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D H Geschwind

Publications and source records attributed to D H Geschwind.

47 records · Page 3Linked to original sources
PubMed1997

Spinocerebellar ataxia type 6. Frequency of the mutation and genotype-phenotype correlations.

Spinocerebellar ataxia type 6 (SCA6) is the most recently identified mutation causing autosomal-dominant cerebellar ataxia without retinal degeneration (ADCA). The SCA6 mutation is allelic with episodic ataxia type 2 (EA-2), but the two differ clinically because of the presence of progressive, rather than episodic, ataxia in SCA6. SCA6 accounts for 12% of families with ADCA in an ethnically heterogeneous population of patients. Clinical examination, quantitative eye movement testing, and imaging data show that the brainstem is normal in most patients with SCA6, especially within the first 10 years of symptoms. Most patients show progressive ataxia from the onset, but several patients show an episodic course resembling EA-2. Thus, SCA6 mutations not only account for patients with ADCA I and ADCA III phenotypes but also for some patients presenting with episodic features that are typical for EA-2. Interestingly, a compound heterozygote for the SCA6 expansion manifested an earlier onset and more rapid course than family members with the same larger expanded allele.

Adolescent↗
PubMed1997

The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia.

The dominant cerebellar ataxias (ADCAs) represent a clinically and genetically heterogeneous group of disorders linked by progressive deterioration in balance and coordination. The utility of genetic classification of the ADCAs has been highlighted by the striking variability in clinical phenotype observed within families and the overlap in clinical phenotype observed between those with different genotypes. The recent demonstration that spinocerebellar ataxia type 2 (SCA2) is caused by a CAG repeat expansion within the ataxin-2 gene has allowed us to determine the frequency of SCA2 compared with SCA1, SCA3/Machado-Joseph disease (MJD), and dentatorubropallidoluysian atrophy (DRPLA) in patients with sporadic and inherited ataxia. SCA2 accounts for 13% of patients with ADCA (without retinal degeneration), intermediate between SCA1 and SCA3/MJD, which account for 6% and 23%, respectively. Together, SCA1, SCA2, and SCA3/MJD constitute >40% of the mutations leading to ADCA I in our population. No patient without a family history of ataxia, or with a pure cerebellar or spastic syndrome, tested positive for SCA1, SCA2, or SCA3. No overlap in ataxin-2 allele size between normal and disease chromosomes, or intermediate-sized alleles, were observed. Repeat length correlated inversely with age at onset, accounting for approximately 80% of the variability in onset age. Haplotype analysis provided no evidence for a single founder chromosome, and diverse ethnic origins were observed among SCA2 kindreds. In addition, a wide spectrum of clinical phenotypes was observed among SCA2 patients, including typical mild dominant ataxia, the MJD phenotype with facial fasciculations and lid retraction, and early-onset ataxia with a rapid course, chorea, and dementia.

Adolescent↗
PubMed1996

Identification and characterization of novel developmentally regulated proteins in rat spinal cord.

We previously used 2-dimensional (2-D) gel electrophoresis to identify novel proteins that may be involved in the genesis of the mammalian nervous system [1]. Several novel proteins that were up- or down-regulated coincident with neurogenesis and neuronal migration in rat neocortex were identified. To further investigate the expression of some of these developmentally regulated proteins during a comparable period in spinal cord development, 2-D electrophoresis is used to study their regulation in the crude membrane and soluble fractions of spinal cord at embryonic day 12 (E12) and embryonic day 21 (E21). This analysis indicates that 7 of the proteins that exhibited large changes in their synthesis in cerebral cortex between embryonic day 14 (E14) and embryonic day 21 (E21) demonstrate similar up- or down-regulation during spinal cord neurogenesis. However, two proteins are restricted in their expression or developmental regulation. One of these, 667-800, appears cortex-specific, while the up-regulation of protein SC.1 appears to be spinal cord specific. Several of these proteins also appear to be enriched in both the cortex and spinal cord relative to non-neural tissues (117, 162, 182, 310 [TOAD-64], 667-800) and may be neural specific. To further characterize its expression, one of these neural-specific, up-regulated proteins, TOAD-64 (protein 310) [2-4], is studied throughout embryonic and postnatal spinal cord development using peptide-specific polyclonal antibodies. As suggested by the 2-D gel analysis and the previously reported expression pattern in cerebral cortex [3], TOAD-64 is transiently expressed in postmitotic spinal cord neurons early in their development and sharply down-regulated after the second postnatal week. In the adult spinal cord, TOAD-64 expression is remarkably restricted to a subset of primary afferents to the spinal cord. This expression pattern, coupled with its recently discovered homology to two proteins implicated in axon pathfinding in the chick and nematode [5,3], suggests that TOAD-64 may have a fundamental role in axon pathfinding.

