bluuebunny/crossref_metadata_2025 huggingface dataset:
Relations of genetic and environmental factors in the etiology of epilepsy
Authors: Ottman Ruth , Annegers John F. , Risch Neil , Hauser W. Allen , Susser Mervyn
Published: January 2005

We assessed the relations of genetic and environmental factors in the etiology of epilepsy. The study population comprised 9,705 first‐degree relatives of 1,951 adults with epilepsy ascertained from voluntary organizations. We calculated standardized morbidity ratios for specific etiologies of epilepsy in the relatives of probands with the same etiologies, using population incidence rates from Rochester, MN, as the reference. Relatives of probands with idiopathic/cryptogenic epilepsy had increased risk for idiopathic/cryptogenic epilepsy and for epilepsy associated with neurological deficit presumed present at birth (cerebral palsy or mental retardation) but not for symptomatic epilepsy associated with postnatal central nervous system insults. Relatives of probands with neurodeficits had increased risks for idiopathic/ cryptogenic epilepsy. Risk for epilepsy was not increased among relatives of probands with postnatal symptomatic epilepsy. The degree of increased risk of idiopathic/cryptogenic epilepsy in relatives of probands with idiopathiclcryptogenic epilepsy diminished with increasing age of the relatives; risk was not increased at age 35 or older. These findings support the possibility of a shared genetic susceptibility to epilepsy and cerebral palsy, and suggest that the genetic contributions to postnatal symptomatic epilepsy are minimal.
Regional metabolic correlates of surgical outcomes following unilateral pallidotomy for parkinson's disease
Authors: Eidelberg D. , Moeller J. R. , Ishikawa T. , Dhawan V. , Spetsieris P. , Silbersweig D. , Stern E. , Woods R. P. , Fazzini E. , Dogali M. , Beric A.
Published: January 2005

Stereotaxic ventral pallidotomy has been employed in the symptomatic treatment of patients with advanced Parkinson's disease (PD). To understand the pathophysiology of clinical outcome following this procedure, we studied 10 PD patients (5 men and 5 women; mean age, 60.0 ± 6.1 years; mean Hoehn and Yahr stage, 3.8 ± 1.0) with quantitative F‐fluorodeoxyglucose (FDG) and positron emission tomography (PET). All patients were scanned preoperatively; 8 of 10 patients were rescanned 6 to 8 months following surgery. Clinical performance was assessed off medications before and after surgery using standardized timed motor tasks. We found that preoperative lentiform metabolism correlated significantly with improvement in contralateral motor scores at 1 week, 3 months, and 6 months following unilateral pallidotomy (p<0.03). Postoperatively, significant metabolic increases were noted in the primary motor cortex, lateral premotor cortex, and dorsolateral prefrontal cortex (p <0.01) of the hemisphere that underwent surgery. Improvement in contralateral limb motor performance correlated significantly with surgical declines in thalamic metabolism (p <0.01) and increases in lateral frontal metabolism (p< 0.05). Principal components analysis disclosed a significant covariance pattern characterized by postoperative declines in ipsilateral lentiform and thalamic metabolism associated with bilateral increases in supplementary motor control metabolism. Subject scores for this pattern correlated significantly with improvements in both contralateral and ipsilateral limb performance (p<0.0005). These results suggest that pallidotomy reduced the preoperative overaction of the inhibitory pallidothalamic projection. Clinical improvement may be associated with modulations in regional brain metabolism occurring remote from the lesion site.
Thalamic metabolism and corticospinal tract integrity determine motor recovery in stroke
Authors: Binkofski F. , Seitz R. J. , Arnold S. , Classen J. , Benecke R. , Freund H.‐J.
Published: January 2005

We studied the role of remote metabolic depressions and pyramidal tract involvement regarding motor recovery following a first hemiparetic ischemic stroke. In 23 patients the regional cerebral glucose metabolism (rCMRGlu) was measured with positron emission tomography and the location and spatial extent of the stroke lesions were assessed by magnetic resonance imaging. Motor impairment during the acute and chronic stages (4 weeks after stroke) was determined by a motor score and recordings of magnetic evoked motor potentials. Twelve patients recovered significantly, whereas 11 patients retained a disabling hemiparesis. In contrast to patients with good motor recovery, rCMRGlu was severely depressed in the thalamus on the lesion side in patients with poor motor recovery. This patient group also showed more severe damage to the pyramidal tract on magnetic resonance images and a more pronounced reduction of the magnetic evoked motor potential amplitude. Neither the size of the stroke lesions nor the spatial extent of the lesional and remote rCMRGlu depressions outside the thalamus correlated with the thalamic hypometabolism and the improvement of the motor score. We conclude that preservation both of parts of the pyramidal tract and of the thalamic circuitry is a major determinant for the quality of hand motor recovery following acute brain ischemia in the adult.
Chromosome 12‐linked autosomal dominant scapuloperoneal muscular dystrophy
Authors: Wilhelmsen K. C. , Blake D. M. , Lynch T. , Mabutas J. , Vera M. De , Neystat M. , Bernstein Ba M. , Hirano M. , Gilliam T. C. , Murphy P. L. , Sola M. D. , Bonilla E. , Schotland D. L. , Hays A. P. , Rowland L. P.
Published: January 2005

