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PubMed2006

Maturity of judgement in decision making for predictive testing for nontreatable adult-onset neurogenetic conditions: a case against predictive testing of minors.

International guidelines developed to minimize harm from predictive testing for adult-onset, nontreatable neurogenetic conditions such as Huntington disease (HD) state that such testing should not be available to minors. Some authors have proposed that predictive testing for these conditions should be available to minors at the request of parents and/or of younger adolescents themselves. They highlight the lack of empirical evidence that predictive testing of minors causes harm and suggest that refusing to test minors may be detrimental. The current study focuses on the context of predictive test requests by adolescents younger than 18 years, and presents arguments and evidence that the risk of potential harm from testing such young people is sufficiently high to justify continued caution in this area. A study based on a model of psychosocial maturity found that the 3 factors involved in maturity of judgement in decision making - responsibility, temperance and perspective - continue to develop into late adolescence. There is also evidence that the prefrontal areas of the brain, which are involved in executive functions such as decision making, are not fully developed until early adulthood. Combined with evidence of adverse long-term effects, from research with adults who have undergone predictive testing, these findings constitute grounds for retaining a minimum age of 18 years for predictive testing for nontreatable conditions. Further research on assessment of maturity will assist with reaching a consensus on this issue.

Adolescent↗
PubMed1987

Neurogenetic adaptive mechanisms in alcoholism.

Clinical, genetic, and neuropsychopharmacological studies of developmental factors in alcoholism are providing a better understanding of the neurobiological bases of personality and learning. Studies of the adopted-away children of alcoholics show that the predisposition to initiate alcohol-seeking behavior is genetically different from susceptibility to loss of control after drinking begins. Alcohol-seeking behavior is a special case of exploratory appetitive behavior and involves different neurogenetic processes than do susceptibility to behavioral tolerance and dependence on the antianxiety or sedative effects of alcohol. Three dimensions of personality have been described that may reflect individual differences in brain systems modulating the activation, maintenance, and inhibition of behavioral responses to the effects of alcohol and other environmental stimuli. These personality traits distinguish alcoholics with different patterns of behavioral, neurophysiological, and neuropharmacological responses to alcohol.

Alcoholism↗
PubMed2006

Computational neurogenetic modelling: a pathway to new discoveries in genetic neuroscience.

The paper presents a methodology for using computational neurogenetic modelling (CNGM) to bring new original insights into how genes influence the dynamics of brain neural networks. CNGM is a novel computational approach to brain neural network modelling that integrates dynamic gene networks with artificial neural network model (ANN). Interaction of genes in neurons affects the dynamics of the whole ANN model through neuronal parameters, which are no longer constant but change as a function of gene expression. Through optimization of interactions within the internal gene regulatory network (GRN), initial gene/protein expression values and ANN parameters, particular target states of the neural network behaviour can be achieved, and statistics about gene interactions can be extracted. In such a way, we have obtained an abstract GRN that contains predictions about particular gene interactions in neurons for subunit genes of AMPA, GABAA and NMDA neuro-receptors. The extent of sequence conservation for 20 subunit proteins of all these receptors was analysed using standard bioinformatics multiple alignment procedures. We have observed abundance of conserved residues but the most interesting observation has been the consistent conservation of phenylalanine (F at position 269) and leucine (L at position 353) in all 20 proteins with no mutations. We hypothesise that these regions can be the basis for mutual interactions. Existing knowledge on evolutionary linkage of their protein families and analysis at molecular level indicate that the expression of these individual subunits should be coordinated, which provides the biological justification for our optimized GRN.

Algorithms↗
PubMed1996

Trinucleotide repeats in neurogenetic disorders.

Trinucleotide repeat expansion is increasingly recognized as a cause of neurogenetic diseases. To date, seven diseases have been identified as expanded repeat disorders: the fragile X syndrome of mental retardation both FRAXA and FRAXE loci), myotonic dystrophy, X-linked spinal and bulbar muscular atrophy, Huntington's disease, spinocerebellar ataxia type I, dentatorubral-pallidoluysian atrophy, and Machado-Joseph disease. All are neurologic disorders, affecting one or more regions of the neuraxis. Moreover, five of the seven (the last five above) are progressive neurodegenerative disorders whose strikingly similar mutations suggest a common mechanism of neuronal degeneration. In this article we discuss specific characteristics of each trinucleotide repeat disease, review their shared clinical and genetic features, and address possible molecular mechanisms underlying the neuropathology in each disease. Particular attention is paid to the neurodegenerative diseases, all of which are caused by CAG repeats encoding polyglutamine tracts in the disease gene protein.

Central Nervous System Diseases↗
PubMed2005

Musical behavior in a neurogenetic developmental disorder: evidence from Williams Syndrome.

