Search

Background Parkin related Parkinson's disease ( PD) is differentiated from idiopathic PD by absent or sparse Lewy bodies, and preserved olfaction. The significance of single Parkin mutations in the pathogenesis of PD is debated. Objectives To assess olfaction results according to Parkin mutation status. To compare the prevalence of Parkin single heterozygous mutations in patients diagnosed with PD to the rate in healthy controls in order to establish whether these single mutations could be a risk factor for developing PD. Methods Parkin gene mutation testing was performed in young onset PD (diagnosed <50 years old) to identify three groups: Parkin homozygous or compound heterozygote mutation carriers, Parkin single heterozygote mutation carriers, and non-carriers of Parkin mutations. Olfaction was tested using the 40-item British version of the University of Pennsylvania smell identification test ( UPSIT). Results Of 344 young onset PD cases tested, 8 (2.3%) were Parkin compound heterozygotes and 13 (3.8%) were Parkin single heterozygotes. Olfaction results were available in 282 cases (eight compound heterozygotes, nine single heterozygotes, and 265 non-carriers). In Parkin compound heterozygotes, the median UPSIT score was 33, interquartile range ( IQR) 28.5-36.5, which was significantly better than in single Parkin heterozygotes (median 19, IQR 18-28) and non-carriers (median score 22, IQR 16-28) ( ANOVA P < 0.001). These differences persisted after adjusting for age, disease duration, gender, and smoking ( P < 0.001). There was no significant difference in UPSIT scores between single heterozygotes and non-carriers ( P = 0.90). Conclusions Patients with Parkin compound heterozygous mutations have relatively preserved olfaction compared to Parkin single heterozygotes and non-carriers. The prevalence of Parkin single heterozygosity is similar to the 3.7% rate reported in healthy controls. [ABSTRACT FROM AUTHOR]

Background: Patients presenting with parkinsonian syndromes share many clinical features, which can make diagnosis difficult. This is important as atypical parkinsonian syndromes (APSs) such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS) carry a poor prognosis, compared with patients with Parkinson's disease (PD). In addition, there is overlap between APS and dementia diseases, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD).Objective: To use a panel of cerebrospinal fluid (CSF) biomarkers to differentiate patients with APS from PD and dementia.Methods: A prospective cohort of 160 patients and 30 control participants were recruited from a single specialist centre. Patients were clinically diagnosed according to current consensus criteria. CSF samples were obtained from patients with clinical diagnoses of PD (n=31), PSP (n=33), CBS (n=14), MSA (n=31), AD (n=26) and FTD (n=16). Healthy, elderly participants (n=30) were included as controls. Total τ (t-τ), phosphorylated τ (p-τ), β-amyloid 1-42 (Aβ42), neurofilament light chain (NFL), α-synuclein (α-syn), amyloid precursor protein soluble metabolites α and β (soluble amyloid precursor protein (sAPP)α, sAPPβ) and two neuroinflammatory markers (monocyte chemoattractant protein-1 and YKL-40) were measured in CSF. A reverse stepwise regression analysis and the false discovery rate procedure were used.Results: CSF NFL (p<0.001), sAPPα (p<0.001) and a-syn (p=0.003) independently predicted diagnosis of PD versus APS. Together, these nine biomarkers could differentiate patients with PD from APS with an area under the curve of 0.95 and subtypes of APS from one another. There was good discriminatory power between parkinsonian groups, dementia disorders and healthy controls.Conclusions: A panel of nine CSF biomarkers was able to differentiate APS from patients with PD and dementia. This may have important clinical utility in improving diagnostic accuracy, allowing better prognostication and earlier access to potential disease-modifying therapies. [ABSTRACT FROM AUTHOR]

Many clinicians view age at onset as an important determinant of clinical phenotype in Parkinson’s disease (PD) and this has been reinforced by the identification of Mendelian genes that account for some cases of younger onset PD. A systematic review of OVID Medline for articles relevant to the relationship between clinical features and age at onset in PD published in English between 1950–2007 was performed. There are very few prospective community based studies which focus on the relationship between age at onset and the features of PD and a variety of case definitions are used in the literature. Most studies of young onset PD are based on specialist clinic referral series. The available evidence suggests that PD patients with a younger age at onset have: (i) a slower disease progression, (ii) an increased rate of dystonia at onset and during treatment, (iii) a lower rate of dementia and (iv) an increased rate of dyskinesias in response tol-DOPA treatment. The majority of the available studies do not report patient genotype data, but it is probably that the clinical heterogeneity of PD will be further refined with detailed clinico-genetic studies. [ABSTRACT FROM AUTHOR]

