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PubMed1994

A behavioral neurogenetics approach to developmental disabilities: gene-brain-behavior associations.

This review provides a discussion of behavioral neurogenetics' contribution to understanding neurodevelopmental pathways in learning and developmental disabilities. A brief overview is given of several common neurogenetic disorders with various genetic etiologies including Down syndrome, Turner syndrome, Prader-Willi syndrome, Angelman syndrome, and Tourette's syndrome. Special emphasis is placed on fragile X syndrome as representative of a newly-discovered class of genetic conditions characterized by an unstable trinucleotide repeat. A spectrum of cognitive, behavioral, and social-emotional phenotypic features associated with fragile X syndrome is examined. Also included are findings from recent neuroimaging research and a discussion of the need for the classification of symptoms on the basis of underlying genetic/medical conditions.

Adult↗

PubMed1995

Why do DNA testing? Practical and ethical implications of new neurogenetic tests.

Direct DNA tests for mutations in neurogenetic disorders are establishing a new era in diagnostic neurology. These highly accurate and specific tests will greatly improve diagnosis and genetic counseling, lead to more accurate assessment of prognosis, and reduce the cost of diagnostic evaluations. However, the use and interpretation of the tests can be complicated, and there are numerous social, psychological, and ethical implications of the testing that need to be recognized and anticipated. To provide the best care for our patients, neurologists need to understand the benefits and risks of this testing and properly apply it in the context of each individual clinical situation.

Ethics↗

PubMed1996

Hypoplasia of the cerebellar vermis in neurogenetic syndromes.

There are conflicting reports on the relationship between cerebellar vermal lobule hypoplasia and autism. Using quantitative magnetic resonance image analysis, we measured the cerebellar vermis in 125 normal individuals with a broad age range and 102 patients with a variety of neurogenetic abnormalities. We conclude that hypoplasia of cerebellar vermal lobules VI and VII is a nonspecific finding that even occurs in several conditions with-out autistic behavior. This suggests that it is not a specific neuroanantomical marker for autism, nor is cerebellar dysgenesis likely to be solely responsible for clinical autistic behaviors.

Abnormalities, Multiple↗

PubMed1987

Segment-related, mosaic neurogenetic pattern in the forebrain and mesencephalon of early chick embryos: I. Topography of AChE-positive neuroblasts up to stage HH18.

Histochemical mapping of AChE-positive neuroblasts in sectioned and whole-mounted preparations of the chick embryo mesencephalon and prosencephalon allows a correlation of early neural tube morphogenesis (segmentation, longitudinal compartmentation) with the heterochronic pattern of neurogenesis. One significant finding is that the initial appearance of neuroblasts in the forebrain does not follow neuromeric segmentation, but evolves in parallel with it. Early neuroblasts appear as separate, distinct groups within specific matrix territories at the center of the transverse neuromeric segments. Neighbouring segments display different spatiotemporal patterns of neurogenesis. Overall gradients of differentiation in the rostrocaudal and ventrodorsal directions are absent, whereas a clear-cut segment-related, mosaic pattern becomes evident. Notwithstanding this, gross regularities of heterochrony in the neurogenetic behavior of the different segments lead to a definition of elemental longitudinal compartments of the forebrain and mesencephalon (floor, paramedian, basal, and alar regions) on the basis of precocious differentiation of the basal region and retarded differentiation of the paramedian and alar regions.

Acetylcholinesterase↗

PubMed2002

The MAGE proteins: emerging roles in cell cycle progression, apoptosis, and neurogenetic disease.