Scapuloperoneal syndromes are characterized by their distribution of muscle weakness and wasting. The reported pattern of inheritance has been variable. Both neurogenic and myopathic forms of autosomally dominantly inherited scapuloperoneal syndrome have been described. It has been suggested that these are variants of other neuromuscular diseases. We examined 44 members from a family with 14 members affected with a scapuloperoneal syndrome. Physiological and histological analysis implied that this condition is predominantly myopathic. Linkage analysis was done to confirm the genetic etiology of the disease in this family and to evaluate the possibility that it is an allelic variant of other neuromuscular diseases. Genetic analysis demonstrated linkage of the disease to chromosome 12, which makes it genetically distinct from other loci known to cause neuromuscular disease. Muscle fibers with hyaline desmin‐containing cytoplasmic inclusions in combination with focal myopathic changes may be a disease‐specific morphological marker of the disease.
Gamma knife pallidotomy in advanced parkinson's disease
Authors: Friedman Joseph H. , Epstein Mel , Sanes Jerome N. , Lieberman Phillip , Cullen K. , Lindquist C. , Daamen Maxim
Published: January 2005

Posteroventral pallidotomy as a treatment for Parkinson's disease (PD) has been the subject of increasing interest. We treated 4 nondemented patients with advanced PD, 2 with severe bradykinesia and a declining response to medication, and 2 with marked clinical fluctuations. All patients received 180 Gy delivered in one sitting to the right posteroventral pallidum site, used by Laitinen and colleagues, adjusted as needed, to avoid the optic tract. Only 1 patient changed significantly. Dyskinesia completely resolved on the side contralateral to the lesion in this patient. This same patient also became transiently demented and psychotic. The other 3 patients suffered no clearly identifiable beneficial or harmful effects. Fol‐low‐up magnetic resonance imaging scans of the brain at 1 year revealed lesions exactly where targeted although of unequal sizes. Our negative experience forces us to conclude that either larger volumes of tissue must be ablated, that physiologic monitoring is required for placing a lesion, that our subjects were poor candidates for the procedure, or that surgical ablation and radiation cause tissue damage of different types with different results.
High apolipoprotein E ε4 allele frequency in Age‐related memory decline
Authors: Blesa Rafael , Adroer Rosa , Santacruz Pilar , Ascaso Carlos , Tolosa Eduardo , Oliva Rafael
Published: January 2005

Many studies have demonstrated a strong association between the presence of one or two ε4 alleles and Alzheimer's disease (AD), although few data are available on the apolipoprotein E (APOE) ε4 frequencies at the preclinical stages of AD. Thus, with a view to determining whether APOE genotyping could be useful in the early detection of AD, we determined the APOE allele frequencies in patients with memory complaints without dementia (age‐related memory decline, ARMD). We found an APOE ε4 allele frequency of 0.315 in the ARMD group, similar to 0.293 in the AD group, in contrast to 0.057 in the control group. Significant differences (t= −2.91, df=25,p=0.008) were found between the Alzheimer's Disease Assessment Scale (ADAS) total scores in the ARMD patients with at least one ε4 allele (mean=24.2) compared with the ARMD patients without the ε4 allele (mean= 14.7). Our results suggest that the patients with memory complaints, a high ADAS score, and the presence of one or two APOE‐4 alleles could be at high risk for developing AD. Thus, we propose that genotyping in conjunction with the ADAS scale may prove useful as diagnostic markers of AD in the presymptomatic stages.
GTP‐cyclohydrolase I gene mutations in hereditary progressive and dopa‐responsive dystonia
Authors: Furukawa Yoshiaki , Shimadzu Mitsunobu , Rajput Ali H. , Shimuzu Yumiko , Tagawa Tetsuzo , Mori Hideo , Yokochi Masayuki , Narabayashi Hirotaro , Hornykiewicz Oleh , Mizuno Yoshikuni , Kish Stephen J.
Published: January 2005

Recently, mutations of the GTP‐cyclohydrolase I (GTP‐CH I) gene, which catalyzes the first step in the tetrahydrobiopterin (BH4) biosynthesis, were discovered in Japanese patients with hereditary progressive dystonial/dopa‐responsive dystonia (HPD/DRD). However, it has not been confirmed that non‐Japanese patients also contain mutations in the same gene, or whether these mutations are specific to HPD/DRD. In this study, two novel nonsense mutations in exon 1 of the GTP‐CH I gene and a new mutation at the splice acceptor site of intron 1 were identified in an autopsied case of English‐Irish descent and 2 Japanese patients with HPD/DRD. In the latter, cerebrospinal fluid (CSF) neopterin levels (which may reflect the GTP‐CH I activity in the brain) were reduced to 18% and 37% of controls. A therapeutic trial of oral BH4 was ineffective, however, in a genetically proven patient. In contrast, no mutations in any exons of the GTP‐CH I gene were found in 2 patients with early‐onset parkinsonism with dystonia (EOP‐D) who developed dopa‐responsive parkinsonism and dystonia at 6 and 8 years old, respectively. Neopterin levels in CSF were well preserved in 6 EOP‐D patients. These data suggest that, among patients of different racial backgrounds, the pathogenesis of HPD/DRD, unlike EOP‐D, involves partial reduction of the brain GTP‐CH I activity consequent to mutations in the GTP‐CH I gene. Measurement of CSF neopterin concentration may be useful for the differential diagnosis between HPD/DRD and EOP‐D.
Immune attack on the schwann cell surface in acute inflammatory demyelinating polyneuropathy
Authors: Hafer‐Macko C. E. , Sheikh K. A. , Li C. Y. , Ho T. W. , Cornblath D. R. , McKhann G. M. , Asbury A. K. , Griffin J. W.
Published: January 2005

