bluuebunny/crossref_metadata_2025 huggingface dataset:
Somatic mosaicism in the central nervous system in spinocerebellar ataxia type 1 and machado‐joseph disease
Authors: Lopes‐Cendes Iscia , Maciel Patrícia , Kish Stephen , Gaspar Claudia , Silveira Isabel , Robitaille Yves , Clark H. Brent , Koeppen Arnulf H. , Nance Martha , Schut Lawrence , Coutinho Paula , Sequeiros Jorge , Rouleau Guy A.
Published: January 2005

Spinocerebellar ataxia type 1 and Machado‐Joseph disease are two autosomal dominant cerebellar ataxias caused by expansions of unstable CAG repeats in the coding region of the causative genes. The selectivity of cell death and the resulting characteristic neuropathological features in each of these diseases are not explained by the gene expression patterns. Since the repeat size correlates with age at onset and severity of these diseases, somatic mosaicims, the result of mitotic instability of the CAG repeat, could be the basis for specificity of neurodegeneration; brain structures with larger expanded repeats would be more severely affected. To study the association between neuropathological changes and somatic mosaicism of the CAG repeat size in the central nervous system of patients with these two ataxias, we determined the size of the (CAG)n expansion in 20 different regions of the brain, brainstem, cerebellum, and spinal cord from 3 patients with spinocerebellar ataxia type 1 and 3 with Machado‐Joseph disease; these regions were selected for their differential neuropathological involvement in the two disorders. We observed a considerable homogeneity of repeat size ranges in all but 1 of the 20 regions examined: The cerebellar cortex showed slightly smaller (CAG)n tracts in all specimens from both groups of patients. Our results suggest that the pattern of repeat size mosaicism, similar in spinocereballar ataxia type 1 and Machado‐Joseph disease, reflects the developmental pathways and cell composition of different central nervous system regions and is not the cause of selective cell death in these disorders.
Spontaneous neurological recovery after stroke and the fate of the ischemic penumbra
Authors: Furlan Mauro , Marchal Gilles , Derlon Jean‐Michel , Baron Jean‐Claude , Viader Fausto
Published: January 2005

We prospectively tested the hypothesis that early recovery after ischemic stroke depends on the ultimate survival of functionally impaired, critically ischemic (i.e., “penumbral”) tissue. From a series of 26 consecutive patients studied with positron emission tomography within 18 hours of first‐ever stroke in the middle cerebral artery territory, all 11 survivors to the 2‐month end point who exhibited increased oxygen extraction fraction were declared eligible. The positron emission tomographic images were compared to ultimate infarction defined by computed tomography performed during the chronic stage. The penumbra (operationally defined by increased oxygen extraction fraction and divided outcome despite uniformly reduced cerebral blood flow) was individually detected in 10 of the 11 patients; cerebral blood flow ranged from 7 to 17 ml/100 gm·min, consistent with that found in monkey studies. The volume of the penumbra that escaped infarction was highly correlated with neurological recovery (p<0.04 to p<0.0001, depending on the scale used). This longitudinal study is the first to characterize the penumbra in humans and to document one mechanism strongly influencing recovery; the surviving penumbra may offer opportunities for secondary perifocal neuronal reorganization. Therapeutic measures to prevent infarction of the penumbra (up to 16 hours in this series) may have reduced residual neurological impairment. Mapping the extent of the penumbra, according to prospective criteria, may allow one to predict each patient's potential for recovery, and to select the most appropriate candidates for therapeutic trials.
Molecular basis of phenotypic heterogeneity in siblings with spinal muscular atrophy
Authors: Parano Enrico , Pavone Lorenzo , Falsaperla Raffaele , Trifiletti Rosario , Wang Ching
Published: January 2005

We report on a family with childhood‐onset spinal muscular atrophy with intrafamilial phenotypic variation. Typical of a large majority of such patients, both the child with spinal muscular atrophy type I and the child with type II were missing both copies of the survival motor neuron telomeric gene (SMNT). The more severely affected child, however, showed genotypic evidence consistent with the de novo loss of DNA sequence in addition to that inherited by both affected children. These data suggest that the intrafamilial phenotypic variation in this family results from a new mutation event in the more severely affected child. Examples of intrafamilial phenotypic variability are quite rare, but some reports exist in the spinal muscular atrophy literature. We present evidence that one explanation for this phenomenon is the occurrence of de novo deletion events at the highly unstable disease locus.
Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype
Authors: Korenke G. Christoph , Wilichowski Ekkehard , Hunneman Donald H. , Hanefeld Folker , Fuchs Sigrid , Krasemann Ernst , Doerr Helmuth G.
Published: January 2005

We report on monozygotic twins with different clinical phenotypes of X‐linked adrenoleukodystrophy. At the age of 10 years both boys were neurologically asymptomatic. The first cranial magnetic resonance examination showed normal findings in the first twin and parietooccipital demyelination in the second. The latter developed behavioral problems 9 months later, followed by visual impairment and gait ataxia. His cranial magnetic resonance image at the age of 11 years showed progressive demyelination. In contrast, neurological status and magnetic resonance images remained normal in the first twin. The same point mutation in exon 8 of the adrenoleukodystrophy gene (C2203T) was detected in both boys. All genotype examinations were consistent with the diagnosis of monozygotic twins, suggesting that some nongenetic factors may be important for different adrenoleukodystrophy phenotypes.
A point mutation associated with a severe phenotype of neurofibromatosis 2
Authors: MaCcollin M. , Davis Kevin , Braverman N. , Viskochil D. , Ruttledge M. , Ojemann R. , Gusella J. , Parry D. M.
Published: January 2005

