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PubMed2004

Magnetic resonance imaging-based volumetry differentiates progressive supranuclear palsy from corticobasal degeneration.

Because there are no biological markers for the clinical diagnosis of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), we established a mathematical model based on three-dimensional magnetic resonance (MR) imaging to differentiate between these parkinsonian disorders. Using MR imaging-based volumetry we studied the pattern of atrophic changes in patients with probable, possible or definite PSP (n = 33) or CBD (n = 18). Patients were compared with 22 controls with similar age. To establish a mathematical model that would allow for differentiation of PSP, CBD and controls we performed a discriminant analysis. We found a significant reduction in average brain, brainstem, midbrain and frontal gray matter volumes in patients with PSP, whereas patients with CBD showed atrophy of parietal cortex and corpus callosum. With the exception of reduced midbrain volumes in PSP, the measured volumes of anatomical structures showed an extensive overlap with the normal range on an individual basis. Using only post mortem confirmed cases of PSP (n = 8) and CBD (n = 7) as well as all controls, the volumes of midbrain, parietal white matter, temporal gray matter, brainstem, frontal white matter and pons were identified to separate best between groups and were used to construct a model with two canonical variables. This model allowed to correctly predict the diagnosis in 95% of controls as well as in 76% of all PSP and 83% of all CBD patients. Similar results were obtained only when patients with a possible and probable diagnosis of PSP and CBD, who were not involved in the development of the discriminant analysis, were classified. 3D-MR imaging-based volumetry may help to differentiate PSP from CBD ante mortem.

Aged↗
PubMed2004

Alanine tracts: the expanding story of human illness and trinucleotide repeats.

Expansions of polyglutamine repeats are known to cause a variety of human neurodegenerative diseases. More recently, expansions of alanine tracts, particularly in transcription factor genes, have been shown to cause at least nine human conditions, including mental retardation and malformations of the brain, digits and other structures. Present knowledge suggests that alanine tract expansions generally, but not always, arise through unequal recombination as opposed to replication slippage, the most likely mechanism in other triplet repeat expansions. The function of alanine tracts is unknown but when alanine expansions occur in transcription factor genes, alanine tracts can result in either loss-of-function or gain of an abnormal function. Given the frequency of alanine tracts in proteins, it is likely that more alanine tract expansions will be discovered in disease genes.

Congenital Abnormalities↗
PubMed2001

Genetic risk factors in familial Alzheimer's disease.

In the last 10 years significant progress has been made to describe and identify the underlying biological mechanisms that cause the different manifestation of Alzheimer's disease. Since the first report of a possible locus on chromosome 21 in a small group of families with early onset familial Alzheimer's disease (FAD), considerable progress has been made. Results from linkage analysis and gene sequencing has provided evidence that a minority of early onset FAD families develops the disease as a result of mutations in the gene coding for the Abeta-amyloid precursor protein, and that mutations in presenilin 1 and 2 genes account for a larger subgroup of early onset families. Several other early onset FAD families are clearly not linked to any of these loci, suggesting that other genetic risk factors may exist. Recent genome-wide scanning studies have revealed the existence of a new locus on chromosome 12, which, together with inheritance of the epsilon4 allele of apolipoprotein E gene, on chromosome 19, represent the most important genetic factors associated with an increased risk of developing the disease in late onset FAD families.

Alzheimer Disease↗
PubMed2003

Pivotal role of attractin in cell survival under oxidative stress in the zitter rat brain with genetic spongiform encephalopathy.