Since the identification of the first MAGE gene in 1991, the MAGE family has expanded dramatically, and over 25 MAGE genes have now been identified in humans. The focus of studies on the MAGE proteins has been their potential for cancer immunotherapy, as a result of the finding that peptides derived from MAGE gene products are bound by major histocompatibility complexes and presented on the cell surface of cancer cells. However, the normal physiological role of MAGE proteins has remained a mystery. Recent studies are now beginning to provide insights into MAGE gene function. Necdin acts as a cell cycle regulatory protein and plays a key role in the pathogenesis of Prader-Willi syndrome, a neurogenetic disorder. MAGE-D1, identified as a binding partner for the p75 neurotrophin receptor, the apoptosis inhibitory protein XIAP, and Dlx/MSX homeodomain proteins, blocks cell cycle progression and enhances apoptosis. This review provides an overview of the human MAGE genes and proteins, summarizes recent findings on their cellular roles, and provides a baseline for future studies on this intriguing gene family.

Animals↗

PubMed1987

Neurogenetic gradients in the hamster visual pathway.

The dorsal lateral geniculate nucleus, suprachiasmatic nucleus and superior colliculus of the hamster were examined autoradiographically after administration of [3H]thymidine for the presence of spatiotemporal gradients of neuron production and for the relationship between neuron cell body size and birthdate. The dorsal lateral geniculate nucleus had a dorsolateral-to-ventromedial (superficial-to-deep) gradient of neuron production, the suprachiasmatic nucleus had a caudoventral to rostrodorsal gradient, and the superior colliculus had a complex laminar gradient. In the lateral geniculate nucleus and in the superior colliculus, labeled neurons were typically larger than unlabeled neurons at early stages and unlabeled neurons were typically larger than labeled neurons at late stages; however, variation in neuron size does not account for the neurogenetic gradients in hamsters.

Animals↗

PubMed2004

The adult central nervous cholinergic system of a neurogenetic model animal, the zebrafish Danio rerio.

The central nervous cholinergic system of the zebrafish (Danio rerio), a model animal for neurogenetics, is documented here using immunohistochemical methods for visualizing choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme. Neuronal cell bodies containing ChAT are present in the telencephalon (lateral nucleus of ventral telencephalic area), preoptic region (anterior/posterior parvocellular and magnocellular preoptic nuclei), diencephalon (habenula, dorsal thalamus, posterior tuberculum), mesencephalon (Edinger-Westphal (EW) nucleus, oculomotor nerve nucleus, rostral tegmental nucleus, tectal type XIV neurons), isthmic region (nucleus lateralis valvulae, secondary gustatory-viscerosensory nucleus, nucleus isthmi (NI), perilemniscal nucleus, superior reticular nucleus (SRN)) and rhombencephalon (trochlear, trigeminal, abducens, facial, glossopharyngeal-vagal motor nerve nuclei, rostral and caudal populations of octavolateralis efferent neurons). In addition, some ChAT positive neurons are present in the rhombencephalic reticular formation, the central gray, and in cells accompanying the descending trigeminal tract. Obvious ChAT positive terminal fields are present in the supracommissural nucleus of area ventralis telencephali and the medial zone of area dorsalis telencephali, parvocellular superficial pretectal nucleus, torus semicircularis, medial octavolateralis nucleus, facial, glossopharyngeal, and vagal lobes, and in the inferior lobe (around the periventricular nucleus of the lateral recess and in the diffuse nucleus). The identification of all central nervous cholinergic systems provided here in this model system is pivotal for future detailed studies of their development and maintenance, e.g., with regard to the zebrafish ventral telencephalic and isthmic superior reticular neuronal populations, likely representing the homologues of at least part of the cholinergic basal forebrain and pedunculopontine/laterodorsal tegmental ascending activating systems of mammals, respectively.

Animals↗

PubMed2005

The neurogenetics and evolution of food-related behaviour.

All organisms must acquire nutrients from the ambient environment to survive. In animals, the need to eat has driven the evolution of a rich array of complex food-related behaviours that ensure appropriate nutrient intake in diverse niches. Here, we review some of the neural and genetic components that contribute to the regulation of food-related behaviour in invertebrates, with emphasis on mechanisms that are conserved throughout various taxa and activities. We focus on synthesizing neurobiological and genetic approaches into a neurogenetic framework that explains food-related behaviour as the product of interactions between neural substrates, genes and internal and external environments.

