Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the degree of binding of the calcium antagonist, [3H]nitrendipine ([3H]NDP), in the prefrontal cortex, caudate nucleus, putamen, pallidum and substantia nigra obtained at autopsy from patients with Parkinson's disease. The specific bindings of [3H]NDP were significantly reduced in the caudate nucleus, putamen and substantia nigra, as compared to the relevant controls. Scatchard analyses revealed that these reductions resulted from decreases in the apparent maximum number of binding sites (Bmax). The affinity constants (Kd) remained unchanged. Thus, it is highly likely that calcium channel antagonist binding sites on nigral dopamine (DA) neurons may be lost in the degenerative process of Parkinson's disease.
 ...
PMID:[3H]Nitrendipine binding sites are decreased in the substantia nigra and striatum of the brain from patients with Parkinson's disease. 294 24

Over the past few years, molecular neurogenetics has developed into one of the most promising and active research fields. The new discipline applies modern molecular genetic techniques to the investigation of classical neurological disorders. In the following article, a definition of neurogenetic disease is introduced, the molecular basis of four groups of neurogenetic disorders is described and recent diagnostic developments are presented. The first group of diseases is caused by trinucleotide expansions. "Expanding" trinucleotide repeats were not known to occur in any species until about three years ago. Today, disorders such as Huntington's disease, spinocerebellar ataxia type 1, fragile X mental retardation, spinobulbar muscular atrophy and myotonic dystrophy are all known to be caused by the expansion of trinucleotides. The second group is characterized by chromosomal deletions or uniparental disomies. Lissencephaly and the Miller-Dieker syndrome, Prader-Willi and Angelman syndromes and Duchenne and Becker muscular dystrophies belong to this category. The third group includes those neurogenetic disorders that are mainly caused by point mutations such as the X-linked leukodystrophies, including Pelizaeus-Merzbacher disease and adrenoleukodystrophy, Charcot-Marie-Tooth syndrome type 1, familial forms of amyotrophic lateral sclerosis, several types of craniosynostoses and some CNS tumor syndromes. Finally, Alzheimer's and Parkinson's disease are discussed as representatives of group four, i.e. genetically heterogeneous neurological disorders.
 ...
PMID:Molecular basis and diagnosis of neurogenetic disorders. 796 63

X-linked dystonia-parkinsonism (XDP), or Lubag syndrome, is known to cause progressive dystonia, with or without parkinsonism, among Filipino male adults with maternal roots from the Philippine island of Panay. We present cinematographic material of 11 cases of Lubag carrying the XDP haplotypes who manifest with a wide spectrum of movement disorders, including dystonia, tremor, parkinsonism, myoclonus, chorea, and myorhythmia. Because of overlapping features, Lubag patients are commonly misdiagnosed as idiopathic dystonia, essential tremor, Parkinson's disease, or Parkinson's-plus syndromes. Thus, it is imperative to elicit an exhaustive family history in any Filipino male adult who presents with a movement disorder.
 ...
PMID:Phenomenology of "Lubag" or X-linked dystonia-parkinsonism. 1246 67

The clinico-pathological study of a new type of familial parkinsonism with striatal degeneration is reported. The inheritance mode was autosomal recessive, and three out of four offspring of married cousins developed parkinsonism in their early adulthood. Their clinical signs were rigidity, bradykinesia, postural instability and dysarthria. These symptoms were slowly progressive and responsive to levodopa therapy to a variable degree. On cerebral magnetic resonance imaging, T2 and proton density-weighted images showed hyperintensity in the bilateral putamina. The neuropathological study of one case revealed atrophy of the bilateral putamina and caudate nuclei, and a severe neuronal loss and gliosis in the putamina. Patchy mosaicism of normal and degenerated tissue was observed in the putamina. A similar mode of the degeneration was mildly seen in the caudate nuclei. The substantia nigra showed atrophy of the pars reticulata, and mild to moderate neuronal loss of the pars compacta with rostral dominance, but no Lewy bodies were observed. These neuropathological findings differed from those of Parkinson's disease or juvenile parkinsonism, but mimic to those of X-linked dystonia parkinsonism (Lubag). It seems that this familial bilateral striatal degeneration is a new variant of familial parkinsonism.
 ...
PMID:Clinico-pathological study of a case of familial parkinsonism with striatal degeneration. 1247 65

3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. HAD has a preference for medium chain substrates, whereas short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) acts on a wide spectrum of substrates, including steroids, cholic acids, and fatty acids, with a preference for short chain methyl-branched acyl-CoAs. Therefore, HAD should not be referred to as SCHAD. SCHAD is not a member of the HAD family, but instead, belongs to the short chain dehydrogenase/reductase superfamily. Previously reported cases of SCHAD deficiency are due to an inherited HAD deficiency. SCHAD, also known as 17beta-hydroxysteroid dehydrogenase type 10, is important in brain development and aging. Abnormal levels of SCHAD in certain brain regions may contribute to the pathogenesis of some neural disorders. The human SCHAD gene and its protein product, SCHAD, are potential targets for intervention in conditions, such as Alzheimer's disease, Parkinson's disease, and an X-linked mental retardation, that may arise from the impaired degradation of branched chain fatty acid and isoleucine.
 ...
PMID:3-Hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase in human health and disease. 1617 62