Previously mutations in a putative protein O-mannosyltransferase (SCO3154, Pmt) and a polyprenol phosphate mannose synthase (SCO1423, Ppm1) were found to cause resistance to phage, φC31, in the antibiotic producing bacteria Streptomyces coelicolor A3(2). It was proposed that these two enzymes were part of a protein O-glycosylation pathway that was necessary for synthesis of the phage receptor. Here we provide the evidence that Pmt and Ppm1 are indeed both required for protein O-glycosylation. The phosphate binding protein PstS was found to be glycosylated with a trihexose in the S. coelicolor parent strain, J1929, but not in the pmt− derivative, DT1025. Ppm1 was necessary for the transfer of mannose to endogenous polyprenol phosphate in membrane preparations of S. coelicolor. A mutation in ppm1 that conferred an E218V substitution in Ppm1 abolished mannose transfer and glycosylation of PstS. Mass spectrometry analysis of extracted lipids showed the presence of a glycosylated polyprenol phosphate (PP) containing nine repeated isoprenyl units (C45-PP). S. coelicolor membranes were also able to catalyse the transfer of mannose to peptides derived from PstS, indicating that these could be targets for Pmt in vivo. [ABSTRACT FROM AUTHOR]

Background: Dentatorubral pallidoluysian atrophy (DRPLA) is a rare, autosomal dominant, clinically heterogeneous neurodegenerative disorder characterised clinically by progressive dementia, ataxia, chorea, myoclonic epilepsy and psychiatric disturbance and pathologically by combined degeneration of the dentatorubral and pallidoluysian systems. DRPLA has a marked ethnic predilection, most commonly reported in Japan and thought to be rare in Caucasian populations.Methods: We describe the clinical and genetic characteristics of 17 patients with DRPLA segregating in four families in South Wales.Results: There was marked clinical heterogeneity with considerable overlap of symptoms and signs between and within families. The age of onset ranged from 34 to 60 years with an earlier onset associated with myoclonic epilepsy and a later onset associated with a Huntington disease-like presentation. We identified a distinct haplotype within one family not present within the other three families, suggesting that the expansion in at least one family did not arise from an immediate common ancestor. Analysis of repeat length polymorphisms in 306 Welsh control patients identified 14 (4.6%) with repeat lengths in the high-normal range, compared with 0% and 7.4% in previously reported north American Caucasian and Japanese control populations, respectively.Conclusions: DRPLA may not be as geographically or ethnically restricted as previously thought and the diagnosis should be considered in non-Asian patients presenting with a wide spectrum of neurological disease, especially if there is a dominant family history of dementia or movement disorder. The prevalence of high-normal length alleles may account for the relatively high prevalence of DRPLA in Wales. [ABSTRACT FROM AUTHOR]

Background: Dentatorubral pallidoluysian atrophy (DRPLA) is a rare, autosomal dominant, clinically heterogeneous neurodegenerative disorder characterised clinically by progressive dementia, ataxia, chorea, myoclonic epilepsy and psychiatric disturbance and pathologically by combined degeneration of the dentatorubral and pallidoluysian systems. DRPLA has a marked ethnic predilection, most commonly reported in Japan and thought to be rare in Caucasian populations. Methods: We describe the clinical and genetic characteristics of 17 patients with DRPLA segregating in four families in South Wales. Results: There was marked clinical heterogeneity with considerable overlap of symptoms and signs between and within families. The age of onset ranged from 34 to 60 years with an earlier onset associated with myoclonic epilepsy and a later onset associated with a Huntington disease-like presentation. We identified a distinct haplotype within one family not present within the other three families, suggesting that the expansion in at least one family did not arise from an immediate common ancestor. Analysis of repeat length polymorphisms in 306 Welsh control patients identified 14 (4.6%) with repeat lengths in the high-normal range, compared with 0% and 7.4% in previously reported north American Caucasian and Japanese control populations, respectively. Conclusions: DRPLA may not be as geographically or ethnically restricted as previously thought and the diagnosis should be considered in non-Asian patients presenting with a wide spectrum of neurological disease, especially if there is a dominant family history of dementia or movement disorder. The prevalence of high-normal length alleles may account for the relatively high prevalence of DRPLA in Wales. [ABSTRACT FROM AUTHOR]