Adaptation, Physiological↗

PubMed2001

The inverted neurogenetic gradient of the mammalian isocortex: development and evolution.

In this paper we review recent evidence on the molecular control of cell migration in the isocortex, and present an hypothesis for the evolutionary origin of the inside-out neurogenetic gradient of this structure. We suggest that there are at least two key factors involved in the acquisition of the inside-out gradient: (i) the expression of the protein reelin, which arrests the migration of cortical plate cells by detaching them from the radial glial fiber. This permits younger neurons to use the same fiber to migrate past the previous neurons; and (ii) the second factor is an intracellular signaling pathway dependent on a cyclin-dependent protein kinase (Cdk5). Cdk5 may work by inhibiting N-cadherin mediated cell aggregation as young cells cross the cortical plate, permitting them to move to the more superficial layers. Interestingly, the mutation in Cdk5 affects the migration of only those cells belonging to superficial layers, which are considered to be an evolutionary acquisition of the mammalian isocortex.

Animals↗

PubMed2000

Brain dystrophin, neurogenetics and mental retardation.

Duchenne muscular dystrophy (DMD) and the allelic disorder Becker muscular dystrophy (BMD) are common X-linked recessive neuromuscular disorders that are associated with a spectrum of genetically based developmental cognitive and behavioral disabilities. Seven promoters scattered throughout the huge DMD/BMD gene locus normally code for distinct isoforms of the gene product, dystrophin, that exhibit nervous system developmental, regional and cell-type specificity. Dystrophin is a complex plasmalemmal-cytoskeletal linker protein that possesses multiple functional domains, autosomal and X-linked homologs and associated binding proteins that form multiunit signaling complexes whose composition is unique to each cellular and developmental context. Through additional interactions with a variety of proteins of the extracellular matrix, plasma membrane, cytoskeleton and distinct intracellular compartments, brain dystrophin acquires the capability to participate in the modulatory actions of a large number of cellular signaling pathways. During neural development, dystrophin is expressed within the neural tube and selected areas of the embryonic and postnatal neuraxis, and may regulate distinct aspects of neurogenesis, neuronal migration and cellular differentiation. By contrast, in the mature brain, dystrophin is preferentially expressed by specific regional neuronal subpopulations within proximal somadendritic microdomains associated with synaptic terminal membranes. Increasing experimental evidence suggests that in adult life, dystrophin normally modulates synaptic terminal integrity, distinct forms of synaptic plasticity and regional cellular signal integration. At a systems level, dystrophin may regulate essential components of an integrated sensorimotor attentional network. Dystrophin deficiency in DMD/BMD patients and in the mdx mouse model appears to impair intracellular calcium homeostasis and to disrupt multiple protein-protein interactions that normally promote information transfer and signal integration from the extracellular environment to the nucleus within regulated microdomains. In DMD/BMD, the individual profiles of cognitive and behavioral deficits, mental retardation and other phenotypic variations appear to depend on complex profiles of transcriptional regulation associated with individual dystrophin mutations that result in the corresponding presence or absence of individual brain dystrophin isoforms that normally exhibit developmental, regional and cell-type-specific expression and functional regulation. This composite experimental model will allow fine-level mapping of cognitive-neurogenetic associations that encompass the interrelationships between molecular, cellular and systems levels of signal integration, and will further our understanding of complex gene-environmental interactions and the pathogenetic basis of developmental disorders associated with mental retardation.

Animals↗

PubMed1989

Tongue protrusion mediated by spared anterior ventrolateral neocortex in neonatally decorticate rats: behavioral support for the neurogenetic hypothesis.