Neurofibromatosis 2 (NF2) is an autosomal dominant disease characterized by bilateral vestibular schwannomas and other nonmalignant tumors of the brain, spinal cord, and peripheral nerves. Although the average age of onset of NF2 is 20 years, some individuals may become symptomatic in childhood. We studied 5 unrelated NF2 patients who became symptomatic before age 13. All 5 had multiple tumors in addition to vestibular schwannoma, and none had a positive family history. Sequence analysis of the NF2 gene revealed identical nonsense mutation of exon 6 in 3 patients. Because this mutation destroys a restriction site, genomic DNA from the 2 other children was directly tested for this change and identical alterations were detected. Although the work of our laboratory and others has not, in general, detected identical mutations in unrelated patients, this mutation seems to occur particularly frequently in the pediatric population and thus may be associated with an especially severe phenotype. Restriction analysis in children with NF2 may be a cost effective way of identifying their mutation. Further work is needed to characterize the effects of this change on the NF2 protein product and its relationship to this severe phenotype.
Inclusion body myositis: Clinical and pathological boundaries
Authors: Amato Anthony A. , Gronseth Gary S. , Jackson Carlayne E. , Wolfe Gil I. , Katz Jon S. , Bryan Wilson W. , Barohn Richard J.
Published: January 2005

Inclusion body myositis, polymyositis, and dermatomyositis are three distinct categories of inflammatory myopathy. Some authorities commented on the selective early weakness of the volar forearm muscles, quadriceps, and ankle dorsiflexors in inclusion body myositis. The most important feature distinguishing inclusion body myositis from the other two inflammatory myopathies is the lack of responsiveness to immunosuppressive treatment. Although most patients with inclusion body myosities have characteristic muscle biopsy findings, some cannot be distinguished histologically early from polymyositis. Presdicting responsiveness to mmunosuppressive medications, independent of muscle histology, would be valuable to clinicians. We retrospectively reviewed the pattern of weakness and other clinical features of 46 patients newly diagnosed with either inclusion body myositis, polymyositis, or dermatomyosities. Asymmetrical muscle weakness with prominent wrist flexor, finger flexor, and knee extensor involvement was specific for inclusion body myositis and unresponsive polymyositis. Male sex, lower creatine kinase levels, slower rate of progression, and peripheral neuropathy were also more common in inclusion body myositis and unresponsive polymyositis than in responsive polymyositis and dermatomyositis patients. Repeat muscle biopsy in 2 patients in teh unresponsive polymyositis group demonstrated histological features of inclusion body myositis. We suspect that patients with clinical features of inclusion body myositis but lacking histological confirmation may nonetheless have inclusion body myositis. Our study supports the recently proposed criteria for defintie and possible inclusion body myositis.
Origin and functional consequences of the complex I defect in Parkinson's disease
Authors: Swerdlow Russell H. , Parks Janice K. , Miller Scott W. , Davis Robert E. , Tuttle Jeremy B. , Trimmer Patricia A. , Sheehan Jason P. , Bennett James P. , Parker W. Davis
Published: January 2005

The mitochondrial electron transport enzyme NADH: ubiquinone oxidoreductase (complex I), which is encoded by both mitochondrial DNA and nuclear DNA, is defective in multiple tissues in persons with Parkinson's disease (PD). The origin of this lesion and its role in the neurodegeneration of PD are unknown. To address these questions, we created an in vitro system in which the potential contributions of environmental toxins, complex I nuclear DNA mutations, and mitochondrial DNA mutations could be systematically analyzed. A clonal line of human neuroblastoma cells containing no mitochondrial DNA was repopulated with mitochondria derived from the platelets of PD or control subjects. After 5 to 6 weeks in culture, these cytoplasmic hybrid (cybrid) cell lines were assayed for electron transport chain activities, production of reactive oxygen species, and sensitivity to induction of apoptotic cell death by 1‐methyl‐4‐phenyl pyridinium (MPP+). In PD cybrids we found a stable 20% decrement in complex I activity, increased oxygen radical production, and increased susceptibility to 1‐methyl‐4‐phenyl pyridinium‐induced programmed cell death. The complex I defect in PD appears to be genetic, arising from mitochondrial DNA, and may play an important role in the neurodegeneration of PD by fostering reactive oxygen species production and conferring increased neuronal susceptibility to mitochondrial toxins.
Apolipoprotein E and α1‐antichymotrypsin polymorphism in Alzheimer's disease
Authors: Nacmias Benedetta , Tedde Andrea , Latorraca Stefania , Piacentini Silvia , Bracco Laura , Amaducci Luigi , Sorbi Sandro , Guarnieri Bianca Maria , Petruzzi Concetta , Ortenzi Luigi
Published: January 2005

A recent observation has shown that a common polymorphism in the α1‐antichymotrypsin (ACT) gene modifies the apolipoprotein E (ApoE) ε4‐associated Alzheimer's disease (AD) risk identifing the combination of the ACT/AA and ApoE ε4/ε4 genotypes as a potential susceptibility marker for AD. We analyzed the segregation of the ApoE and ACT polymorphism in sporadic and familial AD patients. In none of the sporadic AD patients did we find the combination of the ACT/AA and ApoE ε4/ε4 genotypes. The frequency of ApoE ε4/ε4 homozygosity in the AD sample resulted highest for the ACT/TT genotype (17.6%). Our data fail to confirm any additional association with AD beyond the ApoE ε4 allele with any ACT genotype, suggesting that ACT does not represent an additional risk factor for AD.
Exclusion of the DYT1 locus in familial torticollis
Authors: Bressman S. B. , Greene P. E. , Raymond D. , Ford B. , de Leon D. , Fahn S. , Nygaard T. G. , Warner T. T. , Almasy L. , Uitti R. J. , Heiman G. A. , Kramer P. L. , Risch N. J. , Maraganore D. M. , Harding A. E.
Published: January 2005

