Enrico De Vita, Harpreet Hyare, Gerard Ridgway, Marie-Claire Porter, Andrew Thompson, Chris Carswell, Ana Lukic, Rolf Jager, Diana Caine, Peter Rudge, Tarek Yousry, John Collinge, Simon Mead, and John Thornton Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, UCLH NHS Foundation Trust, London, United Kingdom, Academic Neuroradiological Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, United Kingdom, MRC Prion Unit, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, United Kingdom, National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCLH NHS Foundation Trust, London, United Kingdom, Wellcome Department of Cognitive Neurology, UCL Institute of Neurology, London, United Kingdom

Over the last decade remarkable advances in genotyping and sequencing technology have resulted in hundreds of novel gene associations with disease. These have typically involved high frequency alleles in common diseases and with the advent of next generation sequencing, disease causing recessive mutations in rare inherited syndromes. Here we discuss the impact of these advances and other gene discovery methods in the prion diseases. Several quantitative trait loci in mouse have been mapped and their human counterparts analysed (HECTD2, CPNE8); other candidate genes regions have been chosen for functional reasons (SPRN, CTSD). Human genome wide association has been done in variant Creutzfeldt-Jakob disease (CJD) and are ongoing in larger collections of sporadic CJD with findings around, but not clearly beyond, the levels of statistical significance required in these studies (THRB-RARB, STMN2). Future work will include closer integration of animal and human genetic studies, larger and combined genome wide association, analysis of structural genetic variantion and next generation sequencing studies involving the entire coding exome or genome.

There is no doubt that the development of diagnostic criteria has contributed greatly to epidemiological research in prion diseases, and Heath and colleagues emphasize this in surveillance studies of variant Creutzfeldt-Jakob disease (vCJD). We caution, however, against a more broad application in clinical practice, particularly in governing decisions about clinical diagnosis, communication with patients/caregivers, and access to experimental therapies. The physician looking after a young patient with an unexplained rapidly progressive neuropsychiatric syndrome, dementia, or ataxia needs to make prompt clinical decisions. There are treatable alternative diagnoses, and an early firm diagnosis is essential. The pulvinar sign on magnetic resonance imaging is often not identified when patients are first imaged, and a requirement for a clinical duration of 6 months or greater makes a probable diagnosis impossible in the early stages of disease. Physicians who have cared for families affected by vCJD are aware of the complicated psychological issues generated by the perceived mismanagement of the bovine spongiform encephalopathy epidemic, which are often exacerbated by a delay or equivocation about diagnosis. Several families also choose experimental intracerebroventricular pentosan polysulfate therapy, which requires neurosurgery. In the context of these issues, the role of tonsillar biopsy is underemphasized by Heath et al and the criteria. In our experience of 60 biopsies, by far the largest series worldwide, tonsillar biopsy has 100% sensitivity and specificity, at any stage of the disease. Prion protein deposition in the tonsil can be patchy, and at least 20 germinal centers need to be examined. The number examined in 1 French case reported by Heath et al may not have been adequate to avoid a false-negative result. It is notable that of the 6 most recent patients suspected clinically of having vCJD in the United Kingdom, 3 did not meet epidemiological criteria for probable vCJD while alive. Two of these patients would have been misdiagnosed as sporadic CJD according to the updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob Disease criteria; typical vCJD was diagnosed at autopsy in both. In a third patient, with a heterozygous codon 129 genotype reported by Kaski et al, the pulvinar sign was not thought to be present by all neuroradiologists, and no tissue was examined. It is reasonable to expect that tonsillar biopsy may have made the correct diagnosis in each of these cases. Given experience with transfusion-associated secondary vCJD, vCJD prions are likely to be present in significant titer in human blood, a diagnostic blood test based on detection of the infectious agent is clearly possible in principle, and if technologically achieved, will necessitate a complete revision of how we approach diagnosis in this disease.