Accumulation of reactive oxygen species (ROS), which is generated during energy metabolism, is a cause of physiological aging, neuropathogenesis and numerous diseases, such as Parkinson's and Alzheimer's diseases. Zitter rat is an autosomal recessive mutant, characterized by spongiform degeneration and hypomyelination in the brain, and the phenotype has been suggested to be involved in oxidative stress by the accumulation of ROS. To determine the relation between neurodegeneration of the zitter rat and Attractin (Atrn) gene expression, which was identified as a gene responsible for the zitter, we established fibroblast cells from the zitter rat (Fz) and the Wistar tremor control (WTC) rat (Fw), and transduced Fz cells with the Atrn gene (Fz/Atrn). In the Fz/Atrn cells, accumulation of ROS was repressed, and cell survival against oxidative stress was enhanced to the same level as in Fw cells. Interestingly, phosphorylation of ERK was significantly increased in Fz/Atrn cells by H(2)O(2) stimulus, similarly to Fw cells. Furthermore, activation of ERK was confirmed in the brains of WTC and zitter rats by Western blot analysis and immunohistochemistry. These observations suggested that lack of Atrn gene expression induced neurodegeneration by a decrease in active ERK through an intracellular signaling via oxidative stress.

Animals↗
PubMedDate not supplied

Phenotypic correlations in FTDP-17.

Frontotemporal dementias with parkinsonism linked to chromosome 17 (FTDP-17) are hereditary tauopathies affecting at least 50 known kindred worldwide. Most kindred present with severe behavioral or psychiatric manifestations progressing to dementia, while some kindred first manifest a parkinsonian-plus syndrome. Nine missense mutations, one deletion mutation, and two transition mutations not altering the encoded amino acid, have been described in or near the microtubule-binding domains within exons 9, 10, 12, and 13. In addition, five different intronic mutations have been reported in the 5' splice-site of the alternatively spliced exon 10. Missense mutations affecting constitutively expressed exons affect all six major tau isoforms and result in neurofibrillary tangles similar to those present in secondary tauopathies, such as Alzheimer's disease. In contrast, mutations that affect the alternatively spliced exon 10 or its 5' splice regulatory region alter the ratio of the tau isoforms incorporated into the tangles and result in filamentous inclusions resembling those seen in the primary tauopathies, such as progressive supranuclear palsy, corticobasal degeneration, and Pick's disease. The severity and heterogeneity of the clinicomorphologic phenotype may, in part, reflect the diversity in the primary molecular mechanisms of disease in FTDP-17.

Brain↗
PubMed2000

The psychological complexity of predictive testing for late onset neurogenetic diseases and hereditary cancers: implications for multidisciplinary counselling and for genetic education.

Increasing knowledge about the human genome has resulted in the availability of a steadily increasing number of predictive DNA-tests for two major categories of diseases: neurogenetic diseases and hereditary cancers. The psychological complexity of predictive testing for these late onset diseases requires careful consideration. It is the main aim of the present paper to describe this psychological complexity, which necessitates an adequate and systematic multidisciplinary approach, including psychological counselling, as well as ongoing education of professionals and of the general public. Predictive testing for neurogenetic diseases--in an adequate counselling context--so far elicits optimism regarding the short- and mid-term impact of the predictive test result. The psychosocial impact has been most widely studied for Huntington's disease. Longitudinal studies are of the utmost importance in evaluating the long-term impact of predictive testing for neurogenetic diseases on the tested person and his/her family. Given the more recent experience with predictive DNA-testing for hereditary cancers, fewer published scientific data are available. Longitudinal research on the mid- and long-term psychological impact of the predictive test result is essential. Decision making regarding health surveillance or preventive surgery after being detected as a carrier of one of the relevant mutations should receive special attention. Tailoring the professional approach--inside and outside genetic centres--to the families' needs is a continuous challenge. Even if a continuous effort is made, several important questions remain unanswered, last but not least the question regarding the best strategy to guarantee that the availability of predictive genetic testing results in a reduction of suffering caused by genetic disease and in an improvement of the quality of life of families confronted with genetic disease.

Counseling↗
PubMed2000

Canine models for human genetic neurodegenerative diseases.