Clinical‐genetic studies of idiopathic torsion dystonia (ITD) indicate that the DYT1 gene on chromosome 9q34 is responsible for most childhood limb‐onset disease. The genetic basis of adult‐onset ITD is less well studied. In most multiplex adult‐onset ITD families, dystonia is limited to the cervical, cranial, or brachial muscles; in a few rare families, dystonia also involves the legs and trunk. Previous linkage studies have excluded the DYT1 locus in these atypical families. We studied two large non‐Jewish families with adult‐onset ITD limited to the cervical and brachial muscles and excluded the DYT1‐containing region. This study further restricts the role of DYT1 to childhood limb‐onset ITD and suggests that other genes are responsible for focal adult‐onset ITD.
Episodic ataxia and myokymia syndrome: A new mutation of potassium channel gene Kv1.1
Authors: Çomu Sinan , Narayanan Vinodh , Giuliani Michael
Published: January 2005

Episodic ataxia and myokymia syndrome is an autosomal dominant disorder characterized by persistent myokymia and attacks of unsteadiness, slurred speech, and tremulousness. This disease has been associated with point mutations in the potassium channel gene Kv1.1 (KCNA1), located at chromosome 12p13. Here, we describe a novel mutation within this gene in a newly diagnosed family.
Cyclosporine induces neuronal apoptosis and selective oligodendrocyte death in cortical cultures
Authors: McDonald John W. , Goldberg Mark P. , Gwag Byoung J. , Chi Shu‐Ing , Choi Dennis W.
Published: January 2005

Cyclosporine is used clinically as an immunosuppressant, but carries a risk of central nervous system toxicity due to undefined mechanisms. We examined the abiility of cyclosporine expsure to kill cultured mouse cortical neurons and glia. Mixed neuron/glial cultures exposed to 1 to 20 μM cyclosporine for 24 to 48 hours developed concentration‐dependent neuronal death, with most neurons destroyed by 20 μM cyclosporine. This Neuronal death was characterized by cell body shrinkage and bleebbing, chromatin condenstation, and internucleosomal DNA fragmentation, consistent with apoptosis. Neuronal death was reduced by addition of cycloheximide, brain‐derived neurotrophic factor, or insulin‐like growth factor I but not N‐methyl‐D‐aspartate‐ or AMPA‐type glutamate receptor antagonists. Oligodendrocytes were more sensitive to cyclosporine‐induced damage than were neurons, but astrocytes were relatively resistant. Oligodendrocyte death was accompanied by positive TUNEL (terminal deoxynucleotidyl transferase‐mediated deoxyuridinetriphosphate‐biotin nick end‐labeling) staining and was attenuatd by application of ciliary neurotrophic factor or insulin‐like growth factor I but not glutamate receptro antagonists. Present observations raise the possibility that the central nervous system toxicity syndrome associated with cyclosporine may be caused by the drug‐induced death of oligodendrocytes and neurons.
Onset of dementia is associated with apolipoprotein E ε4 in Down's syndrome
Authors: Schupf Nicole , Lee Joseph H. , Kapell Deborah , Zigman Warren , Canto Basilisa , Tycko Benjamin , Mayeux Richard
Published: January 2005

We examined the influence of apolipoprotein E (apoE) genotype on risk of dementia in 82 adults with Down's syndrome (DS). Compared with those with an apoE 3/3 genotype, the group of adults with DS with apoE 2/4, 3/4, and 4/4 genotypes were 5 times more likely to become demented (RR = 4.7; 95% CI = 1.2, 17.9). We hypothesize that the increased risk of dementia may be mediated by exacerbation of β‐amyloid deposition.
Presynaptic monoaminergic vesicles in Parkinson's disease and normal aging
Authors: Frey Kirk A. , Koeppe Robert A. , Kilbourn Michael R. , Vander Borght Thierry M. , Albin Roger L. , Gilman Sid , Kuhl David E.
Published: January 2005

We present development and human application of a method for determining the regional cerebral density of the type 2 vesicular monoamine transporter (VMAT2) using positron emission tomography (PET) and [11C]dihydrotetrabenazine (DTBZ). Previous animal studies indicate striatal VMAT2 density is linearly related to the integrity of substantia nigra dopamine neurons and is not subject to drug‐or lesion‐compensatory regulation. In the present studies, kinetic compartmental modeling was employed to estimate blood‐brain [11C]DTBZ transport (K1,) and VMAT2 binding site density (tissue‐to‐plasma DTBZ distribution volume, DV)from the cerebral and plasma DTBZ time courses her intravenous tracer injection. In controls, we found reductions of putamen DTBZ DV with advancing age, corresponding to losses of 0.77% per year in specific VMAT2 binding. Parkinson's disease (PD) patients had reduction in specific DTBZ DV in the putamen (−61%) and in the caudate nucleus (−43%). There was no overlap of lowest specific putamen DTBZ DV between individual elderly controls and PD patients. The present results indicate the suitability of [11C]DTBZ PET for objective quantification of nigrostriatal integrity, including evaluation of PD progression and its possible therapeutic modification.
Decreased striatal monoaminergic terminals in olivopontocerebellar atrophy and multiple system atrophy demonstrated with positron emission tomography
Authors: Gilman Sid , Junck Larry , Lohman Mary , Martorello Susan , Frey Kirk A. , Koeppe Robert A. , Vander Borght Thierry M. , Lee Lihsueh C. , Jewett Douglas M. , Kilbourn Michael R. , Little Roderick
Published: January 2005