Many changes in anatomical organization and behavior follow circumscribed, neonatal cortical ablations. These include functional sparing and compensatory anatomical changes. An objective of this study was to examine the generality of such changes by reversing the usual experimental procedure, removing all cortex but a circumscribed area and examining whether the remnant made new anatomical connections, adopted new functions and whether it continued to subserve the typical functions of that area. All neocortex and cingulate cortex, except a small portion of anterior-lateral neocortex, which is normally involved in tongue and mouth use, was removed from one-day-old or adult rats. Fluorescent labelling and behavioral tests were used to evaluate its function. The results showed: (1) The remnant cortical tissue maintained similar connections in neonatal and adult groups and similar connections to those found in rats that had received no lesions. (2) The rats still displayed behaviors normally supported by this cortex, including tongue protrusion to obtain food and picking up and eating hard food efficiently. (3) Impairments were obtained on tests normally mediated by the ablated cortex, including skilled reaching and grooming. (4) When the cortical remnant was removed, tongue protrusion and efficiency of food consumption were similarly impaired in both neonate and adult groups. An additional serendipitous finding was a dissociation between two types of tongue movement: licking from a ventrally-located surface survived cortical removal but tongue protrusion did not. The results show that bilaterally spared small remnants of neocortex maintain normal functions and do not assume new functions or make new connections despite neonatal decortication. The results provide behavioral support for the neurogenetic hypothesis, which postulates that cortical circuitry is specified during early embryonic development. This suggests that there are constraints on neural remodelling and behavioral recovery following neonatal lesions. The implications of these results are discussed with respect to the documented remodelling and sparing that occur following partial or unilateral lesions within functional systems.

Animals↗

PubMed2002

Approaches to the patient with neurogenetic disease.

The approach to a patient with a possible neurogenetic disorder is a complex process that challenges the physician's knowledge, diagnostic acumen and counseling abilities. This article focuses on six aspects of the process: 1. Clues suggesting the presence of a genetic disease, 2. The importance of family history, 3. The interpretation of sporadic cases, 4. Genetic counseling, 5. Genetic testing and 6. Available resources.

Central Nervous System Diseases↗

PubMed1999

Molecular neurogenetics of sexual differentiation and behaviour.

Sex and death. Two things that come once in a lifetime. Only after death you're not nauseous. - Woody Allen 'Sleeper'. The brain and nervous system functions that underlie sex-specific behaviour are of obvious importance to all animals, including humans. To understand behaviour related to sex, it is important to distinguish those aspects that are controlled genetically. Much of the recent progress in studies of the molecular neurogenetics of sexual differentiation and behaviour has come from the use of genetically tractable organisms (i.e. fruitflies and nematode worms) that exhibit a full range of sexually dimorphic phenotypes.

Animals↗

PubMed1998

Neurochemical and neurogenetic correlates of Parkinson's disease.

We discuss neurochemical and neurogenetic correlates of Parkinson's disease (PD) based on the recent progress in the study of its etiology and pathogenesis. Nigral degeneration with the presence of Lewy bodies in the remaining neurons is the pathologic hallmark of PD, and the resultant loss of striatal dopamine is responsible for most of the clinical manifestations. Although the primary cause is still unknown, mitochondrial respiratory failure and oxidative stress appear to be two major contributors to the nigral cell death. Many endogenous and exogenous compounds with structural similarity to MPTP have been postulated as potential neurotoxins inducing nigral cell death in PD, but there is little evidence of accumulation of such compounds in the nigra. Genetic influence has increasingly been recognized as an important risk factor for PD. In this respect, genetic linkage analysis and molecular cloning of the disease genes in familial parkinsonism are of utmost importance today. Recently, the disease gene for one of the autosomal dominant forms of familial PD was identified, and we cloned the gene for an autosomal recessive type of familial parkinsonism that had been mapped to the long arm of chromosome 6 by our group. Information obtained on familial parkinsonism will contribute to the studies on sporadic PD as well.

Brain↗

PubMed2005

[Predictive testing: presymptomatic diagnosis in neurogenetic disorders].