The localization, mode of action, and roles of complement in the Guillain‐Barré syndrome have been controversial. We used high‐resolution immunocytochemistry to localize complement activation products in early stages of the acute inflammatory demyelinating polyneuropathy (AIDP) pattern of Guillain‐Barré syndrome. Three AIDP subjects who were autopsied had had symptoms for 3 to 9 days at the time of death. Immunocytochemistry was performed on etched, epoxy resin‐embedded sections, and the next thin section was compared by electron microscopy (thick/thin sections). Many fibers had a rim of the complement activation marker C3d and the terminal complement complex neoantigen C5b‐9 along the outer surface of the Schwann cells. Ultrastructural analysis of these C3d‐positive fibers showed mild vesicular changes of the outermost myelin lamellae. Vesicular degeneration was seen before the invasion of macrophages into the myelin, and was the predominant change in the subject with symptoms for 3 days. C3d staining was not found on myelin membranes. The results suggest that at least some forms of AIDP are complement mediated. We speculate that complement is activated by antibody bound to epitopes on the outer surface of the Schwann cell and that the resulting complement activation initiates the vesiculation of myelin.
A newly recognized autosomal dominant limb girdle muscular dystrophy with cardiac involvement
Authors: van der Kooi A. J. , Ledderhof T. M. , DeVoogt W. G. , Res J. C. J. , Bouwsma G. , Troost D. , Busch H. F. M. , Becker A. E. , DeVisser M.
Published: January 2005

Sixty‐five members of three families with limb girdle muscular dystrophy (LGMD) underwent neurological, cardiological, and ancillary investigations. Thirty‐five individuals were diagnosed as having slowly progressive autosomal dominant LGMD. Symmetrical weakness started in the proximal lower limb muscles, and gradually upper limb muscles also became affected. Early contractures of the spine were absent. Contractures of elbows and Achilles tendons were either minimal or late. Serum creatine kinase activity was normal to moderately elevated. Electromyogram and muscle biopsy were consistent with a mild muscular dystrophy. Cardiological abnormalities, found in more than one‐half the patients, included dysrhythmias and atrioventricular (AV) conduction disturbances presenting as bradycardia, syncopal attacks necessitating pacemaker implantation, and sudden cardiac death. There was a significant relation between the severity of AV conduction disturbances and age. In nearly all patients, neuromuscular symptomatology preceded cardiological involvement. The early recognition of this previously not described, autosomal dominant LGMD with life‐threatening cardiac involvement offers an opportunity for therapeutic intervention.
Acute paresis of extraocular muscles associated with IgG Anti‐GQ1b antibody
Authors: Yuki Nobuhiro
Published: January 2005

There have been several case reports of acute ophthalmoparesis without ataxia subsequent to infection or immunization. The nosological position and therapy for acute ophthalmoparesis have yet to be established. Sera from patients are reported to have IgG anti‐GQ1b antibody, which is frequently found in sera from patients with Fisher's syndrome. To establish the etiology of acute ophthalmoparesis, I tested sera from 8 patients with acute ophthalmoparesis for anti‐GQ1b antibody. High IgG anti‐GQ1b antibody titers were present in sera from patients in the acute phase of the illness. I describe the successful treatment with plasmapheresis and intravenous immunoglobulin. Some cases of acute ophthalmoparesis following infection or immunization may be categorized as an autoimmune disease related to Fisher's syndrome.
A novel point mutation in the mcleod syndrome gene in neuroacanthocytosis
Authors: Ho M. F. , Chalmers R. M. , Davis M. B. , Harding A. E. , Monaco A. P. MD
Published: January 2005

McLeod syndrome is an X‐linked recessive disorder, characterized by neuromuscular and hematopoietic dysfunction. Two cases of McLeod syndrome were reported in a family with neuroacanthocytosis and, remarkably, 1 of them was female. Direct sequence analysis of the McLeod gene in 12 members of the family revealed a novel point mutation in exon 2 that creates a frameshift and results in premature termination of translation. There was marked skewing of X inactivation in the severely affected female.
Expression of Hel‐N1 and HeL‐N2 in small‐cell lung carcinoma
Authors: King Peter H. , Dropcho Edward J.
Published: January 2005

Hel‐Nl and HuD are neuron‐specific RNA‐binding proteins that are antigenic targets of anti‐Hu antibodies. Although expression of Hu antigens is most commonly seen in small‐cell lung carcinoma, their exact identity (e.g., Hel‐N1, HeLN2, HuD, and HuC) cannot be distinguished by immunological methods. Analysis of messenger RNA expression is needed for this distinctian. Here we demonstrate that Hel‐Nl and Hel‐N2 are expressed in small‐cell lung carcinoma using reverse transcription‐polymerase chain reaction.
Abnormalities of smooth eye and head movement control in parhson's disease
Authors: Waterston John A. , Barnes Graham R. , Grealy Madeleine A. , Collins Sue
Published: January 2005

The control of horizontal head and eye movements was examined in 13 nondemented patients with Parkinson's disease (PD) of mild to moderate severity. During pursuit of single‐frequency sine waves, smooth component eye velocity was lower in the PD group at frequencies of 1.2 Hz and above; but the differences in overall eye displacement were even greater, indicating an impaired ability to generate catch‐up saccades at high frequencies. A corresponding deficit in saccadic performance was observed during a high‐frequency saccadic tracking task where predictive saccades of reduced gain and variable timing were generated. During pursuit of pseudo‐random target motion with varying degrees of predictability, small differences in smooth component eye velocity were observed, but prediction was otherwise well preserved in the patient group. Vestibulo‐ocular reflex (VOR) suppression was also normal during head‐free pursuit. No major improvement in smooth pursuit gain could be attributed to drug treatment, based on a comparison of patient results before and after administration of levodopa.
DR2/DQwl Inheritance and haplotype sharing in affected siblings from multiple sclergis families
Authors: Voskuhl Rhonda R. , Goldstein Alisa M. , Voskuhl Toni , Davey Richard J. , McFarland Henry F.
Published: January 2005