As the vCJD outbreak evolves we are alert to possible changes in the clinicopathological phenotype, investigations and genetic analysis. MRI typically shows high signal in the pulvinar nucleus on T2W images and has recently been added to the CJD diagnostic criteria. Here we report MRI findings prompting a diagnosis of sporadic CJD by the current WHO criteria in two recent British patients seen by the NHS National Prion Clinic. Quantitative analysis confirmed greater T2W signal hyperintensity in caudate and putamen than the pulvinar. The neuropathological analysis showed characteristic PrP deposition diagnostic of vCJD, in addition to intense and widespread accumulation of abnormally phosphorylated tau protein. PRNP sequencing revealed methionine homozygosity at codon 129 in both patients. Correct diagnosis during life might have been obtained by tonsillar biopsy. Our retrospective blinded review of 60 suspected vCJD patients showed that while MRI had considerable diagnostic value, there were false positive and negative studies, particularly in early vCJD. Tonsillar biopsy had 100% sensitivity and specificity at all disease stages. Biopsy may allow early diagnosis in atypical clinico-pathological phenotypes of vCJD, avoiding unnecessary investigations, and allow rapid inclusion in therapeutic trials. A conclusive diagnosis during life can be of importance to patients and carers.

Aims To ascertain the frequency and geographical distribution of patients diagnosed with known genetic causes of Alzheimer's disease (AD) and inherited prion disease (IPD) in the UK 2001–2005. By comparison with frequencies predicted from published population studies, to estimate the proportion of patients with these conditions who are being accurately diagnosed. Methods All the positive diagnostic test results (from both genetic testing centres) were identified for mutations in presenilin-1 (PSEN1), presenilin-2 (PSEN2), amyloid precursor protein (APP) and prion protein genes (PRNP) for patients resident in the UK in a 5 year period. The variation in the incidence of mutation detection between UK regions was assessed with census population data. Published studies of the genetic epidemiology of familial early onset AD (EOAD) were reviewed to produce estimates of the number of patients in the UK that should be detected. Results The rate of detection of EOAD and IPD varied very significantly and consistently between regions of the UK with low rates of detection in Northern and Western Britain (72% less detection in these regions compared with Central and Southeast Britain). The estimates from population studies further suggest a greater number of patients with EOAD than are diagnosed by genetic testing throughout the UK. Conclusions It is likely that patients with EOAD and IPD are not being recognised and referred for testing. With the prospect of meaningful disease modifying therapeutics for these diseases, this study highlights an issue of relevance to neurologists and those planning for provision of National Health Services.

BACKGROUND Genetic variants of the prion protein gene (PRNP) strongly determine susceptibility to prion diseases. All tested patients with definite variant Creutzfeldt-Jakob disease (vCJD) are homozygous for methionine at a common polymorphism at codon 129. A further genetic polymorphism at codon 219, a common variant in several Asian populations, is considered protective against sporadic CJD. OBJECTIVE To report a finding of heterozygosity at codon 219 in 2 patients with vCJD. DESIGN Case reports. SETTING MRC (Medical Research Council) Prion Unit and Department of Neurodegenerative Disease, University College London Institute of Neurology, and National Prion Clinic, National Hospital for Neurology and Neurosurgery. Patients Two patients with clinical and investigation findings consistent with the diagnoses of probable vCJD. MAIN OUTCOME MEASURES Clinical and genetic findings. RESULTS A 34-year-old man had a 15-month history of behavioral change progressing to ataxia, dysarthria, involuntary choreiform movements, and severe cognitive impairment. Cerebrospinal fluid analysis was positive for 14-3-3 protein, electroencephalography showed generalized slowing, and magnetic resonance imaging revealed thalamic high signal bilaterally, typical of vCJD. A 31-year-old woman had a 16-month history of cognitive decline, ataxia, involuntary choreiform movements, and myoclonic jerks. Magnetic resonance imaging showed bilateral pulvinar high signal. The diagnosis was confirmed by a tonsillar biopsy demonstrating abnormal prion protein deposition in a typical pattern for vCJD. PRNP sequencing showed a methionine homozygous codon 129 genotype and an E219K polymorphism in both patients. CONCLUSIONS The E219K polymorphism is neutral or may even confer susceptibility to vCJD. The observations are interpretable in the context of the conformational selection model of prion replication. A barrier to prion disease transmission depends on the degree to which permitted pathologic conformations of the prion protein overlap between the inoculum and the host.

