers. We investigated the nature and evolution of deficits in visual processing in HD, and whether subtle deficits could be recognized by formal testing in asymptomatic carriers. We studied 35 patients with HD in stages 1-3 of functional disability, and 26 symptom-free relatives at 50% risk for the disease. We administered the Mini Mental State Examination to assess overall cognitive function and tests to assess visuospatial skills such as visual attention and ocular scanning (Cancellation Task and Line Bisection Test), visuoconstructive abilities (Copy of Rey's Complex Figure), and visuoperception (Hooper Visual Organization Test). The group at risk comprised 15 asymptomatic carriers (AC) and 11 non-carriers (NC) and was assessed by investigators blinded to gene status. HD patients were impaired in most of the tasks compared with AC and NC, and the scores declined steadily from stage 1 to 3. However, the difference between patients in stage 1 of HD and AC and NC in most of the tasks was not significant. Only the Hooper Test, which requires complex visual integration, was highly discriminative of early symptomatic from asymptomatic carriers (P < 0.05). There were no significant differences between AC and NC in any of the tasks. We conclude deficits in visual processing develop with other manifestations of the disease and are not significant on formal testing at presymptomatic stages; also, early visual deficits in HD seem to be related to disorders in complex visual processing.

Language-activated single-photon emission tomography imaging in the evaluation of language lateralization--evidence from a case of crossed aphasia: case report.

We report a right-handed patient who developed a nonfluent aphasia after surgery for a right parietal arteriovenous malformation. Resting brain single-photon emission tomography displayed decreased regional cerebral blood flow only in the right hemisphere, with spared regional cerebral blood flow in the left hemisphere. Single-photon emission tomography performed after a language activation task (Boston Naming Task) showed a consistent area of increased regional cerebral blood flow in the right inferior and posterior frontal lobe, supporting a right hemisphere dominance for language. These results suggest a potential role for this noninvasive study in the evaluation of language lateralization.

Postoperative cognitive and single photon emission computed tomography assessment of patients with resection of perioperative high-risk arteriovenous malformations.

We studied the outcome of 10 patients who had undergone high-risk surgery for an arteriovenous malformation at our institution between November 1991 and November 1993. All of the lesions were located in the dominant (left) hemisphere. Perioperative risk was assessed by the location of the lesion in functionally eloquent cortex (seven patients) or deep structures (two patients) or the lesion's large volume (two patients). Our patients included six women and four men, and their ages ranged from 22 to 53 years (mean, 35.8). Our follow-up study included the evaluation of neurological sequelae but mainly emphasized the study of cognitive deficits (seven major functional clusters), the incidence of depression and behavioral changes, and the assessment of regional cerebral blood flow with single photon emission computed tomography. Six patients returned to a seemingly "normal" daily life with some minor deficits postoperatively, three developed contralateral hemiparesis, and one had disabling cognitive deficits. Our comprehensive cognitive assessment, in particular, showed that although patients might appear "normal" on a routine neurological examination, most patients showed a mild deficit in at least one cognitive function and three were severely impaired. In addition, the single photon emission computed tomographic studies pointed out hypoperfusion in more extensive regions than the surgical defects shown by magnetic resonance imaging or computed tomographic studies. These single photon emission computed tomography images helped to explain some of the cognitive and behavioral changes better than the anatomic studies. This information will make it possible for the physician to offer continuing supportive care for the patient in postoperative transition to normal life activities.

Microvascular anatomy of the anterior surface of the medulla oblongata and olive.