Although the human leukocyte antigen DFWDQwl allele has been associated with multiple sclerosis, studies of DRZ/DQwl inheritance in multiple sclerosis multiplex families have yielded conflicting results. We examined this question in “highincidence” families, defined as families with more than 50% of siblings affected. DR2/ DQwl allele frequencies were significantly increased, particularly in mothers and affected siblings (p < 0.0001). The transmission of DR2IDQwl from both parents was more frequent in affected offspring (p = 0.005). While evidence for segregation of disease with a particular parental allele was lacking in most families, the frequency of haplotype sharing was higher in affected sib pairs (p < 0.01).
Cerebrovascular complications of Fabry's disease
Authors: Mitsias Panyiotis , Levine Steven R.
Published: January 2005

Fabry's disease (FD) is a rare, sex‐linked disorder resulting from α‐galactosidase deficiency. Cerebrovascular complications have been reported in the literature but have not been systematically analyzed. We report 2 patients and review 51 previously reported cases (descriptive meta‐analysis) to clarify the clinical, radiologic, and pathologic features. The average age at onset of cerebrovascular symptoms was 33.8 years for hemizygous individuals (n = 43) and 40.3 years of heterozygotes (n = 10). The most frequent symptoms and signs were as follows (in descending order of frequency): hemiparesis, vertigo/dizziness, diplopia, dysarthria, nystagmus, nausea/vomiting, head pain, hemiataxia, and ataxia of gait, in the hemizygote group; and memory loss, dizziness, ataxia, hemiparesis, loss of consciousness and hemisensory symptoms, in the heterozygote group. The vertebrobasilar circulation was symptomatic in 67% of the hemizygotes and 60% of the heterozygotes. Intracerebral hemorrhage was found in 4 patients (3 hemizygotes and 1 heterozygote). Elongated, ectatic, tortuous vertebral and basilar arteries were the most common angiographic and pathologic features. For the hemizygotes, the recurrence rate for cerebrovascular disease was 76% and the death rate was 55%; 86% of the heterozygotes had recurrent cerebrovascular event(s) and 40% died. The cerebrovascular manifestations of FD, in both hemizygotes and heterozygotes, are predominantly due to dilative arteriopathy of the vertebrobasilar circulation, frequently recur, and portend a poor prognosis.
Acute multiple sclerosis (marburg type) is associated with developmentally immature myelin basic protein
Authors: Wood D. D. , Moscarello M. A. , Bilbao J. M. , O'Connors P.
Published: January 2005

We have studied a case of acute, fulminating multiple sclerosis (MS) (Marburg type) at the pathological and biochemical levels. Postmortem examination of the brain revealed extensive areas of gross rarefaction in the hemispheric white matter. Histologically, well‐demarcated areas of demyelination with a large influx of macrophages and a subtle perivascular infiltration of lymphocytes were seen with relative preservation of the axis cylinders. Myelin basic protein (MBP) was isolated and purifed from noninvolved white matter. It was slightly larger in molecular weight than MBP from normal brain or from chronic MS brain. The increase in mass was accounted for, in part, by the deimination of 18 of 19 arginyl residues to citrulline, making the patient's MBP much less cationic than MBP from normal white matter. When expressed as the ratio of least cationic form of MBP to the most cationic (C‐8/C‐1), the normal ratio was 0.82, chronic MS 2.5, and the patient in this study 6.7. Because the ratio of 6.7 was similar to 7.5 found for a 15‐month‐old infant, MBP was considered to be of the immature form. The data are consistent with a genetic factor influencing the charge microheterogeneity of MBP. The resulting less cationic MBP cannot carry out its normal function of compacting multilayers.
Language cortex representation: Effects of developmental versus acquired pathology
Authors: Duchowny Michael , Jayakar Prasanna , Harvey A. Simon , Resnick Trevor , Alvarez Luis , Dean Patricia , Levin Bonnie
Published: January 2005

Relatively little is known about language cortex representation in patients with developmental pathology and epilepsy. We report the results of mapping language by electrical stimulation of chronically implanted subdural electrodes in 34 patients (mean age, 12.2 years) evaluated for epilepsy surgery, 28 of whom had magnetic resonance imaging or histological evidence of developmental tumors or cortical dysplasia. Language cortex was identified in the temporal or frontal lobe of 19 patients (left hemisphere in 17, right hemisphere in 2), and overlapped or bordered the epileptogenic region in 12. Language cortex was not found in the frontal or temporal lobe of 15 patients (left hemisphere in 4, right hemisphere in 11) and was presumed to be contralateral to grid placement. Three patients with left‐hemisphere perinatal or postnatal cerebral insults before the age of 5 years had no language in the left hemisphere, while 3 patients with insults between the ages of 6 and 16 years had preserved left‐hemisphere language. Developmental lesions and early onset seizures do not displace language cortex from prenatally determined sites, whereas lesions acquired before the age of 5 years may cause language to relocate to the opposite hemisphere, but only when language cortex is destroyed.
Cortical myoclonus in angelman syndrome
Authors: Guerrini Renzo , Bonanni Paolo , de Lorey Timothy M. , Serratosa José M. , Moncla Anne , Malzac Perrine , Dravet Charlotte , Igvet Marie Odile , Bureau Michelle , Genton Pierre , Suisse Georges , Thomas Pierre , Sartucci Ferdinando , Simi Paolo
Published: January 2005