Amino Acid Sequence↗
PubMed1996

A biotinylated MutS fusion protein and its use in a rapid mutation screening technique.

The Escherichia coli DNA mismatch repair protein, MutS, binds single base pair mismatches and short deletions in vivo and in vitro. To adapt this protein for mutation detection, a fusion protein of E. coli MutS with a biotinylated peptide domain has been constructed (MutSb). The biotinylation tag facilitates MutS detection and binding by avidin without significantly altering the DNA mismatch binding properties of MutS in vitro. We describe a novel and rapid mutation detection method with MutSb using streptavidin-coated magnetic beads and demonstrate that MutSb can also be used to remove mismatch containing DNA fragments from a mixture of DNA fragments in solution.

Adenosine Triphosphatases↗
PubMed1995

Early postmitotic neurons transiently express TOAD-64, a neural specific protein.

To identify proteins involved in the early development of the mammalian cerebral cortex, we previously used two-dimensional gels to compare proteins synthesized at different stages in corticogenesis in the embryonic rat at embryonic day 14 (E14), E17, and E21. During this period, the cortex develops from a morphologically homogeneous population of proliferative precursor cells into a complex structure containing a diverse array of terminally differentiated neurons. Several proteins are up-regulated coincident with the generation of postmitotic neurons. Here we describe the purification, partial amino acid sequencing, and characterization of one of these proteins, TOAD-64 (Turned On After Division; 64 kDa), using polyclonal antisera to two synthetic peptides from the protein. This analysis reveals that TOAD-64 is a 64,000 Da protein that increases in abundance over the period of corticogenesis and then subsequently decreases to very low levels in the adult. The protein is neural specific and is expressed by postmitotic neurons as they begin their migration out of the ventricular zone into the developing cortical plate. It is expressed in advance of most other neuronal proteins. Progenitor cells do not express TOAD-64. Therefore, this protein is a marker for postmitotic cells that have made a commitment to a neuronal phenotype. The extremely early expression, the relative abundance in newly born neurons, as well as the restriction in expression to the period of initial neuronal differentiation suggest that TOAD-64 may be a key structural protein for early neuronal function.

Amino Acid Sequence↗
PubMed1995

Sneddon's syndrome is a thrombotic vasculopathy: neuropathologic and neuroradiologic evidence.

We report the first case of pathologic findings from brain biopsy in a patient with Sneddon's syndrome. The observations suggest that Sneddon's syndrome is not a vasculitis but is more comparable to the autoimmune vasculopathies such as the antiphospholipid antibody syndrome. Vascular thrombosis and emboli from cardiac sources are the likely causes of stroke in most cases. The success of warfarin in the treatment of antiphospholipid syndromes and the failure of immunosuppression and aspirin in the treatment of Sneddon's syndrome argue that warfarin anticoagulation may be the most appropriate intervention currently available.

Cerebrovascular Disorders↗
PubMed1995

Alien hand syndrome: interhemispheric motor disconnection due to a lesion in the midbody of the corpus callosum.

The neuroanatomic substrate of the alien hand syndrome has remained controversial due to the noncircumscribed nature of cerebral injuries present in most cases. There have been few cases studied in which damage was restricted to portions of the body of the callosum, and most of those involved surgical callosotomy for tumors or epilepsy. We report the case of a woman with a transient alien hand syndrome caused by a stroke limited to the middle and posterior portions of the body of the corpus callosum. This case provides supportive evidence for damage to the midbody of the corpus callosum as the anatomic basis of nondominant alien hand syndrome and conforms to a model of interhemispheric motor disconnection as the essential component of this unusual behavioral syndrome. This disconnection can occur with injuries involving interhemispheric premotor and motor fibers traveling in the midportion of the callosum in individuals with left hemisphere dominance for motor activities.

