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D H Geschwind

Publications and source records attributed to D H Geschwind.

At least 19 recordsLinked to original sources
PubMed2001

SCA8 repeat expansions in ataxia: a controversial association.

The observation of large SCA8 alleles in healthy control subjects and nonataxic patients, together with a lack of segregation of the expanded repeat with ataxia in several families, has raised questions about the pathogenic role of the SCA8 expansion. The authors found allele sizes within the proposed pathogenic range in three patients with ataxia of unknown etiology, in two individuals from pedigrees with either SCA2 or Friedreich's ataxia, and in two patients with Alzheimer's disease. Sizing of SCA8 alleles should not be a routine diagnostic test until its etiologic role is clarified and the pathogenic threshold is determined.

Adult↗
PubMed2001

Molecular approaches to cerebral laterality: development and neurodegeneration.

Little is understood about the genetic or epigenetic mechanisms that underlie brain asymmetry. Because higher cognitive functions such as language, constructional and spatial abilities, and attention are organized along the left/right axis, understanding the underpinnings of this process has significant implications for both developmental biology and cognitive neuroscience. However, scientists have begun to explore, in only the most preliminary manner, the influences of subtle biologically inherited brain asymmetries on human behavior and disease. Because brain asymmetry develops prenatally, the recognition of asymmetry in neurodegeneration implies a possible relationship between the development of cerebral laterality and regional vulnerability in neurodegenerative diseases. This suggests that the study of cerebral asymmetry and laterality is likely to be relevant to a number of degenerative conditions that were previously considered to be only diseases of aging. In this article, I will outline our perspective and some of the approaches that my laboratory has begun to take to characterize the molecular basis of cerebral asymmetry. Most of these data are preliminary and the models presented are highly speculative, reflecting the primitive stage of work defining the molecular basis of cerebral asymmetry.

Brain↗
PubMed2001

From hematopoiesis to neuropoiesis: evidence of overlapping genetic programs.

It is reasonable to propose that gene expression profiles of purified stem cells could give clues for the molecular mechanisms of stem cell behavior. We took advantage of cDNA subtraction to identify a set of genes selectively expressed in mouse adult hematopoietic stem cells (HSC) as opposed to bone marrow (BM). Analysis of HSC-enriched genes revealed several key regulatory gene candidates, including two novel seven transmembrane (7TM) receptors. Furthermore, by using cDNA microarray techniques we found a large set of HSC-enriched genes that are expressed in mouse neurospheres (a population greatly enriched for neural progenitor cells), but not present in terminally differentiated neural cells. In situ hybridization demonstrated that many of them, including one HSC-enriched 7TM receptor, were selectively expressed in the germinal zones of fetal and adult brain, the regions harboring mouse neural stem cells. We propose that at least some of the transcripts that are selectively and commonly expressed in two or more types of stem cells define a functionally conserved group of genes evolved to participate in basic stem cell functions, including stem cell self-renewal.

Animals↗
PubMed2001

Association of moderate polyglutamine tract expansions in the slow calcium-activated potassium channel type 3 with ataxia.

BACKGROUND: The small-conductance calcium-activated potassium channel gene (hSKCa3) contains 2 CAG repeats, 1 of which is highly polymorphic. Although this repeat is not pathologically expanded in patients with schizophrenia, some studies have suggested an allelic association with schizophrenia. CAG expansions in other genes such as the alpha1 subunit of a brain-specific P/Q-type calcium channel gene cause spinocerebellar ataxia type 6, whereas the length of the CAG repeat in the RAI1 gene modifies the age of onset of spinocerebellar ataxia type 2. OBJECTIVES: To evaluate expansions in the hSKCa3 polyglutamine domain as causative for ataxia, and to study the association between the length of the polyglutamine repeat and the presence of ataxia. METHODS: We analyzed this repeat in 122 patients with autosomal dominant cerebellar ataxia, or sporadic ataxia, and compared allele distribution with 750 alleles seen in 2 healthy control groups and 172 alleles in patients with Parkinson disease. RESULTS: The distribution of alleles in ataxia patients and controls was significantly different by Wilcoxon rank test (P <.001). Twenty-two or more polyglutamine tracts were more common in ataxia patients compared with controls by chi2 analysis (P<.001). CONCLUSION: Longer stretches of polyglutamines in a human potassium channel are not causative for ataxia, but they are associated with the presence of ataxia. There is no association with the presence of Parkinson disease.

Age of Onset↗
PubMed2001

The SCA12 mutation as a rare cause of spinocerebellar ataxia.