The arterial supply and the microanatomy of the anterior surface of the medulla oblongata and olive were studied in 11 cadaveric specimens, with investigation of the size, course, and length of the arteries. Two distinct anatomical entities divide the vascular supply in this region: 1) the pyramid, which is the anterior surface of the medulla; and 2) the olive, which is adjacent to the lateral aspect of the pyramid. Primary vascularization of the pyramid was via small branches of the anterior spinal artery, a branch of the vertebral artery. Minute perforators from the anterior spinal artery were found in all specimens. Arterial supply to the olive varied by location: its anterior aspect was primarily supplied by the anterior spinal artery; the upper portion of the posterior aspect of the olive was supplied by the vertebral artery, the anterior inferior cerebellar artery, and the basilar artery; and the middle and lower portions of the posterior aspect were fed by the vertebral artery and posterior inferior cerebellar artery. These arteries supplied the medulla through the small branches directed toward the olive. The authors observed a wide anastomotic net connecting the small arteries in this area. These patterns of microvascular supply of the pyramid and olive may deepen the understanding of clinical and pathological conditions resulting from arterial occlusion. The existence of an anastomotic net may account for the rare incidence of medullary infarction in the olive region.

Bradykinesia in Huntington's disease.

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.

Microsurgical anatomy of the intracranial part of the vertebral artery.

We studied the intracranial portion of the vertebral artery and its branches in 11 cadaveric specimens. We evaluated the course of vessels and their dimensions (external diameter and length), as well as relationships between each of them. The vertebral artery was larger on the left side in two cases, on the right in five cases, and equal on both sides in four cases. The right and left vertebral arteries joined each other forming the basilar artery at the level of the pontomedullary junction in four cases, 2 mm below it in one case, and 1 to 7 mm above it in six cases. We divided all branches of the intracranial vertebral artery into two groups: the medial branches and the lateral branches. Two major types of medial branches were observed: the anterior spinal artery and the branches of the foramen caecum. The origin of the anterior spinal artery was located 6.5 mm (5-11 mm) proximal to vertebrobasilar junction on the right and 8.5 mm (6-17 mm) on the left. The anterior spinal artery was absent on the right in two cases and on the left in one. Branches arising from the vertebral artery to the foramen caecum were found in four brains. Lateral branches originated from the posterolateral or lateral aspect of vertebral artery. The posterior inferior cerebellar artery, the largest branch of the vertebral artery, was included in this group. Other branches were mostly located between the origin of the posterior inferior cerebellar artery and the vertebrobasilar junction. Forty-six lateral branches originating from the vertebral artery were found in 11 brains (26 on the right and 20 on the left). Lateral branches widely anastomosed with perforators from the basilar artery, posterior inferior cerebral artery, and the anterior inferior cerebellar artery.

Selective deficit of one language in a bilingual patient following surgery in the left perisylvian area.

We report on a right-handed bilingual patient with a left perisylvian arteriovenous malformation that caused a mild naming deficit evident only on formal language testing in both languages. Sodium amytal injected in the left carotid artery (Wada test) before surgery resulted in speech arrest for both languages. Following surgery for removal of the lesion she developed additional deficits in her native language without alteration in her second language. Selective impairment in one language after surgery demonstrates that each language has different anatomical representation within the perisylvian dominant area.

[Cognitive disorders in patients with Huntington's disease]. / Trastornos cogitivos en pacientes con enfermedad de Huntington.

INTRODUCTION: Huntington s disease has been clearly recognized since 1872. It is characterized by the appearance of a motor disorder (chorea) accompanied by selective cognitive deterioration which is not interfered with by aging. DEVELOPMENT: Since the genetic defect causing it has been identified (expansion of CAG triplets on the IT 15 gene of chromosome 4) it has been possible to study families from the preclinical stage (asymptomatic persons who carried the mutation) to the stage of full development of the clinical syndrome. The behaviour disorders most often seen in these patients are depression, mania, schizophrenia, paranoia, anxiety, obsessive and obsessive compulsive disorders although other disorders may also occur. Different clinical forms of motor disorders and dementia have been reported in relation to the age of onset of the symptoms. The commonest cognitive symptoms are defects of attention, memory, planning, sequencing and visuo spatial deficits, as occurs in subcortical dementia. Our objective is to present the different clinical forms of the disorder according to the age of presentation, implication of the symptoms, severity of the genetic defect (number of CAG triplets) and to describe the study made of asymptomatic carriers so as to be able to detect incipient cognitive deterioration in these persons.

CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion.

OBJECTIVE: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. METHODS: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. RESULTS: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. CONCLUSIONS: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.