This paper reviews a series of studies performed to assess the musical abilities and behaviors of individuals with Williams syndrome, a neurogenetic developmental disorder, in the hope of eventually being able to link genes, neurodevelopment, and cognition. Two questionnaire studies addressing the role of music in everyday life, and unusual reactions to sound, are described. Additionally, the findings from two empirical behavioral studies and a neuroimaging study are reviewed. The findings show that individuals with Williams syndrome tend to be more engaged in musical activities than others, and I report a possible neuroanatomical correlate of this engagement, with increased activation in the right amygdala to music and to noise. Williams syndrome represents a compelling model of the relationship between genes, brains, and such complex cognitive behaviors as music.

Adolescent↗
PubMed2005

Molecular diagnosis of neurogenetic disorders involving trinucleotide repeat expansions.

There are more than 15 known neurogenetic disorders involving trinucleotide repeat expansion. Expanded repeats range from small expansions of 20-100 copies to larger expansions of up to several thousand units. These dynamic expansions result in variability in age of onset, degree of severity and clinical presentation. Individuals carrying alleles in the intermediate range, known as premutation alleles, are often asymptomatic, but can potentially transmit a further expanded allele to his/her offspring. For autosomal dominant adult-onset disorders, carriers are asymptomatic prior to disease onset. With current molecular tools, it is now possible to determine the presence and number of expanded repeats for accurate diagnosis, presymptomatic testing and carrier status screening. This review examines some of the current approaches for molecular diagnosis and discusses the issues unique to triplet repeat diseases.

Clinical Laboratory Techniques↗
PubMed1999

Global CNS gene transfer for a childhood neurogenetic enzyme deficiency: Canavan disease.

The neurogenetic prototypic disease on which we chose to test our gene therapy strategy is Canavan disease (CD). CD is an autosomal recessive leukodystrophy associated with spongiform degeneration of the brain. At present the disease is uniformly fatal in affected probands. CD is characterized by mutations in the aspartoacylase (ASPA) gene, resulting in loss of enzyme activity. In this review, recent evidence is summarized on the etiology and possible treatments for CD. In particular, we discuss two gene delivery systems representing recent advances in both viral and liposome technology: a novel cationic liposome-polymer-DNA (LPD) complex, DCChol/DOPE-protamine, as well as recombinant adeno-associated virus (AAV) vectors.

Acetates↗
PubMed2006

[Paroxysmal neurogenetic and neurometabolic disorders].

AIM: To provide an overview of those neurological disorders that are mainly characterized by a paroxysmal pattern of involvement, and in which a clear genetic or metabolic etiology has been identified. DEVELOPMENT: The term 'paroxysmal' refers to the abrupt onset of clinical manifestations in a relatively stereotyped manner, usually upon exposure to specific triggering factors with an almost complete resolution of such findings between attacks. They are commonly not associated to either a relentless progression or a stepwise deterioration, and the majority of them do not lead to the development of gross neuropathological abnormalities. Although they are difficult to classify due to the heterogeneity of their clinical manifestations and underlying deficits, a neuroaxis-based approach is proposed for practical purposes, for example, from those conditions affecting predominantly cortical grey matter (manifesting mainly with seizures) to those with an almost exclusive muscular and/or neuromuscular pattern of involvement. The majority of them are caused by genetic defects in either transporters or neuronal channels, which can be either ions or neurotransmitters. In recent years, the concept of 'channelopathies' has grown in acceptance in the medical field, although not all of the described disorders are caused by defects in molecular channels. CONCLUSIONS: Despite their individual rarity, as a group, they are important to the neurologist due to the advances that their understanding have provided for the development of the field of neurogenetics and neurosciences in general.

Humans↗
PubMed1991

[Neurogenetics--the challenge for neurology. Part 1. Gene mapping and gene diagnostics].

Recent advances in gene mapping have provided distinct chromosomal locations for a number of neurological disease genes. Mapping strategies include the identification of chromosomal aberrations associated with disorders and the candidate gene approach which requires correct assumptions about the primary biochemical defect. The most successful strategy, linkage analysis, relies on family studies and allows the mapping of genes without knowledge of the molecular cause of a disorder. Once the chromosomal position for a disease gene is known, indirect DNA diagnosis becomes available, providing risk estimates for individuals in affected families. Identification of the disease gene itself allows the characterization of the protein involved and direct diagnosis at DNA and protein level, thus leading to a greater understanding of the molecular pathology of neurogenetic disorders.

Chromosome Mapping↗
PubMed1995

[Molecular pathology of neurogenetic diseases].