1. Canine models of human neurodegenerative disorders are uncommon. However, the similarity between canines and humans in body sizes and physiology provides an exceptional opportunity to use these models to study human diseases. 2. The authors will present a review on the neurological deficits that have been observed in canine models of genetic neurodegenerative diseases, and summarize the current gene therapy treatments being developed for some of these conditions.

Animals↗
PubMed2001

Gamma-aminobutyric acid(B) autoreceptors in substantia nigra and neostriatum of the weaver mutant mouse.

The weaver mutation causes cell loss in the center of the substantia nigra, pars compacta. We compared the depression of gamma-aminobutyric acid (GABA)(A) synaptic currents by the GABA(B) agonist R-baclofen in pars compacta neurons of weaver mice which were largely spared from cell degeneration and of wild-type mice. In weaver neurons the suppression of GABA(A) synaptic currents by R-baclofen was reduced compared to wild-type neurons. The EC(50) of R-baclofen was 6.3 times higher in weaver than in wild-type mice. In the neostriatum, which is not a target of the mutation, such a difference did not exist. We conclude that in the pars compacta the weaver mutation leads to a reduced presynaptic autoinhibition through GABA(B) receptors which may promote survival of a subset of weaver neurons in the pars compacta.

Animals↗
PubMed2001

A Japanese girl with leukoencephalopathy with vanishing white matter.

A Japanese girl with peculiar leukoencephalopathy was reported. Following normal development until 1 year of age, she showed progressive neurological deterioration with ataxia, epilepsy, pyramidal tract signs and choreic movement. Serial brain computed tomographies (CTs) revealed markedly low density and progressive volume loss in whole white matter. In extensive laboratory investigations, the level of glycine in the urine was elevated. She died at the age of 4 years, and the neuropathological findings were comprised of severe extensive changes in cerebral and cerebellar white matter, such as marked rarefaction or cystic degeneration with axonal loss. The pontine central tegmental tracts were also affected. Neuronal loss was seen in the cerebellar cortex. These features were compatible with leukoencephalopathy with vanishing white matter, which was recently established as a clinical entity. To our knowledge, this is the first report of a non-Caucasian patient with this new type of leukoencephalopathy.

Brain↗
PubMed2003

Infantile sialic acid storage disease and protein-losing gastroenteropathy.

We report on a boy who presented at birth with gastroschisis and thereafter developed the characteristic clinical symptoms of infantile sialic acid storage disease within the first two months of life. Measurements of free sialic acid excretion (tenfold increase) in the urine and a 15-fold elevation of free sialic acid in cultured fibroblasts proved the diagnosis. The clinical course was complicated by hypertrophic cardiomyopathy, recurrent infections, hypothyroidism, and intestinal protein losses, which had never been described before in an infantile sialic acid storage disease patient. The child died at the age of 10 months. Clinical and laboratory findings are discussed and compared with other cases described in the literature.

Cardiomyopathy, Hypertrophic↗
PubMed2001

Identification and characterization of the Drosophila tau homolog.

A pathological hallmark of neurodegenerative tauopathies, including Alzheimer's disease and a group of clinically heterogeneous frontotemporal dementias, is the presence of intracellular neurofibrillary protein lesions (reviewed in Spillantini and Goedert, TINS 10 (1998) 428). The principal component of these structures is the microtubule-associated protein tau. Although tau is normally a highly soluble protein enriched in axons, in these deposits, it is abnormally hyperphosphorylated, insoluble, and redistributed to the somatodendritic compartments of neurons. Through ultrastructual analyses, it has been determined that the tau protein in these lesions is filamentous and organized into paired-helical filaments, straight filaments, or ribbon-like filaments (Goedert et al., The Molecular and Genetic Basis of Neurological Disease (1997) 613). By the dynamic binding of microtubules, tau is thought to promote the structural stability of axons, but whether tau aggregates contribute to neurodegeneration through a direct toxicity on normal cellular functions such as organelle transport or an indirect effect on microtubule stability, is currently unknown. The identification of mutations in the tau locus in patients with familial frontotemporal dementia and Parkinsonism linked to chromosome 17 has demonstrated that mutations in tau are sufficient to cause neurodegenerative disease (Poorkaj et al., Ann. Neurol. 43 (1998) 815; Hutton et al., Nature 393 (1998) 702). To elucidate the mechanisms by which tau dysfunction contributes to neuronal loss, we have sought to model human tauopathies in a genetically tractable organism. Here we describe the isolation of a Drosophila tau cDNA (GenBank accession number AY032977), the production of antibodies that recognize the encoded protein, and their use in determining the expression and subcellular localization of the fly tau protein.