BACKGROUND: Spinocerebellar ataxias are a group of phenotypically and genetically heterogeneous disorders characterized by progressive degeneration of the cerebellum. The expansion of a CAG repeat upstream of the PP2APR55beta gene has been recently reported as a novel cause of a dominantly inherited ataxia (SCA12) in a kindred with limb tremor as an early feature. OBJECTIVE: To explore the relative frequency of SCA12 among familial and sporadic spinocerebellar ataxias in an ethnically diverse patient population. METHODS: We used polymerase chain reaction to analyze CAG repeat size in a series of patients presenting to an ataxia clinic in California. RESULTS: The SCA12 expansion was not detected in any of the cases investigated. The largest allele found had 22 repeats, a finding within the proposed nonpathogenic range. Distribution of repeat size and heterozygosity were similar to that described previously. CONCLUSIONS: These results, coupled with findings in other populations, indicate that the SCA12 mutation is a rare cause of spinocerebellar degeneration. Diagnostic testing for SCA12 should be considered in patients with cerebellum disorders and an atypical clinical phenotype, especially when tremor is initially present.

Alleles↗
PubMed2001

Dementia and neurodevelopmental predisposition: cognitive dysfunction in presymptomatic subjects precedes dementia by decades in frontotemporal dementia.

Dementia is typically thought of as a disease caused by the process of aging. Few studies have addressed the premorbid neuropsychological alterations in subjects at risk for the disease--an issue of great importance for the understanding and treatment of degenerative dementias. We used knowledge of the mutation carrier status in a family with inherited dementia to address this issue more efficiently than is possible in the general population, or in cases of inherited dementia where the mutational basis is unknown. Standard neuropsychological tests were used to detect evidence of dysfunction in frontal executive systems in 10 presymptomatic subjects with known mutation carrier status in the highly penetrant condition, frontotemporal dementia and parkinsonism linked to chromosome 17. Presymptomatic carriers demonstrated cognitive dysfunction that was not present in 6 nonmutation-carrying relatives. Strikingly, frontal-executive dysfunction was apparent in some of the youngest mutation carriers many decades prior to the predicted onset of dementia. Thus, this dysfunction may reflect the native cognitive capacities of affected subjects. These results suggest a potentially important neurodevelopmental component to a dementing condition that has been predominantly considered to be a disease of aging; accordingly, this issue warrants study in other families to assess the applicability of these findings.

Adolescent↗
PubMed2001

Microarray applications in neuroscience.

Advances in all facets of technology from molecular biology to imaging and computational biology offer unprecedented opportunities for improving our understanding of the brain in health and disease. Oligonucleotide and cDNA microarray analysis, using a variety of "DNA chips," is a recently developed high-throughput technique that allows for tour-de-force analysis of gene expression. We review this powerful technique, developed in genetics laboratories, with reference to applications in neurologic diseases in humans and the use of animal models. The typical microarray experiment is multistaged and includes preparation or purchase of arrays, preparation of target DNA and probe, target DNA hybridization, microarray scanning, and image analysis. The power and pitfalls of this technology are discussed in the context of neuroscience paradigms. Since unprecedented amounts of data are produced from microarray experiments, bioinformatics and modeling expertise are increasingly becoming critical components of this approach.

Animals↗
PubMed2001

A genetic analysis of neural progenitor differentiation.

Genetic mechanisms regulating CNS progenitor function and differentiation are not well understood. We have used microarrays derived from a representational difference analysis (RDA) subtraction in a heterogeneous stem cell culture system to systematically study the gene expression patterns of CNS progenitors. This analysis identified both known and novel genes enriched in progenitor cultures. In situ hybridization in a subset of clones demonstrated that many of these genes were expressed preferentially in germinal zones, some showing distinct ventricular or subventricular zone labeling. Several genes were also enriched in hematopoietic stem cells, suggesting an overlap of gene expression in neural and hematopoietic progenitors. This combination of methods demonstrates the power of using custom microarrays derived from RDA-subtracted libraries for both gene discovery and gene expression analysis in the central nervous system.

Animals↗
PubMed2001

Neuropsychological profiles of adults with Klinefelter syndrome.

Children and adolescents with Klinefelter syndrome (XXY) have been reported to show deficits in language processing including VIQ < PIQ and a learning disability in reading and spelling. However, whether this is characteristic of adults with Klinefelter syndrome has not been established. Thirty-five men with Klinefelter syndrome, aged 16 to 61, and 22 controls were evaluated with a comprehensive neuropsychological battery. The Klinefelter patients scored significantly below controls in language skills, verbal processing speed, verbal and nonverbal executive abilities, and motor dexterity. Within the Klinefelter sample, three cognitive subgroups were identified: VIQ 7 or more points below PIQ (n = 10), VIQ within 6 points of PIQ (n = 12), and PIQ 7 or more points below VIQ (n = 12). The deficits detected in language, verbal processing speed, and verbal executive skills were found to be isolated to the VIQ < PIQ subgroup, while the abnormalities in motor dexterity and nonverbal executive skills were confined to the PIQ < VIQ subgroup. Older age was significantly correlated with increases in VIQ relative to PIQ in the patient group, which suggests the intriguing possibility that the PIQ < VIQ subgroup primarily emerges in young adulthood, perhaps in response to the reported hormonal abnormalities detected in Klinefelter syndrome patients during puberty.