We used [11C]dihydrotetrabenazine, a new ligand for the type 2 vesicular monoamine transporter (VMAT2), with positron emission tomography to study striatal monoaminergic presynaptic terminals in 4 patients with multiple system atrophy, 8 with sporadic olivopontocerebellar atrophy, and 9 normal control subjects. Specific binding in the striatum was significantly reduced in the multiple system atrophy patients as compared with the normal control group, with average reductions of 61% in the caudate nucleus (p = 0.002) and 58% in the putamen (p = 0.009). Smaller reductions were found in the sporadic olivopontocerebellar atrophy group, averaging 26% in the caudate nucleus (p = 0.05) and 24% in the putamen (p = 0.11).Mean blood‐to‐brain [11C]dihydrotetrabenazine transport (K1) was significantly different between groups only in the cerebellum, with values for the sporadic olivopontocerebellar atrophy group diminished compared with the normal control group. Cerebellar K1 was not significantly decreased in the multiple system atrophy group. The finding of reduced striatal WT2 in sporadic olivopontocerebellar atrophy patients suggests nigrostriatal pathology, indicating that some may later develop symptomatic extrapyramidal disease.
Unusual clinical presentations of cortical‐basal ganglionic degeneration
Authors: Bergeron C. , Pollanen M. S. , Weyer L. , Black S. E. , Lang A. E.
Published: January 2005

Cortical‐basal ganglionic degeneration classically presents predominantly as a motor disorder with a unique constellation of histological alterations characterized by the presence of neuronal loss and gliosis in a selective distribution, swollen achromasic neurons, and extensive deposition of abnormal tau in neurons and glia. We now report 3 patients with this distinctive pathology who presented with cognitive changes and only mild or delayed motor symptoms. In 2 patients with severe dementia, pathological changes were extensive in the anterior frontal lobe, amygdala, and hippocampus. In a third patient who had an isolated speech disturbance for 5 years before developing the more typical motor features of cortical‐basal ganglionic degeneration, the most severe changes were observed in the left motor cortex and adjacent Broca's area. It is therefore apparent that the histological changes of cortical‐basal ganglionic degeneration result in a variety of clinical presentations depending on the topography of the lesions. On this basis we conclude that cortical‐ basal ganglionic degeneration should be considered in the differential diagnosis of language disturbances and dementia, particularly when the latter is accompanied by frontal lobe symptomatology, early speech alterations, or parkinsonism.
Muscular dystrophy associated with β‐dystroglycan deficiency
Authors: Salih Mustafa A. M. , Sunada Yoshihide , Al‐Nasser M. , Ozo C. O. , Al‐Turaiki M. H. S. , Akbar Maksood , Campbell Kevin P.
Published: January 2005

β‐Dystroglycan, a 43‐kd transmembrane dystrophinassociated glycoprotein, plays an important role in linking dystrophin to the laminin‐binding α‐dystroglycan. α‐/β‐Dystroglycan is encoded by a single gene on chromosome 3p21 and ubiquitously expressed in muscle and nonmuscle tissues. No known human diseases have been mapped to this locus. Here, we describe the selective deficiency of β‐dystroglycan in a 4‐year‐old Saudi boy with muscular dystrophy. The patient had a borderline elevation of serum creatine kinase level and early‐onset proximal symmetrical muscle weakness and wasting without calf hypertrophy. The milder phenotype may suggest a secondary deficiency of β‐dystroglycan; however, the unique immunofluorescence labeling suggests that the patient may present a novel form of muscular dystrophy.
Wide range in age of onset for chromosome 1‐related familial Alzheimer's disease
Authors: Bird Thomas D. , Levy‐Lahad Ephrat , Poorkaj Parvoneh , Sharma Vikram , Nemens Ellen , Lahad Amnon , Lampe Thomas H. , Schellenberg Gerard D.
Published: January 2005

Mutations in three different genes on chromosomes 1, 14, and 21 cause autosomal dominant forms of familial Alzheimer's disease (FAD). Most result in an early‐onset phenotype. However, several kindreds of Volga German ancestry have the same chromosome 1 gene mutation and demonstrate a relatively older mean age of onset and include individuals with late age of onset. In these families, the mean age of onset is 54.9 ± 8.4 years (range, 40–75 years), mean age at death is 65.9 ± 10.2 years (range, 43–88 years), and mean disease duration is 11.3 ± 4.6 years (range, 5–23 years). This contrasts with a group of 7 families with chromosome 14 mutations in which the mean age of onset is 44.8 ± 4.8 years (range, 30–55 years), mean age at death is 52.6 ± 5.7 years (range, 39–65 years), and mean disease duration is 7.6 ± 3.2 years (range, 2–17 years). (All means are significantly different in the 2 groups of families, p < 0.005.) In the chromo‐some 1 families, 7 persons (16%) had an age of onset at or older than 65 years and 22 (54%) survived to age 65 or older versus none in the chromosome 14 families. An example of probable nonpenetrance of disease at age 89 was also found in a chromosome 1 kindred. It is concluded that, unlike the chromosome 14 gene, mutations in the chromosome 1 FAD gene may result in individuals with a late age of onset overlapping with the more common sporadic form of the disease occurring in the general population. In light of the great variability in age of onset in persons with identical mutations, study of the genetic and environmental factors contributing to delayed onset of disease in chromosomal 1 FAD kindreds will be an important area for further investigation. Apolipoprotein E genotype may be one such factor that plays a partial role in this variability.
Loss of tuberin from cerebral tissues with tuberous sclerosis and astrocytoma
Authors: Mizuguchi Masashi , Kato Mitsuhiro , Yamanouchi Hideo , Ikeda Kazuhiko , Takashima Sachio
Published: January 2005