Family-based association methods have been developed primarily for autosomal markers. The X-linked sibling transmission/disequilibrium test (XS-TDT) and the reconstruction-combined TDT for X-chromosome markers (XRC-TDT) are the first association-based methods for testing markers on the X chromosome in family data sets. These are valid tests of association in family triads or discordant sib pairs but are not theoretically valid in multiplex families when linkage is present. Recently, XPDT and XMCPDT, modified versions of the pedigree disequilibrium test (PDT), were proposed. Like the PDT, XPDT compares genotype transmissions from parents to affected offspring or genotypes of discordant siblings; however, the XPDT can have low power if there are many missing parental genotypes. XMCPDT uses a Monte Carlo sampling approach to infer missing parental genotypes on the basis of true or estimated population allele frequencies. Although the XMCPDT was shown to be more powerful than the XPDT, variability in the statistic due to the use of an estimate of allele frequency is not properly accounted for. Here, we present a novel family-based test of association, X-APL, a modification of the test for association in the presence of linkage (APL) test. Like the APL, X-APL can use singleton or multiplex families and properly infers missing parental genotypes in linkage regions by considering identity-by-descent parameters for affected siblings. Sampling variability of parameter estimates is accounted for through a bootstrap procedure. X-APL can test individual marker loci or X-chromosome haplotypes. To allow for different penetrances in males and females, separate sex-specific tests are provided. Using simulated data, we demonstrated validity and showed that the X-APL is more powerful than alternative tests. To show its utility and to discuss interpretation in real-data analysis, we also applied the X-APL to candidate-gene data in a sample of families with Parkinson disease.
 ...
PMID:X-APL: an improved family-based test of association in the presence of linkage for the X chromosome. 1825 35

"Lubag" or X-linked dystonia-parkinsonism (XDP) is a genetic syndrome afflicting Filipino men. Intracranial surgical procedures for Lubag have been unsuccessful. We report a 45-year-old Filipino male with genetically confirmed XDP who underwent bilateral pallidal deep brain stimulation (DBS) surgery. The patient started to exhibit improvement on initial programming, most notably of his severe jaw-opening dystonia. At 1-year follow-up, his Burke-Fahn-Marsden dystonia score and motor Unified Parkinson's Disease Rating Scale score were improved by 71% and 62%, respectively, with the stimulators on compared to stimulators off state. Bilateral pallidal DBS may be a viable option for Lubag patients with medically refractory symptoms.
 ...
PMID:First case of X-linked dystonia-parkinsonism ("Lubag") to demonstrate a response to bilateral pallidal stimulation. 1757 61

Recently, there has been interest in family-based tests of association to identify X-chromosome genes. However, none of the approaches allow for estimation of genetic risks. We propose a likelihood approach to estimate disease-related marker relative risks and test genotype association using a case-parents design. The test uses nuclear families with a single affected proband and allows additional siblings and missing parental genotypes. Extension to a haplotype test is based on assumptions of random mating and multiplicative penetrance. We investigate power and type I error rate of the likelihood-based test, using simulated data and apply our method to marker data from the monoamine oxidase A&B genes in families with Parkinson disease. We show how efficiency with missing parental information can be improved with additional sibling genotype information. Our likelihood approach offers great flexibility for testing different penetrance relationships within and between sexes. In addition, estimation of disease-related marker relative risks provides a measure of the magnitude of X-linked genetic effects on complex disorders.
 ...
PMID:X-LRT: a likelihood approach to estimate genetic risks and test association with X-linked markers using a case-parents design. 1827 16

Family-based association methods for detecting quantitative trait loci (QTL) have been developed primarily for autosomes, and comparable methods for X-linked QTL have received less attention. We have developed a family-based association test for quantitative traits, named XQTL, which uses X-linked markers in a nuclear family design. XQTL adopts the framework of the orthogonal model implemented in the QTDT program, modifying the sex-specific score for X-linked genotypes. XQTL also takes into account the dosage effect due to female X chromosome inactivation. Restricted maximum likelihood (REML) and Fisher's scoring method are used to estimate variance components of random effects. Fixed effects, derived from the phenotypic differences among and within families, are estimated by the least-squares method. Our proposed XQTL can perform allelic and two-locus haplotypic association tests and can provide estimates of additive genetic effects and variance components. Simulation studies show correct type I error rates under the null hypothesis and robust statistical power under alternative scenarios. The loss of power observed when parental genotypes are missing can be compensated by an increase of offspring number. By treating age at onset of Parkinson disease as a quantitative trait, we illustrate our method, using MAO polymorphisms in 780 families.
 ...
PMID:Association test for X-linked QTL in family-based designs. 1934 75

Parkinson's disease (PD), a common neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and their terminations in the basal ganglia, is thought to be related to genetic and environmental factors. Although the pathophysiology of PD neurodegeneration remains unclear, protein misfolding, mitochondrial abnormalities, glutamate dysfunction and/or oxidative stress have been implicated. In this study, we report that a rare T1492G variant in GLUD2, an X-linked gene encoding a glutamate dehydrogenase (a mitochondrial enzyme central to glutamate metabolism) that is expressed in brain (hGDH2), interacted significantly with age at PD onset in Caucasian populations. Individuals hemizygous for this GLUD2 coding change that results in substitution of Ala for Ser445 in the regulatory domain of hGDH2 developed PD 6-13 years earlier than did subjects with other genotypes in two independent Greek PD groups and one North American PD cohort. However, this effect was not present in female PD patients who were heterozygous for the DNA change. The variant enzyme, obtained by substitution of Ala for Ser445, showed an enhanced basal activity that was resistant to GTP inhibition but markedly sensitive to modification by estrogens. Thus, a gain-of-function rare polymorphism in hGDH2 hastens the onset of PD in hemizygous subjects, probably by damaging nigral cells through enhanced glutamate oxidative dehydrogenation. The lack of effect in female heterozygous PD patients could be related to a modification of the overactive variant enzyme by estrogens.
 ...
PMID:Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset. 1982 50


1 2 3 4 Next >>