Adolescent↗
PubMed2001

Sharing gene expression data: an array of options.

Sharing of microarray data has many advantages for the scientific and biomedical community, and should be advocated by neuroscience journals. The goals of sharing are manifold, and include improving analysis and confidence in results, and facilitating global comparisons between experiments, while at the same time, not penalizing those who share. The sharing of microarray data poses unique challenges relative to more generic data such as DNA sequences. These challenges are surmountable, and various sharing formats are possible. Centralized non-commercial databases are being developed to facilitate this process.

Animals↗
PubMed2000

Neurobehavioral phenotype of Klinefelter syndrome.

A defined genetic syndrome with neurobehavioral components offers an unusual paradigm for the correlation of genetic defects with neurodevelopmental abnormalities. The power of the combination of detailed behavioral, neuroanatomical, and genetic studies has been demonstrated in studies of other conditions involving the sex chromosomes, such as Fragile X syndrome (Mazzocco [2000] Ment Retard Develop Disabil Res Rev. 6:96-106) and Turner syndrome (Ross [2000] Ment Retard Develop Disabil Res Rev. 6:135-141). Although the behavioral and neurologic difficulties that have been identified in Klinefelter syndrome (KS) are in most cases milder than the consequences of many other genetic syndromes, the deficits in KS cause significant morbidity, representing a more common, but poorly understood, subtype of those with learning disabilities. Both as children and as adults, KS subjects appear to offer a powerful genetic model for the study of language and language-based learning disabilities. Although it has been proposed that the language-based learning difficulties of KS boys are similar to those of nonaneuploidic dyslexics [Bender et al., 1986; Geschwind et al., 1998], this is not yet well established. The co-morbid frontal-executive dysfunction observed in KS is also a likely contributor to learning difficulties and, perhaps, social cognition, in many KS patients. It is also proposed that altered left-hemisphere functioning, whether causing, or due to, altered functional and anatomical cerebral dominance, is at the core of KS subjects' language problems. Although X chromosomal loci can provide only part of the picture, the study of KS subjects, a population with a relatively homogeneous etiology for dyslexia/dysphasia and frontal-executive dysfunction, offers many advantages over such a study in the general population, in which both dyslexia and attentional disorders are quite genetically heterogeneous [Decker and Bender, 1988; Pennington, 1990; Grigorenko et al., 1997; Geschwind et al., 1998]. Furthermore, the interaction of genetic factors and hormonal influences in the cognitive phenotypes described remains an unexplored area for future investigation. MRDD Research Reviews 2000;6:117-124.

Behavior↗
PubMed1999

Inheritance of frontotemporal dementia.

BACKGROUND: Previous studies of families with fronto-temporal dementia (FTD) support an autosomal dominant inheritance pattern, but most studies have described genetic transmission in individual families specifically selected for the presence of multiple affected individuals. OBJECTIVE: To investigate the familial presentation and inheritance of FTD and related disorders among a large group of FTD index cases unselected for family history of dementia. DESIGN AND SETTING: We interviewed family members and reviewed medical records and autopsy reports at a university hospital and a university-affiliated hospital to determine the frequency of familial FTD and the most likely mode of inheritance. Characteristic families with the disorder are described, along with the history, clinical findings, and neuroimaging results in affected members of these families. PATIENTS AND PARTICIPANTS: The 42 index cases of FTD had a mean age of onset of 56.1 years (range, 40-69 years). Of these patients, 21 (50%) were women. All but one of the patients were white. Participants included male and female spouses and children of the index cases. family member with an FTD spectrum disorder and were considered familial cases. The majority (17 [89%]) of familial FTD cases showed a pattern consistent with dominant inheritance. If depression is excluded, familial cases decrease from 19 (45%) to 17 (40%), of which 15 (88%) showed a dominant transmission pattern. The initial presentations in the nonindex familial cases varied but most frequently consisted of personality and behavioral changes that preceded cognitive impairment (19 [43%]), followed by psychiatric illness (14 [33%]), dementia without behavioral change (5 [11%]), amyotrophic lateral sclerosis (5 [11%]), and parkinsonism (2[5%]). Two of the affected nonindex cases had dual presenting diagnoses. The average age of onset was 56.1 years and did not differ significantly between familial and nonfamilial cases. Onset of FTD-related symptoms occurred after the age of 65 years in only 4(10%) of 42 index cases and 3 (5%) of 60 affected relatives. CONCLUSIONS: Familial FTD is usually inherited in an autosomal dominant pattern. The initial onset is insidious, often consisting of mood and behavioral changes occurring in presenile years that are often erroneously attributed to other nonneurologic causes. Although the precise incidence of FTD in North America is not known, it is one of the most common presenile dementias.

Adult↗