We studied the expression of tuberin, the TSC2 gene product, in cerebra with or without tuberous sclerosis. Tuberin was abundant in the gray matter of normal cerebra, but was undetectable in the subependymal astrocytomas from 3 patients with tuberous sclerosis. In 1 patient, cortical tubers and normally appearing cortical tissue also showed a marked loss of tuberin. These results indicate the critical role of tuberin in the neuropathology of tuberous sclerosis.
Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease
Authors: Gómez‐Isla Teresa , Hollister Richard , West Howard , Mui Stina , Growdon John H. , Petersen Ronald C. , Parisi Joseph E. , Hyman Bradley T.
Published: January 2005

To assess the relationship between dementia, neuronal loss, and neuropathological findings in Alzheimer's disease (AD), we counted the number of neurons, senile plaques, and neurofibrillary tangles in a high‐order association cortex. We studied the superior temporal sulcus of 34 individuals with AD and 17 nondemented control subjects, using statistically unbiased, stereological counting techniques. The number of superior temporal sulcus neurons in nondemented control subjects was stable across the sixth to ninth decades. In AD, more than 50% of the neurons were lost. Both neuronal loss and neurofibrillary tangles increased in parallel with the duration and severity of illness, but the amount of neuronal loss exceeded by manyfold the amount of neurofibrillary tangles accumulated. In contrast to the correlation between neurofibrillary tangels and neuronal loss, the number of senile plaques and the percentage of the superior temporal sulcus that was covered by Aβ (amyloid burden) were not related to neuronal loss, number of neurofibrillary tangles, or duration of disease. Neither the amount nor the rate of neuronal loss in the superior temporal sulcus in AD correlated with apolipoprotein E genotype. These data suggest that neuronal loss in association areas such as the superior temporal sulcus contributes directly to cognitive impairment in AD.
The Role of MRI in clinical trials of multiple sclerosis: Comparison of image processing techniques
Authors: Evans A. C. , Frank J. A. , Antel J. , Miller D. H.
Published: January 2005

Magnetic resonance imaging (MRI) has received considerable attention in recent years its potential for providing indics of multiple sclerosis activity and progression in clinical trials of new pharmaceuticals. The percieved advantages of MRI‐derived measurements include greather objectivity, sensitivity, and reproducibility when compared with clinical rating scales. Clinical scales are also somewhat biased toward lesions affecting locomotion. However, the myriad permutations of MRI acquisition parameters, analysis methodologies, and disease indices demand careful cosideration when employing MRI. Moreover, the use of MRI in research into the basic mechanisms of a disease may have different requirements than its use in a clinical trial setting. Consequently, a conference was held, sponsored by the US and Canadian multiple sclerosis societies, to review the present status of various MRI processing strategies and their potential role in clinical trials. Thirteen labortories from North America and Europe as well as regulatory agencies and statistical condultants made formal presentations followed by extended discussion. This report presents the conclusions reached and recommendations for further action that emerged from the meeting.
Deletion and conversion in spinal muscular atrophy patients: Is there a relationship to severity?
Authors: Didonato Christine J. , Ingraham Susan E. , Mendell Jerry R. , Prior Thomas W. , Lenard Sharon , Moxley Richard T. , Florence Julaine , Burghes Arthur H. M.
Published: January 2005

The spinal muscular atrophy—determining gene, survival motor neuron (SMN), is present in two copies, telSMN and cenSMN, which can be distinguished by base‐pair changes in exons 7 and 8. The telSMN gene is often absent in spinal muscular atrophy patients, which could be due to deletion or sequence conversion (telSMN conversion to cenSMN giving rise to two cenSMN genes). To test for conversion events in spinal muscular atrophy, we amplified a 1‐kb fragment that spanned exons 7 and 8 of SMN from 5 patients who retained telSMN exon 8 but lacked exon 7. In all patients, sequence analysis demonstrated that cenSMN exon 7 was adjacent to telSMN exon 8, indicating conversion. All 5 patients with this mutation had type II or III spinal muscular atrophy, strongly supporting an association with chronic spinal muscular atrophy. We also identified 3 families in which 2 siblings had no detectable telSMN but presented with markedly different phenotypes. We suggest that sequence conversion is a common event in spinal muscular atrophy and is associated with the milder form of the disease. The severity, however, can be modified in either a positive or negative direction by other factors that influence splicing or expression of the sequence converted SMN gene.
A novel mitochondrial tRNA phenylalanine mutation presenting with acute rhabdomyolysis
Authors: Chinnery P. F. , Johnson M. A. , Taylor R. W. , Lightowlers R. N. , Turnbull D. M.
Published: January 2005