Angelman syndrome (AS) results from lack of genetic contribution from maternal chromosome 15q11–13. This region encompasses three GABAA receptor subunit genes (β3, α5, and γ3). The characteristic phenotype of AS is severe mental retardation, ataxic gait, tremulousness, and jerky movements. We studied the movement disorder in 11 AS patients, aged 3 to 28 years. Two patients had paternal uniparental disomy for chromosome 15, 8 had a <3 Mb deletion, and 1 had a microdeletion involving loci D15S10, D15S113, and GABRB3. All patients exhibited quasicontinuous rhythmic myoclonus mainly involving hands and face, accompained by rhythmic 5‐ to 10‐Hz electroencephalographic (EEG) activity. Electromyographic bursts lasted 35 ± 13 msec and had a frequency of 11 ± 2.4 Hz. Burst‐locked EEG averaging in 5 patients, generated a premyoclonus transient preceding the burst by 19 ± 5 msec. A cortical spread pattern of myoclonic cortical activity was observed. Seven patients also demonstrated myoclonic seizures. No giant somatosensory evoked potentials or C‐reflex were observed. The silent period following motor evoked potentials was shortened by 70%, indicating motor cortex hyperexcitability. Treatment with piracetam in 5 patients significantly improved myoclonus. We conclude that spontaneous, rhythmic, fast‐bursting cortical myoclonus is a prominent feature of AS.
Striatal D1 and D2 dopamine receptor loss in asymptomatic mutation carriers of Huntington's disease
Authors: Weeks R. A. , Piccini P. , Harding A. E. , Brooks D. J.
Published: January 2005

We have investigated striatal dopamine D1 and D2 receptor binding in asymptomatic subjects from Huntington's disease (HD) families using positron emission tomography. Nineteen adult subjects at risk of developing HD were scanned with 11C‐SCH 23390 and 11C‐raclopride to calculate the D1 and D2 receptor binding potential, respectively. Eight of the 19 were shown to have the HD mutation; of these, 4 subjects had significant reductions in striatal dopamine receptor binding. Abnormalities were more common in older subjects and were not correlated with the size of the HD mutation. There was a strong coefficient of correlation between individual levels of striatal D1 and D2 binding in subjects with the mutation. Of 6 other cases with a 50% risk of carrying the HD gene, 1 showed subclinical loss of caudate and putamen D2 binding. Our study suggests that both striatal D1 and D2 dopamine receptors are lost in parallel from both cauudate and putamen in presymptomatic HD and that dopamine receptor binding provides a sensitive means of detecting subclinical striatal dysfunction.
X‐linked nonprogressive congenital cerebellar hypoplasia: Clinical description and mapping to chromosome Xq
Authors: Illarioshkin Sergei N. , Tanaka Hajime , Tsuji Shoji , Markova Elena D. , Nikolskay Natalya N. , Ivanova‐Samolenskay Irina A.
Published: January 2005

We examined a large family in which an X‐linked recessive congenital ataxia manifested in 7 males from three generations. The affected boys first exhibited a marked delay of early developmental motor milestones. A neurological syndrome became evident by 5 to 7 years of age and included cerebellar ataxia, dysarthria, and external ophthalmoplegia; there were no symptoms of mental retardation, spastic paraparesis, or sensory loss. Neuroimaging studies revealed hypoplasia of cerebellar hemispheres and vermis. The disease showed no progression beyond early childhood. The unique heredity and clinical features clearly distinguish this new entity from a variety of previously described familial ataxias. Pairwise linkage analysis and haplotype reconstruction allowed us to map the gene responsible for this disorder to a 38‐cM interval on chromosome Xp11.21‐q24 flanked by the loci DXS991 and DXS1001. Upon multipoint linkage analysis, the disease gene was determined to be located most likely in the proximal part of chromosome Xq, with the maximal lod score of 4.66 at the locus DXS1059 (Xq23). This is the first example of the genetic mapping of a pure congenital cerebellar hypoplasia syndrome.
Multiple mutations in the GALC gene in a patient with adult‐onset krabbe disease
Authors: Luzi Paola , Rafi Mohammad A. , Wenger David A.
Published: January 2005

A 53‐year‐old man was diagnosed 8 years earlier with globod cell leukodystrophy (GLD, Krabbe disease) by his severe deficiency of galactocerebrosidase (GALC) activity. He was found to have eight nucleotide changes on the two copies of his GALC gene, including two in the leader sequence, four considered polymorphisms, and two unique mutations.
Amyloid β protein (Aβ) deposition in chromosome 14–linked Alzheimer's disease: Predominance of Aβ42(43)
Authors: Mann D. M. A. , Iwatsubo T. , Cairns N. J. , Lantos P. L. , Nochlin D. , Sumi S. M. , Bird T. D. , Poorkaj P. , Hardy J. , Hutton M. , Prihar G. , Crook R. , Rossor M. N. , Haltia M.
Published: January 2005

Amyloid β protein (Aβ) deposition was investigated in the frontal cortex of 8 cases of (genetically confirmed) chromosome 14–linked Alzheimer's disease (AD) using the end‐specific monoclonal antibodies BA27 and BC05 to detect the presnce of Aβ40 and Aβ42(43), respectively. IN all patients, Aβ42(43) was the predominant peptide species present. The total amount of Aβ40 and Aβ42(43) deposited was more than twice the amount deposited in cases of sporadic AD of similar disease duration, although the ratio between the extent of Aβ40 and Aβ42(43) deposition was unaltered, compared with sporadic AD. Therefore, (one of) the effects of the mutations in the presenilin 1:PS‐1 (S182) gene may be to cause or at least promote an early and excessive deposition of Aβ42(43) within the brain, a property shared with other inherited forms of AD, such as those due to amyloid precursor protein mutations, and Down's syndrome (trisomy 21).
Mitochondrial DNA and RNA processing in MELAS
Authors: Kaufmann Petra , Shanske Sara , Hirano Michio , DiMauro Salvatore , King Michael P. , Koga Yasutoshi , Schon Eric A.
Published: January 2005