Recently, techniques of molecular biology have been widely applied to child neurology, and a new aspect of the pathogenesis of neurogenetic diseases has been revealed. In this article, recent results of molecular analysis in my laboratory were briefly reviewed on hereditary beta-galactosidase deficiency. After cDNA cloning, a number of gene mutations have been identified; mainly missense mutations, such as single-base substitution, duplication, insertion, and splice site mutation. A clear phenotype-genotype correlation was established for some mutations specific to the late-onset forms of the disease. Intracellular events of mutant proteins expressed by these mutant genes were heterogeneous, and expected to be closely connected to the pathogenesis of each phenotype. On the basis of these data, a unified clinical classification was proposed for GM1-gangliosidosis and Morquio B disease, together with a new concept of "beta-galactosidosis" for the diseases with beta-galactosidase gene mutations.

Gangliosidosis, GM1↗
PubMed1993

The role of neurogenetics in Gaucher disease.

Gaucher disease is the most prevalent hereditary metabolic storage disorder, and the most common genetic disease in individuals of Ashkenazic Jewish ancestry. Patients with Gaucher disease have been classified into three clinical phenotypes. Patients with type 1 disease exhibit markedly variable hepatosplenomegaly, anemia, thrombocytopenia, skeletal, and, to a lesser extent, pulmonary and kidney involvement. The central nervous system does not appear to be involved. In patients with type 2 Gaucher disease, hepatosplenomegaly and extensive central nervous system damage are apparent in infancy. These patients usually die between 1 and 2 years of age. Patients with type 3 Gaucher disease have been subclassified into types 3a and 3b. Type 3a patients exhibit mild-to-moderate hepatosplenomegaly and slowly progressive neurologic deterioration. Recurrent myoclonic seizures are common. Patients with type 3b Gaucher disease exhibit splenomegaly along with extensive hepatomegaly that is frequently accompanied by esophageal varices. Horizontal supranuclear gaze paresis is the major neurologic sign. Excessive quantities of glucocerebroside accumulate in the organs of patients with Gaucher disease because of a deficiency of the enzyme glucocerebrosidase. In the vast majority of patients, the reduction of glucocerebrosidase activity is caused by mutations in the gene that codes for glucocerebrosidase. In a few instances, glucocerebroside accumulates due to a lack of saposin C, a cohydrolase that is required in addition to glucocerebrosidase for the catabolism of glucocerebroside. Mutations in the glucocerebrosidase gene are discussed in the context of the severity of disease and the presence or absence of nervous system involvement. Enzyme replacement therapy is highly beneficial for patients with type 1 Gaucher disease. Enzyme replacement is also being investigated for patients with type 3b Gaucher disease. Novel procedures must be developed to deliver glucocerebrosidase to the nervous system so that patients with type 2 and type 3a Gaucher disease can be helped. Exploration of gene therapy for Gaucher disease is under way.

Alleles↗
PubMed1989

Dominantly inherited dementia and parkinsonism, with non-Alzheimer amyloid plaques: a new neurogenetic disorder.

A family is described in which a dominant form of inheritance, probably autosomal dominant, expresses severe dementia and parkinsonism as the major clinical features. Neuropathological correlates in two autopsied members of this family consisted of extracellular hyaline eosinophilic, congophilic amyloid plaques in decreasing order of frequency in the cerebral cortex, basal ganglia, thalamus, and substantia nigra, and atrophy and gliosis of the basal ganglia and substantia nigra. The extracellular plaques did not stain with antibody raised against the prion protein nor with two separate anti-amyloid A4 antibodies. The combination of dominantly inherited dementia with parkinsonism and extracellular plaques in this distribution that are amyloid and prion protein antibody negative has not been previously reported and thus may represent a new neurological genetic disorder.

Alzheimer Disease↗
PubMed1997

Molecular neurogenetics of chemotaxis and thermotaxis in the nematode Caenorhabditis elegans.

Chemotaxis and thermotaxis in Caenorhabditis elegans are based on the chemical senses (smell and taste) and the thermal sense, respectively, which are important for the life of the animal. Laser ablation experiments have allowed identification of sensory neurons and some interneurons required for these senses. Many mutants that exhibit various abnormalities have been isolated and analyzed. These studies have predicted novel signaling pathways whose components include a putative odorant specific transmembrane receptor (ODR-10) and a cyclic nucleotide-gated channel (TAX-4/TAX-2) functioning in taste and thermosensation as well as in smell. The emerging picture of the mechanisms of sensory transduction in C. elegans seems to be basically similar to what is known of visual and olfactory sensory transduction in vertebrates. Thus, molecular and cellular analyses of chemotaxis and thermotaxis in C. elegans have proved useful and will continue to provide significant implications for the molecular basis of sensory systems in higher animals.

Animals↗