We describe a patient who presented with acute rhabdomyolysis and had 68% cytochrome c oxidase (COX)‐deficient fibers in skeletal muscle. Further investigations confirmed a respiratory chain defect that was associated with a novel heteroplasmic point mutation in the phenylalanine tRNA gene of the mitochondrial genome (mtDNA). Analysis of single muscle fibers revealed a significantly greater level of mutant mtDNA in COX‐negative fibers. This is the first case of a mitochondrial tRNA gene point mutation presenting with acute rhabdomyolysis and recurrent myoglobinuria.
Acetylcholine receptor expression in human extraocular muscles and their susceptibility to myasthenia gravis
Authors: MacLennan C. , Beeson D. , Buijs A.‐M. , Vincent A. , Newsom‐Davis J.
Published: January 2005

In myasthenia gravis (MG), extraocular muscle (EOM) weakness is often an initial and persisting symptom. It has been proposed that acetylcholine receptor (AChR) from EOM is antigenically different from AChR of other innervated muscles and that the presence of antibodies to fetal AChR expressed in EOM causes their weakness. We have (1) studied mRNA expression for each of the AChR subunits (α, β, γ, δ, and ϵ) in human muscle, including EOM, and (2) compared the binding of sera from ocular myasthenia gravis (OMG) patients with fetal (α2βγδ) and adult (α2βϵδ) human AChRs. RNase protection assays showed that expression of the AChR γ‐subunit (fetal‐type) mRNA in EOM was comparable with that in other innervated muscle types. By contrast, ϵ‐subunit (adult‐type) mRNA was expressed at much higher levels in EOM than in other muscles studied. Moreover, some OMG sera bound specifically to adult AChR. These results do not support the contention that susceptibility of EOM in MG results from expression of fetal AChR and indicate that the inclusion of antigen from a source rich in adult AChR in the MG diagnostic assay will increase the yield of positive results in OMG patients.
Gene locus for autosomal recessive distal myopathy with rimmed vacuoles maps to chromosome 9
Authors: Ikeuchi Takeshi , Asaka Tomoya , Saito Masaaki , Tanaka Hajime , Higuchi Sari , Tanaka Keiko , Saida Kyoko , Uyama Eiichiro , Mizusawa Hidenobu , Fukuhara Nobuyoshi , Nonaka Ikuya , Takamori Masaharu , Tsuji Shoji
Published: January 2005

Distal myopathy with rimmed vacuoles is an autosomal recessive muscular disorder, characterized clinically by weakness of the distal muscles in the lower limbs in early adulthood. Recently, the gene locus for familial vacuolar myopathy with autosomal recessive inheritance (hereditary inclusion body myopathy) was mapped to chromosome 9 by genome‐wide linkage analysis of nine Persian‐Jewish families. Since both disease conditions share similar clinical, genetic, and histopathological features, we analyzed seven families with distal myopathy with rimmed vacuoles using ten microsatellite markers within the region of the hereditary inclusion body myopathy locus. Significantly high cumulative pairwise lod scores were obtained with three markers: D9S248 (Zmax = 5.90 at Θ = 0), D9S43 (Zmax = 5.25 at Θ = 0), and D9S50 (Zmax = 4.23 at Θ = 0). Detection of obligate recombination events as well as multipoint linkage analysis revealed that the most likely location of the distal myopathy with rimmed vacuoles gene is in a 23.3‐cM interval defined by D9S319 and D9S276 on chromosome 9. The results raise the possibility that distal myopathy with rimmed vacuoles and hereditary inclusio body myopathy in Persian Jews are allelic diseases.
A familial syndrome of congenital cataract, mental impairment, and dentate gyrus atrophy
Authors: Hudson Arthur J. , Munoz David G.
Published: January 2005

We present a family with congenital cataract with, in some cases, mental retardation and emotional instability, but intellectual deterioration in all affected members. The latter was accompanied by psychosis in some. The inheritance is most likely autosomal dominant, affecting two generations and consisting of a congenitally blind parent and 6 of 11 of her offspring. In addition to these features, some affected individuals had dysphagia and movement disorder, especially choreiform movements. They all showed small body mass, due possibly to poor nutrition from dysphagia. The pathological findings were unique, demonstrating selective atrophy of the granule cell layer of the dentate gyrus. There was selective expression in paraffin‐embedded sections of αB‐crystallin (CRYA2) in oligodendroglia in all areas of the nervous system examined. αB‐Crystallin is a major optic lens protein but also a heat shock protein and molecular chaperone found in brain and a number of other tissues. Because of the association of congenital cataract and the accumulation in oligodendroglia of αB‐crystallin, the gene for this protein was sequenced for possible mutation. No mutation was found indicating other genetic locus. This family appears to have a newly recognized genetic disorder.
Clinical utility of diffusion‐weighted magnetic resonance imaging in the assessment of ischemic stroke
Authors: Lutsep H. L. , Albers G. W. , Decrespigny A. , Kamat G. N. , Marks M. P. , Moseley M. E.
Published: January 2005