Progressive supranuclear palsy is a neurodegenerative disease which affects the brainstem and basal ganglia. Patients present with disturbance of balance, a disorder of downward gaze and L-DOPA-unresponsive parkinsonism and usually develop progressive dysphagia and dysarthria leading to death from the complications of immobility and aspiration. Treatment remains largely supportive but, potentially, treatments based on cholinergic therapy may be useful. As in Alzheimer's disease, the neuronal degeneration is associated with the deposition of hyperphosphorylated tau protein as neurofibrillary tangles but there are important distinctions between the two diseases. Evidence from familial fronto-temporal dementia with parkinsonism linked to chromosome 17 suggests that tau protein deposition is a primary pathogenic event in some neurodegenerative diseases. The understanding of the mechanism of tau deposition in progressive supranuclear palsy is likely to be of importance in unravelling its aetiology. [ABSTRACT FROM AUTHOR]

Presents research which showed that xanthurenic acid induces gametocytes to undergo gametogenesis in the transmission of malaria. How malaria is transmitted; What induction requires; Acidity of mosquito bloodmeal in vivo; Inducing gametogenesis in vitro; Possibilities for development of methods to interrupt the transmission of malaria.

Progressive supranuclear palsy (PSP) is a tau deposition neurodegenerative disorder which usually occurs in sporadic form and is associated with a common variant of the tau gene. Rare familial forms of PSP have been described. Recently familial frontotemporal dementia linked to chromosome 17 (FTDP-17) has been shown to be due to mutations in tau and there may be a clinical and pathological overlap between PSP and FTDP-17. In this study we have analysed the tau sequence in two small families with PSP, and a number of clinically typical and atypical sporadic cases with pathological confirmation of the diagnosis. The tau mutations described in FTDP-17 were not found in the most clinically diagnosed patients with PSP. This suggests that usually FTDP-17 and PSP, including the rare familial form of PSP, are likely to be separate conditions and that usually PSP and typical PSP-like syndromes are not due to mutations in tau. [ABSTRACT FROM AUTHOR]

Three cases of late onset Gilles de la Tourette's syndrome are presented. The motor tics were mainly induced by an unexpected startling stimulus, but the startle reflex was not exaggerated. The tics developed after physical trauma or a period of undue emotional stress. Reflex tics may occur in Gilles de la Tourette's syndrome, but have not been described in late onset Tourette's syndrome. Such tics must be distinguished from psychogenic myoclonus and the culture bound startle syndromes. [ABSTRACT FROM AUTHOR]

Progressive supranuclear palsy is characterised pathologically by the deposition of neurofibrillary tangles consisting of tau protein. Patients with the disease have been reported to have a more frequent occurrence of one allele of an intronic polymorphism of the tau gene. Other diseases which may involve tau deposition include frontotemporal dementia and corticobasal degeneration. This polymorphism has been studied in a series of subjects with progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, idiopathic Parkinson's disease, and normal controls to (1) confirm this association in a large series and (2) to investigate a possible role for this association in other disorders which involve tau deposition. The results confirm the finding of an overrepresentation of the A0 allele and the A0/A0 genotype in patients with progressive supranuclear palsy, in the largest series reported to date. The A0 allele was found in 91% of patients with progressive supranuclear palsy as opposed to 73% of controls (p<0.001) and the A0/A0 genotype was seen in 84% of patients as compared with 53% of controls (p<0.01). There was no significant difference between patients with Parkinson's disease, frontotemporal dementia, or corticobasal degeneration, and controls. The A0 allele may have a direct effect on tau isoform expression in progressive supranuclear palsy or it may be in linkage disequilibrium with an adjacent determinant of tau gene expression. The explanation for this difference between a predisposition factor to progressive supranuclear palsy and the other conditions may lie in the molecular pathology of these diseases. [ABSTRACT FROM AUTHOR]

It has been suggested that early myoclonic status after cardiorespiratory arrest is an agonal event. Here we describe three cases who developed early myoclonic status during a coma after cardiorespiratory arrest due to acute asthma. As consciousness improved, each patient developed Lance-Adams type multifocal myoclonus, but the eventual outcome was satisfactory. Only one patient needed assistance to walk, and all three were self caring. One patient had persistent dyscalculia. Early myoclonic status is not necessarily an agonal event, particularly when it follows arrest due to acute asthma or asphyxia. [ABSTRACT FROM AUTHOR]

Glycodelins are glycoproteins synthesized in various glands, with sequence homology to beta-lactoglobulins, and named according to their unique oligosaccharide structures. We purified, cloned and sequenced endometrium- and seminal plasma-derived glycodelins (GdA and GdS respectively) and found that they are involved in various types of cell-cell communications. These include interactions between the spermatozoon and the egg, and between immune cells and their targets. Endometrial GdA inhibits sperm-egg binding, whereas the differently glycosylated GdS in seminal plasma does not. These observation are of interest for reproductive physiology, detection of causes of infertility, and they also may have potential for contraceptive development. [ABSTRACT FROM AUTHOR]