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS), a maternally inherited disorder, is usually associated with a point mutation in mitochondrial DNA (mtDNA) at position 3,243 in the tRNALeu(UUR) gene. To further study the pathogenesis of MELAS, we analyzed tissues from 8 MELAS‐3,243 patients. Southern blot anlaysis showed an increase in the ratio of mtDNA to nuclear DNA in almost all tissues examined, implying that mitochondrial proliferation is ubiquitous and is not confined to ragged‐red fibers in muscle. By northern blot analysis, we demonstrated increased steady‐state levels of RNA 19, a polycistronic transcript corresponding to the 16S rRNA + tRNALeu(UUR) + ND1 genes (which are contiguous in the mtDNA) in heart, kidney, and musscle. These results provide further evidence that altered mitochondrial nucleic acid metabolism may have pathogenic significance in MELAS.
Familial temporal lobe epilepsy: A common disorder identified in twins
Authors: Berkovic Samuel F. , McIntosh Anne , Howell R. Anne , Mitchell Anne , Sheffield Leslie J. , Hopper John L.
Published: January 2005

We describe a new syndrome of familial temporal lobe epilepsy in 38 individuals from 13 unrelated white families. The disorder was first identified in 5 concordant monozygotic twin pairs as part of a large‐scale twin study of epilepsy. When idiopathic partial epilepsy syndromes were excluded, the 5 pairs accounted for 23% of monozygotic pairs with partial epilepsies, and 38% of monozygotic pairs with partial epilepsy and no known etiology. Seizure onset for twin and nontwin subjects usually occurred during adolescence or early adult life. Seizure types were simple partial seizures with psychic or autonomic symptoms, infrequent complex partial seizures, and rare secondarily generalized seizures. Electroencephalograms revealed sparse focal temporal interictal epileptiform discharges in 22% of subjects. Magnetic resonance images appeared normal. Nine affected family members (24%) had not been diagnosed prior to the study. Pedigree analysis suggested autosomal dominant inheritance with age‐dependent penetrance. The estimated segregation ratio was 0.3, indicating an overall penetrance of 60% assuming autosomal dominant inheritance. The mild and often subtle nature of the symptoms in some family members may account for lack of prior recognition of this common familial partial epilepsy. This disorder has similarities to the El mouse, a genetic model of temporal lobe epilepsy with a major gene on mouse chromosome 9, which is homologous with a region on human chromosome 3.
Lack of association of very low density lipoprotein receptor gene polymorphism with caucasian Alzheimer's disease
Authors: Okuizumi Kaoru , Onodera Osamu , Tanaka Hajime , Tsuji Shoji , Seki Koji , Namba Yoshio , Ikeda Kazuhiko , Saunders Ann M. , Pericak‐Vance Margaret A. , Roses Allen D.
Published: January 2005

To determine whether the association of the very low density lipoprotein receptor (VLDL‐R) gene with Alzheimer's disease (AD), which has recently been identified in Japanese AD patients, is commonly observed in AD patients of other ethnic backgrounds, we have investigated the allele frequency of the polymorphic CGG repeat in the 5‐UTR of the VLDL‐R gene using a data set of 84 caucasian AD patients with 104 caucasian controls. Although the allele frequency of the 8‐repeat allele was slightly lower, and that of 9‐repeat allele was slightly higher, in the caucasian AD patients than in caucasian controls, the differences were not statistically significant. Multiple logistic regression analysis using apolipoprotein E4 (APOE4) allele, 5‐, 8‐, or 9‐repeat allele of the VLDL‐R gene, sex, and age at onset as the predictors revealed that only the APOE4 allele was significantly associated with AD in the data set of the caucasian AD patients and controls.
Early american professorships in neurology
Authors: Goetz Christopher G. , Pappert Eric J.
Published: January 2005

American universities recognized and institutionalized the emerging importance of neuroscience in medicine by establishing neurological professorships as early as the 1860s. Nearly 20 years before Charcot assumed his celebrated chaired professorship for Diseases of the Nervous System in France, Harvard University created a professorship of Physiology and Pathology of the Nervous System (1864), naming Brown‐Séquard as its recipient. In 1867, the new Bellevue Hospital Medical School established a combined neurology/psychiatry chair with William A. Hammond as professor, and the University of Pennsylvania created a clinical professorship devoted specifically to neurology in 1875, naming Horatio C. Wood. Although modest in their university power base and their clinical research/laboratory programs, these American posts were internationally unique for their time and solidly entrenched neurology as a specific division in early US medical education.
Effects of antiepileptic drugs on motor cortex excitability in humans: A transcranial magnetic stimulation study
Authors: Ziemann U. , Lönnecker S. , Steinhoff B. J. , Paulus W.
Published: January 2005

The effect of a single oral dose of various antiepileptic drugs on the excitability of the motor system was studied in healthy volunteers by means of transcranial magnetic stimulation. Motor threshold, duration of the cortical silent period, and intracortical excitability after double‐shock transcranial stimulation were tested before and at defined intervals after drug intake. Antiepileptic drugs that support the action of the inhibitory neurotransmitter γ‐aminobutyric acid (GABA) in the neocortex (vigabatrin, baclofen) reduced intracortical excitability but had no effect on motor threshold. Gabapentin, whose mechanism of action has not yet been unequivocally identified, showed a similar profile. By contrast, sodium and calcium channel blockers without considerable neurotransmitter properties (carbamazepine, lamotrigine, losigamone) elevated motor threshold but did not change intracortical excitability. The cortical silent period was lengthened by gabapentin and carbamazepine. Changes in peripheral motor excitability (maximum M wave, peripheral silent period) were not observed. We conclude that the changes in intracortical excitability are caused by GABA‐controlled interneuronal circuits in the motor cortex while changes in motor threshold are dependent on ion channel conductivity and may reflect membrane excitability. Transcranial magnetic stimulation may be a promising noninvasive approach to study the selective effects of antiepileptic drugs on brain function.
Altered expression of bcl‐2 and bax mRNA in amyotrophic lateral sclerosis spinal cord motor neurons
Authors: Mu Xiaojun , He Jin , Anderson David W. , Springer Joe E. , Trojanowski John Q.
Published: January 2005