Diffusion‐weighted imaging (DWI) detects small changes in water diffusion that occur in ischemic brain. This study evaluated the clinical usefulness of a phase‐navigated spin‐echo DWI sequence compared with T2‐weighted magnetic resonance imaging (T2W MRI) in patients with cerebral ischemia and assessed apparent diffusion coefficient (ADC) and T2‐weighted imaging (T2WI) changes over time. ADC values and T2 ratios of image intensity were measured from the region of ischemia and from the corresponding contralateral brain region. The clinical histories of patients with DWI scans obtained over the course of 1 year were reviewed to ascertain whether DWI aided in clinical diagnosis or management. Of 103 scans obtained a mean of 10.4 days after symptom onset, DWI detected six lesions not seen on T2WI and discriminated two new infarcts from old lesions. DWI was most useful within 48 hours of the ictus. The evolution of ADC values and T2 ratios was evaluated in 26 cases with known symptom onset times. ADC values were low at less than 1 week after stroke onset and became elevated at chronic time points. T2 ratios were near normal acutely, increasing thereafter. DWI was superior to T2W MRI in detecting acute stroke, whereas both techniques assisted in determining lesion age.
Altered intrathymic T‐cell repertoire in human myasthenia gravis
Authors: Truffault Frédérique , Cohen‐Kaminsky Sylvia , Khalil Iman , Levasseur Philippe , Berrih‐Aknin Sonia
Published: January 2005

In myasthenia gravis, the thymus is thought to be the primary site of autosensitization. We investigated the Vβ T‐cell repertoire at different intrathymic differentiation stages in 17 patients with myasthenia gravis and 8 age‐matched control subjects by tricolor immunofluorescence, using a panel of six anti‐Vβ antibodies. We observed an increased expression of Vβ5.1 and Vβ8 subfamilies in the patients compared to the control subjects. These increases were observed not only in mature cells but also in the latest thymic precursors of mature cells (double‐positive CD3 high), while there was no change in intermediate precursors (double‐positive CD3 low), pointing to biased selection during intrathymic differentiation. In addition, there was a strong correlation between the percentage of Vβ5.1+ and Vβ8+ cells among both the CD4 and CD8 subsets in the patients, but not in control subjects, suggesting that thymic events relevant to the disease lead to these selected populations. Finally, location studies of Vβ5.1+ cells on thymic sections indicated that these cells were overrepresented both in the core of germinal centers and in perifollicular areas of hyperplastic thymuses, suggesting a role in the autoimmune response. Taken together, these findings are compatible with the hypothesis of a biased intrathymic selection in myasthenia gravis.
Presenilin‐1 protein expression in familial and sporadic Alzheimer's disease
Authors: Levey Allan I. , Heilman Craig J. , Lah James J. , Nash Norman R. , Rees Howard D. , Wakai Masakazu , Mirra Suzanne S. , Rye David B. , Nochlin David , Bird Thomas D. , Mufson Elliott J.
Published: January 2005

Mutations of the presenilin PS1 and PS2 genes are closely linked to aggressive forms of early‐onset (<60 years) familial Alzheimer's disease. A highly specific monoclonal antibody was developed to identify and characterize the native PS1 protein. Western blot analyses revealed a predominant 32‐kd immunoreactive polypeptide in a variety of samples, including PC12 cells transfected with human PS1 complementary DNA, brain biopsy specimens from demented patients, and postmortem samples of frontal neocortex from early‐onset familial Alzheimer's disease cases (PS1 and PS2), lateonset sporadic Alzheimer's disease cases, and cases of other degenerative disorders. This truncated polypeptide contains the N‐terminus of PS1 and appeared unchaged across cases. In 2 early‐onset cases linked to missense mutations in the PS1 gene, a PS1 immunoreactive protein (∼49 kd) accumulated in the frontal cortex. This protein was similar in size to full‐length PS1 protein present in transfected cells overexpressing PS1 complementary DNA, and in lymphocytes from an affected individual with a deletion of exon 9 of the PS1 gene, suggesting that mutations of the PS1 gene perturb the endoproteolytic processing of the protein. Immunohistochemical studies of control brains revealed that PS1 is expressed primarily in neurons, with the protein localized in the soma and dendritic processes. In contrast, PS1 showed striking localization to the neuropathology in early‐onset familial Alzheimer's disease and sporadic Alzheimer's disease cases. PS1 immunoreactivity was present in the neuritic component of senile plaques as well as in neurofibrillary tangles. Localization of PS1 immunoreactivity in familial and sporadic Alzheimer's disease suggests that genetically heterogeneous forms of the disease share a common pathophysiology involving PS1 protein.
Multiple sclerosis: Re‐expression of a developmental gene in chronic lesions correlates with remyelination
Authors: Capello Elisabetta , Voskuhl Rhonda R. , McFarland Henry F. , Raine Cedric S.
Published: January 2005

Central nervous system tissue from multiple sclerosis and non‐multiple sclerosis subjects was studied for the expression of exon 2 myelin basic protein gene products at the protein and message levels by immunocytochemistry and in situ hybridization, respectively. The exon 2‐encoded protein sequence is normally expressed during development (myelination) within the 21 · 5‐ and 20 · 2‐kd isoforms of myelin basic protein and is downregulated in the adult central nervous system where the 18 · 5‐ and 17 · 2‐kd isoforms predominate, the latter devoid of exon 2 owing to alternative splicing. Exon 2 myelin basic protein gene products were readily demonstrable in multiple sclerosis samples, the highest levels correlating with remyelination in chronic lesions while normal adult central nervous system and non‐multiple sclerosis material showed very low levels and fetal human central nervous system tissue (a positive control) showed high levels. We conclude that recapitulation of ontogenetic events during myelin repair accounts for the increased expression of the exon 2‐encoded protein sequence in the adult central nervous system during multiple sclerosis, an event that might underly the previously observed T‐cell activation to this protein sequence during relapses.
Dopamine D1 and D2 receptor gene expression in the striatum in Huntington's disease
Authors: Augood S. J. , Faull R. L. M. , Emson P. C.
Published: January 2005