E. De Vita, H. Hyare, C. Carswell, A. Thompson, A. Lukic, T. Yousry, P. Rudge , S. Mead, J. Collinge, and J. Thornton Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, UCLH NHS Foundation Trust, London, United Kingdom, Academic Neuroradiological Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, United Kingdom, MRC Prion Unit, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, United Kingdom, National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCLH NHS Foundation Trust, London, United Kingdom

Uricni artritis je recidivirajuca upala jednoga ili vise zglobova zbog hipersaturacije uricne kiseline i odlaganja kristala urata, sklona stvaranju tofa i deformacije zglobova, bubrežnih kamenaca i uricne nefropatije. Akutni uricni artritis obicno nastaje nakon dugogodisnje hiperuricemije u korelaciji s koncentracijom uricne kiseline u serumu, trajanjem hiperuricemije i staroscu bolesnika. Purinske baze, adenin, gvanin, ksantin i hipoksantin nastaju razgradnjom endogenih i egzogenih nukleoproteina i biosintezom, pod utjecajem brojnih enzima. Oksidacijom hipoksantina i ksantina pomocu ksantinoksidaze nastaje uricna kiselina. Nedostatak ili poremecaj aktivnosti pojedinih enzima uzrokuje uricni artritis, tofe, nefrolitijazom i teske neuroloske simptome, pa i teska imunoloska ostecenja. Vecina bolesnika s uricnim artritisom ima prekomjernu tjelesnu masu. Cak 68% bolesnika s uricnim artritisom je pretilo. Racuna se, da su ti bolesnici za 15 do 25% teži od normale. Pretilost i osobito naglo debljanje u mladosti povecavaju rizik za razvoj uricnog artritisa. Najveci rizik imaju najdeblji bolesnici. Dokazana je cvrsta korelacija tjelesne mase i koncentracije urata u serumu. Lijecenje asimptomatske hiperuricemije treba svesti na postupno i kontinuirano smanjenje tjelesne mase. Redukcija potrosnje hrane bogate purinima, alkohola, piva, i medicinski opravdano smanjenom primjenom lijekova koji smanjuju izlucivanje uricne kiseline, te pijenje vece kolicine vode, može se izbjeci hipersaturacija uricne kiseline u mokracnim putevima i prevenirati stvaranje uratnih kamenaca kao i kamenaca od kalcijevog oksalata i fosfata u mnogih bolesnika. U sažetku može se zakljuciti da su osnovna pravila dijetetskog tretmana od momenta otkrivanja hiperuricemije kao i u bolesnika s uricnim artritisom prehrana mora biti hipoproteinska, hipopurinska te hipolipidna i konacno postepeno smanjenje pretilosti hipokaloricnom hranom pretilih bolesnika.

Dijeteticko istraživanje, provedeno dijeteickim upitnikom, ukazuje na prisutnost znacajnih pokazatelja nepravilne prehrane koji su mogli djelovati na patogenezu gastroezofagusne refluksne bolesti i adenokarcinoma jednjaka. Bolesnici sa Barettovim jednjakom i adenokarcinomom jednjaka uglavnom konzumiraju hranu brzo (70-85%), preferiraju jako vruce ili hladnu hranu (80-90%) te jako zacinjenu hranu (60-75%), dimljenu hranu (55-75%) te konzumiraju alkoholna pica (70-75%)i crnu kavu (100%) i pusaci su (80-90%).