Presymptomatic testing is available since 15 years for Huntington disease and it is now possible for a number of other neurogenetic disorders, mostly neurodegenerative disorders. The possibility of determining the genetic status of an at-risk person for the disorder which run in his family raises questions because of the absence of preventive and curative treatments in most instances. In addition, being carrier does not tell you when the disease will start and how it will evolve, impairing the possibilities of planning the future. A pluridisciplinary approach to predictive testing with care before, during and after the test taking into account the medical, social and psychological aspects of the disease is good practice. At the present time, only a minority of at-risk individuals request presymptomatic testing and almost 50 % do not pursue until the results. The consequences of the test may be harmful, more frequently after an unfavorable than after a favorable result. Although the motivations and the outcome in terms of request for prenatal testing after a carrier result are different in Huntington's disease and spinocerebellar ataxias, our experience underlines the benefit of pluridisciplinary care and of time for decision taking. For other disorders like familial Alzheimer's disease, or familial Creutzfeldt-Jakob disease, the experience in presymptomatic testing is still limited but the situation seems similar to Huntington's disease because of the presence of dementia. It will be interesting to study the motivations and the outcome of the tests in disorders like autosomal dominant spastic paraplegias which usually do not reduce the life expectancy. Nevertheless, the overall situation might change greatly when efficient treatments will become available in these disorders.

Adult↗

PubMed1999

Risks and benefits of DNA testing for neurogenetic disorders.

DNA testing for mutations in genes causing neurogenetic disorders is becoming a common practice in clinical neurology. The tests are highly sensitive and specific. They are especially valuable in establishing diagnoses in symptomatic patients. These DNA tests are also used in asymptomatic persons at risk for genetic diseases who wish to determine whether or not they have inherited an abnormal gene. There are risks and benefits to such asymptomatic, predictive testing. A number of complex issues need to be considered including precipitation of depression, prenatal diagnosis and testing of children, impact on insurance and employment, legal aspects, possible third-party coercion, and an understanding of each test's limitations. Therefore, these DNA tests need to be used with careful clinical judgment and in the context of each individual patient and family.

Cost-Benefit Analysis↗

PubMed2006

Mechanisms of working memory dysfunction after mild and moderate TBI: evidence from functional MRI and neurogenetics.

Cognitive complaints are a frequent source of distress and disability after mild and moderate traumatic brain injury (TBI). While there are deficits in several cognitive domains, many aspects of these complaints and deficits suggest that problems in working memory (WM) play an important role. Functional imaging studies in healthy individuals have outlined the neural substrate of WM and have shown that regions important in WM circuitry overlap with regions commonly vulnerable to damage in TBI. Use of functional MRI (fMRI) in individuals with mild and moderate TBI suggests that they can have problems in the activation and allocation of WM, and several lines of evidence suggest that subtle alterations in central catecholaminergic sensitivity may underlie these problems. We review the evidence from fMRI and neurogenetic studies that support the role of catecholaminergic dysregulation in the etiology of WM complaints and deficits after mild and moderate TBI.

Brain Injuries↗

PubMed2002

Developmental neurogenetics and neuro-ophthalmology.

The field of developmental neurogenetics has burgeoned over the past decade. Through the combined efforts of developmental biologists, geneticists, and clinicians, genetic defects resulting in neuro-ophthalmic disorders such as holoprosencephaly, microphthalmia, dominant optic atrophy, and optic nerve colobomas have been identified and characterized at the molecular level. Experimental studies in model organisms are continuing to identify novel genes critical for ocular and central nervous system development. Mutations in some of these genes have revealed a spectrum of pathology similar to that observed in septo-optic dysplasia, Möebius syndrome, and Duane retraction syndrome. This review examines our current knowledge of the molecular genetics of neuro-ophthalmic disease and focuses on several candidate genes for afferent and efferent visual system disorders.

Developmental Biology↗