The cellular expression of dopamine D1 and D2 receptor mRNAs was investigated in the postmortem human caudate nucleus of control cases and genetically and pathologically confirmed cases of Huntington's disease (HD) by using quantitative in situ hybridization. The HD cases were categorized (0–4) by severity of striatal neuropathology according to the Vonsattel scale. For the HD grade 0 case, a pronounced reduction in the number of D1 and D2 mRNA‐positive cells was observed compared with controls; however, the abundance of both receptor mRNAs per remaining cell was within the control range. For D2 receptor mRNA, the number of detectable D2−positive medium‐sized cells decreased with increasing pathology; this decrease was accompanied by a gradual reduction in the intensity of D2 signal per cell. By contrast, for D1 receptor mRNA, despite a decrease in the number of D1 mRNA‐positive cells detected, the average cellular expression of D1 mRNA was markedly reduced in the HD grade 1 case and then increased (relative to the grade 1 case) with increasing pathology, presumably reflecting the relative survival of D1−expressing striatal interneurons. The implications of these findings for providing further information on the neurodegenerative process in HD are discussed.
Apolipoprotein E genotypes in a neuropathological series from the consortium to establish a registry for Alzheimer's disease
Authors: Welsh‐Bohmer Kathleen A. , Gearing Marla , Saunders Ann M. , Roses Allen D. , Mirra Suzanne
Published: January 2005

We evaluated the sensitivity, specificity, and predictive value of the apolipoprotein E (ApoE) ε4 allele for the neuropathological diagnosis of Alzheimer disease (AD) in a clinical series of well‐characterized AD patients and controls followed longitudinally in the multicenter study of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). In the 162 patients for whom autopsy and ApoE genotype data were available, the clinical diagnosis of AD was verified as the primary cause of dementia in 139 cases (139 of 162, or 86%). The sensitivity and specificity of the ε4 allele for AD were both 83%. The positive predictive value of the ε4 allele was very high at 97% (115 of 119); whereas, the negative predictive value was 44% (19 of 43), providing no useful information for diagnosis of AD when the ε4 allele is not present. Of the cases where AD was not considered the primary or sole cause of dementia (n = 23), 6 cases exhibited concomitant neuropathological findings of definite or probable AD and 2 of these 6 cases had at least one ε4 allele. These multicenter data extend previous obsevations reported from smaller case series of single laboratories and demonstrate that once the clinical diagnosis of AD is established, the presence of an ε4 allele reliably predicts the ultimate CERAD neuropathological diagnosis of AD. The findings also suggest that ApoE genotype information is useful clinically in bolstering diagnostic confidence when an ε4 allele is present and in identifying a group of patients for whom additional diagnostic evaluations may be warranted when the 4 allele is absent.
Apolipoprotein E ε2 does not increase risk of early‐onset sporadic Alzheimer's disease
Authors: Scott W. K. , Saunders A. M. , Gaskell P. C. , Locke P. A. , Growdon J. H. , Farrer L. A. , Auerbach S. A. , Roses A. D. , Haines J. L. , Pericak‐Vance M. A.
Published: January 2005

We examined the association of apolipoprotien E (ApoE) genotype and the risk of early‐onset Alzheimer's disease (AD) in 209 white early‐onset sporadic cases (43% male) and 303 white controls (48% male) of similar age distribution. The risk of AD was significantly increased, relative to the 3/3 genotype, in people with the 4/4, 3/4, and 2/4 genotypes, controlling for age at time of examination and sex. The 2/3 genotype reduced slightly the risk of AD, although the effect was not statistically significant. We conclude, contrary to some previous reprots, that the ApoE ε2 allele does not increase the risk of early‐onset sporadic AD.
Melatonin: A clinical perspective
Authors: Penev Palmen D. , Zee Phyllis C.
Published: January 2005

Over the last several decades the pineal gland has emerged as an active neuroendocrine transducer of important environmental information. However, the current understanding of the function of its major hormone, melatonin, in humans remains ill defined and based exclusively on corelative observations. In a similar manner, the multitude of phenomenological descriptions of the effects of exogenous melatonin is contrasted by the limited understanding of the underlying mechanisms and the lack of firmly established clinical applications for the hormone. Future randomized, double‐blind, placebo‐controlled clinical studies wil be necessary to determine the precise indications, treatment regimens, and safety of melatonin in clinical practice. The recent rapid progress in the area of melatonin research should lead to a better understanding of its role in human health and disease.
Functional magnetic resonance imaging of single motor events reveals human presupplementary motor area
Authors: Humberstone Miles , Sawle Guy V. , Clare Stuart , Hykin Jonathan , Coxon Ronald , Bowtell Richard , Macdonald Ian A. , Morris Peter G.
Published: January 2005

Conventional functional imaging paradigms use periods of repetitive task performance to generate sustained functional signal changes. We have developed a technique of imaging the small, transient signal changes that occur after single cognitive events. The technique uses echo‐planar imaging at 3 T to generate functional images of the whole brain with a temporal resolution of 3 seconds. It uses a signal averaging technique to create time sweeps of functional activity. After a single cognitive event, widely distributed patterns of brain activation can be detected and their time course measured. This technique enables the individual cognitive tasks that constitute a paradigm to be analyzed separately and compared. We describe the application of this new technique to separate the cognitive elements in a simple “go/no‐go” motor paradigm. Comparison of activation patterns during “go” and “no‐go” responses reveals hierarchical subdivision of the medial premotor cortex into an anterior region (presupplementary motor area) involved in movement decision making and a posterior region (supplementary motor area proper) directly involved in motor execution.