Aged↗
PubMed1995

TOAD-64, a gene expressed early in neuronal differentiation in the rat, is related to unc-33, a C. elegans gene involved in axon outgrowth.

Using two-dimensional gel electrophoresis we previously identified membrane-associated proteins that are upregulated over the course of neurogenesis. One of these, TOAD-64 (Turned On After Division, 64 kDa), is expressed immediately after neuronal birth and is dramatically downregulated in the adult. The gene encoding TOAD-64 has now been cloned, and its sequence shows homology to the unc-33 gene from C. elegans, mutations in which lead to aberrations in axon outgrowth. Northern and in situ hybridization show that TOAD-64 mRNA is enriched in the nervous system and is developmentally regulated in parallel with the protein. The expression of the TOAD-64 protein and gene coincident with initial neuronal differentiation and the downregulation when the majority of axon growth is complete suggests a role in axon elaboration. Three additional lines of evidence support this possibility: TOAD-64 is upregulated following neuronal induction of P19 and PC12 cells; the protein is found in lamellipodia and filopodia of growth cones; and axotomy of the sciatic nerve induces reexpression. While the sequence of TOAD-64 lacks a signal sequence and therefore is likely to encode a cytoplasmic protein, biochemical experiments demonstrate that the protein is tightly, but noncovalently, associated with membranes. The data presented here suggest that TOAD-64 could be a central element in the machinery underlying axonal outgrowth and pathfinding, perhaps playing a role in the signal transduction processes that permit growing axons to choose correct routes and targets.

Aging↗
PubMed1989

Distribution of major neurotransmitter receptors in the motor and somatosensory cortex of the rhesus monkey.

The in vitro quantitative autoradiographic technique was used to characterize the distributions of alpha 1, alpha 2, beta 1 and beta 2 adrenergic, D1 and D2 dopaminergic, 5-HT1 and 5-HT2 serotonergic, M1 and M2 cholinergic, GABAA and benzodiazepine receptors in the motor (Brodmann's area 4) and somatosensory (Brodmann's areas 3, 1 and 2) cortex of the adult rhesus monkey. All receptor subtypes studied were present throughout all layers of both areas. In the somatosensory cortex, each receptor had its own laminar distribution. Some subtypes of the same receptor (5-HT1 and 5-HT2; alpha 1 and alpha 2) had complementary distributions while others (beta 1 and beta 2; D1 and D2; M1 and M2) had largely overlapping distributions. In contrast, different receptors had remarkably coincidental distributions in the motor cortex. In this area, they all tended to concentrate in layers I, II and the upper part of layer III. However, such coextensive distribution of many types of neurotransmitter receptors is not observed in motor cortex of rats and humans and therefore may be a distinctive feature of motor cortex in the rhesus monkey. The findings described in this paper indicate that somatosensory and motor areas are distinct in their receptor architecture and that receptor autoradiography provides a useful complement to classical histological techniques in elucidating areal differences in the cortex.

Animals↗
PubMed1989

Identification of proteins that are developmentally regulated during early cerebral corticogenesis in the rat.

Between embryonic day 14 (E14) and embryonic day 21 (E21), the rat neopallium develops from a relatively homogeneous band of mitotic precursor cells into a complex laminated structure containing diverse classes of neurons. In order to identify some of the molecular components underlying this process, 2-dimensional PAGE was used to compare proteins expressed before cortical neurons are born (E14) with those expressed during neurogenesis and neuronal migration (E17 and E21). This approach has permitted the identification of 15 proteins that show greater than 3-fold changes in their rate of accumulation between E14 and E21. Six proteins show consistent up-regulation, ranging from 3.2- to 10.7-fold. Five proteins show consistent down-regulation ranging from 9- to 22-fold. Four proteins that appear at E21 are not detectable on fluorograms of E14 cortex, even after long exposures, and thus are up-regulated more than 200-fold from E14 to E21 and may be considered to appear de novo. The molecular weights and isoelectric points of most of these 15 suggest that they are previously unreported, developmentally regulated proteins. Comparisons of gels of cortex to gels of lung and heart suggest that several of these proteins are enriched in brain relative to non-neural tissues. This analysis also indicates that, despite the large morphogenic changes observed during this developmental period, few proteins (less than 3%) among the total spectrum analyzed show large changes in their rates of synthesis.

Animals↗