One of the primary neurodegenerative events occurring in amyotrophic lateral sclerosis (ALS) is the selective loss of spinal cord α motor neurons. To study the potential role of apoptosis in the degeneration of these motor neurons, in situ hybridization was used to measure the expression of two apoptotic cell death genes, bcl‐2 and bax, in control and ALS lumbar spinal cord sections. The strongest hybridization signal for bcl‐2 mRNA in neurological and nonneurological control spinal cords was found primarily in lamina IX α motor neurons, while a weaker hybridization signal was found in neurons of Clarke's nucleus and the proper sensory nucleus of the dorsal horn. Surviving lamina IX motor neurons in ALS spinal cord sections also expressed bcl‐2 mRNA, but at levels that were significantly and selectively decreased (4.7‐fold) compared with control. bax mRNA hybridization signal was detected in several cells throughout the gray matter in control and ALS lumbar spinal cord, but was significantly and selectively increased (2.8‐fold) in ALS motor neurons. Given the proposed interactive roles of these genes in apoptosis, the present findings favor a scenario in which this mode of cell death would contribute to spinal cord motor neuron degeneration in ALS.
Striatal dopamine, dopamine transporter, and vesicular monoamine transporter in chronic cocaine users
Authors: Wilson Julie M. , Shannak Kathleen , Kish Stephen J. , Levey Allan I. , Bergeron Catherine , Deck John , Kalasinsky Kathryn , Ang Lee , Peretti Frank , Adams Vernard I. , Smialek John , Anderson William R. , Niznik Hyman B.
Published: January 2005

Depletion of striatal dopamine (DA) has been hypothesized to explain some of the neurological and psychiatric complications of chronic use of cocaine, including increased risk for neuroleptic‐precipitated movement disorders. We measured levels of DA, as well as two DA nerve terminal indices, namely, the DA transporter (DAT) and the vesicular monoamine transporter (VMAT2) in autopsied brain of 12 chronic cocaine users. Mean DA levels were normal in the putamen, the motor component of the striatum; however, 4 of the 12 subjects had DA values below the lower limit of the control range. DA concentrations were significantly reduced in the caudate head (head, –33%; tail, –39%) with a trend for reduction in nucleus accumbens (–27%). Striatal DAT protein (–25 to –46%) and VMAT2 (–17 to –22%) were reduced, whereas DAT determined by [3H]WIN 35,428 binding was normal. In conclusion, our data suggest that chronic cocaine use is associated with modestly reduced levels of striatal DA and the DA transporter in some subjects and that these changes might contribute to the neurological and psychiatric effects of the drug.
Epstein‐barr virus–associated acute autonomic neuropathy
Authors: Bennett Jeffrey L. , Mahalingam Ravi , Wellish Mary C. , Gilden Donald H.
Published: January 2005

A 44‐year‐old man developed blurry vision, photosensitivity, orthostasis, constipation, and acrodysesthesias after a febrile illness. The neurologic examination and ancillary studies were consistent with a dysautonomic small fiber neuropathy. The cerebrospinal fluid (CSF) contained both Epstein‐Barr virus (EBV) DNA and antibody to EBV. This is the first report of an acute autonomic neuropathy with documented EBV infection in CSF.
The glial glutamate transporter complementary DNA in patients with amyotrophic lateral sclerosis
Authors: Meyer Thomas , Meyer Bientje , Sitte Wolfgang , Ludolph Albert C. , Speer Astrid , Küther Gerald
Published: January 2005

Here, we report a mutation screening by single‐stranded conformational analysis of the astroglial human brain glutamate transporter (HBGT) II complementary DNA in patients with amyotrophic lateral sclerosis. The conformational analysis data indicate a lack of sequence variations in the HBGT II coding region in 6 patients with amyotrophic lateral sclerosis and the same number of nonneurological control subjects. In both groups, three variants of the HBGT II 5′ untranslated region were isolated. We have no evidence that the reported complementary DNA variants are disease specific.
Sequence variants in human neurofilament proteins: Absence of linkage to familial amyotrophic lateral sclerosis
Authors: Vechio Janet D. , Bruijn Lucie I. , Xu Zuoshang , Brown Robert H. , Cleveland Don W.
Published: January 2005

Neurofilaments, assembled from NF‐L (68 Kd), NF‐M (95 Kd), and NF‐H (115 kd), are the most abundatn structural components in large myelinated axons, particularly those of motor neurons. Aberrant neurofilament accumulation in cell bodies and axons of motor neurons is a prominent pathological feature of several motor neuron diseases, including sporadic and familial amyotrophic lateral sclerosis (ALS). Transgenic methods have proved in mice that mutation in or increased expression of neurofilament subunits can be primary causes of motor neuron disease that mimics the neurofilamentous pathology often reported in human disease. To examine whether mutation in neurofilament subunits causes or predisposes to ALS, we used single‐strand conformation polymorphism coupled with DNA sequencing to search for mutations in the entirety of the human NF‐L, NF‐M, and NF‐H genes from 100 familial ALS patients known not to carry mutations in superoxide dismutase 1 (SOD1), as well as from 75 sporadic ALS patients. Six polypeptide sequence variants were identified in rod and tail domains of NF‐L, NF‐M, or NF‐H. However, all were found at comparable frequency in DNAs from normal individuals and no variant cosegregated with familial disease. Two deletions found previously in NF‐H genes of sporadic ALS patients were not seen in this group of familial or sporadic ALS patiens.
HIV‐1 DNA in brains in AIDS and pre‐AIDS: Correlation with the stage of disease
Authors: An Shu F. , Giometto Bruno , Scaravilli Francesco
Published: January 2005