Amino Acid Sequence↗
PubMed2003

Hereditary neuropathy with liability to pressure palsies (HNPP) in a toddler presenting with toe-walking, pain and stiffness.

The typical clinical presentation of hereditary neuropathy with liability to pressure palsies is an adult-onset recurrent, painless monoparesis. Electrophysiological abnormalities--decreased nerve conduction velocities and delayed distal latencies--can be detected even in asymptomatic patients. We describe a toddler, who presented with asymmetric toe walking, painful cramps and stiffness in the legs. He had calf hypertrophy, brisk tendon reflexes and bilateral Babinski signs and the electrophysiological examination was normal. The unlikely diagnosis of hereditary neuropathy with liability to pressure palsies was reached 5 years later, when the boy started to complain of episodic numbness and weakness in the upper extremities. His father, paternal aunt and grandmother had similar symptoms, but they had never been investigated. The typical 1.5 Mb deletion on chromosome 17p11.2-12 was found in our patient and his affected relatives.

Child↗
PubMed2003

Hereditary causes of chorea in childhood.

Chorea and athetosis are rare presenting symptoms in childhood. Chorea can be a presenting symptom in a number of hereditary diseases, including neurodegenerative diseases, paroxysmal diseases, and metabolic diseases. In these situations, family history, associated symptoms, and other physical findings will often enable a correct diagnosis. Benign childhood chorea is probably a genetically heterogeneous group of disorders, generally without other symptoms. Clinical aspects of these disorders are reviewed here.

Athetosis↗
PubMed2003

Rare forms of autosomal recessive neurodegenerative ataxia.

There has been a recent explosion in knowledge regarding the genetic basis of several autosomal recessive ataxias. This article summarizes current information regarding rare forms of recessive ataxias. Friedreich's ataxia and ataxia telangiectasia are dealt with in other articles in this issue. The rarer recessive ataxias can be clinically classified as sensory and spinocerbellar ataxias, cerebellar ataxia with sensory-motor polyneuropathy, and purely cerebellar ataxias. Examples of the first category include ataxia with isolated vitamin E deficiency, abetalipoproteinemia, Refsum's disease, infantile-onset spinocerebellar ataxia, and ataxia with blindness and deafness. Examples of ataxia with sensory-motor polyneuropathy include ataxia with oculomotor apraxia 1 and 2 and spinocerebellar ataxia with neuropathy 1. Examples of purely cerebellar ataxia include autosomal recessive spastic ataxia of Charlevoix-Saguenay and ataxia with hypogonadotropic hypogonadism. This review summarizes the clinical and genetic features of these entities and concludes that the pathogenic basis of such ataxias at this time appear to involve two broad types of processes: free-radical injury and defects of DNA single- or double-strand break repair.

Cerebellar Ataxia↗
PubMed2003

Genes and parkinsonism.

Genetic studies in families with mendelian inheritance of Parkinson's disease (PD) have reported the cloning of several disease-associated genes. These studies of rare familial forms of the disease have cast doubt on our understanding of the role of genetics in typical PD and have complicated the classification of the disorder. However, this genetic information might help us to construct a hypothesis for the pathogenetic processes that underlie PD. In this review we describe the molecular genetics of PD as currently understood to help explain the pathways that underlie neurodegeneration.

Heredodegenerative Disorders, Nervous System↗