Seventeen asymptomatic individuals positive for human immunodeficiency virus type 1 (HIV‐1) and 16 patients with acquired immunodeficiency syndrome (AIDS), all with polymerase chain reaction evidence of HIV‐1 DNA, were selected for quantitative analysis to correlate the levels of HIV‐1 DNA in brain tissue with the stage of infection. The AIDS patients either were clinically asymptomatic or presented various abnormalities. Neuropathological lesions were assessed by morphological and immunohistochemical methods. To determine the level of HIV‐1 DNA, semiquantitative nested polymerase chain reaction was applied using a digoxigenin‐labeled primer and chemiluminescence. Serial dilutions of standard HIV DNA were run in parallel with brain DNA samples. Among the 16 AIDS brains studied, 9 showed changes characteristic of HIV encephalitis/leukoencephalopathy while 1 showed focal pontine leukoencphalopathy and 6 showed no obvious neuropathological lesions. Abnormalities in pre‐AIDS individuals included meningitis, microgliosis, and astrogliosis. Copy numbers of HIV‐1 DNA in the brains of AIDS patients were higher than those in asymptomatic individuals (median, 135 vs 45 copies/150,000 cells). However, there was some degree of overlapping between the two groups, with some AIDS patients showing low figures while 3 asymptomatic individuals had high copy numbers. This suggests that the use of HIV‐1 DNA load in the central nervous system as an indicator of progression of the disease should be restricted to large series and not single patients.
Cognitive and brain magnetic resonance imaging findings in adrenomyeloneuropathy
Authors: Edwin David , Speedie Lynn J. , Kohler Wolfgang , Naidu Sakkubai , Moser Hugo W. , Kruse Bernd
Published: January 2005

Neuropsychological functioning and brain magnetic resonance imaging (MRI) were evaluated in 84 men with adrenomyeloneuropathy (AMN). MRI was normal in 61%, the “pure AMN” group, while 39%, the “cerebral AMN” group, showed brain white matter abnormalities. Except for mild deficits in psychomotor speed and visual memory, neuropsychological function was normal in pure AMN. Most patients with cerebral AMN had normal IQ and language but evidenced impaired psychomotor speed, spatial cognition, memory, and executive functions. Patients with MRI evidence of very severe cerebral disease had global and language impairment as well, and deficits in all patients were highly correlated with degree of brain MRI involvement.
Clonal expansion of mitochondrial DNA with multiple deletions in autosomal dominant progressive external ophthalmoplegia
Authors: Moslemi Ali‐Reza , Oldfors Anders , Melberg Atle , Holme Elisabeth
Published: January 2005

Sporadic progressive external ophthalmoplegia and Kearns‐Sayre syndrome are usually associated with single large‐scale mitochondrial DNA deletions in muscle. In progressive external ophthalmoplegia with autosomal dominant inheritance, multiple mitochondrial DNA deletions have been reported. We studied several members of a Swedish family with autosomal dominant progressive external ophthalmoplegia and multiple mitochondrial DNA deletions by polymerase chain reaction analysis of singl emuscle fibers and by in sit hybridization, combined with enzyme histochemical analysis. Muscle fiber segments with deficiency of cytochrome c oxidase, which is partially encoded by mitochondrial DNA, had accumulated mitochondrial DNA with deletions and showed reduced levels of wild‐type mitochondrial DNA. The deletions varied between individual muscle fibers. There was one predominant deletion in each cytochrome c oxidase‐deficient muscle fiber segment. Sequencing of the deletion breakpoints showed that most but not all of the deletions were flanked by direct repeats. Young, clinically affected individuals of this family without limb muscle symptoms did not show mitochondral DNA deletions or cytochorme c oxidase‐deficient muscle fibers. Our result indicate that a nuclear factor predisposes to the developement of somatic multiple mitochondrial DNA deletions. Mitochondrial DNA with multiple different deletions shows clonal expansion, which leads to mitochondrial myopathy with ragged‐red fibers and muscle weakness.
Human T‐cell lymphotropic virus type II–associated myelopathy: Clinical and immunologic profiles
Authors: Lehky Tanya J. , Flerlage Nicholas , McFarland Henry F. , Jacobson Steven , Katz David , Houff Sidney , Hall Willaim H. , Ishii Kazuyoshi , Monken Claude , Dhib‐Jalbut Suhayl
Published: January 2005

Human T‐cell lymphotropic virus type II (HTLV‐II) is endemic in several ethnic tribes and among intravenous drug users in metorpolitan areas. Despite the presence of HTLV‐II in these various populations, the association of HTLV‐II with disease is sparse and mainly limited to isolated case reports. This study is an extension of an earlier description of an HTLV‐II‐infected patient with neurologic disease and presents the clinical and immunologic findings of 4 patients with HTLV‐II seropositivity and spastic paraparesis. The patients are of African‐American orgin with 3 of the patients with HTLV‐II seropositivity and spastic paraparesis. The patients are of African‐American origin with 3 of the patients being of Amerindian descent. All of the patients are seronegative for the human immunodeficiency virus (HIV). The patients progressed to a nonambulatory state in less than 5 years. Magnetic resonacne imaging studies obtained jfrom 3 of the patients demonstratd white matter disease in the cerebrum and spinal cord. The cerebrospinal fluid and serum contained antibodies to HTLV‐II. Ther presence of proviral HTLV‐II was confirmed by polymerase chain reaction analysis of peripheral blood lymphocytes (PBLs). A spinal cord biopsy from 1 patient demonstratd HTLV RNA within a lesion. Immunolgic studies on 2 patients demonstrated that spontaneous lymphoproliferation of PBLs was present but decreased relative to HTLV‐I‐infected patients. The clinical and immunologic findings from these HTLV‐II‐infected patient resemble those found in HTLV‐I‐associated myelopathy/tropical spastic paraparesis.