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Lege Artis Medicinae

MAY 26, 2008

[THE REAL FACE OF JUVENILE POLYPOSIS SYNDROME - MALIGNANCY IN A DISEASE PREVIOUSLY THOUGHT TO BE BENIGN]

TAM Beatrix, SALAMON Ágnes, BAJTAI Attila, NÉMETH Annamária, KISS János, SIMON László

[INTRODUCTION - The majority of colorectal cancer cases is sporadic, but familial and autosomal dominant forms should also be considered. Juvenile polyposis syndrome is an autosomal dominant condition caused by mutations in the SMAD4 or the BMPR1A gene. Typically, numerous hamartomatous polyps develop in the upper gastrointestinal and the colorectal area. In contrast to earlier opinions, some of these polyps may transform malignantly, like in the case presented here, at the age of 34-35 years on average. CASE REPORT - During the eighteen-year continuous care of the young man treated for juvenile polyposis, more than a hundred polyps were resected from the gastrointestinal tract. After an eigth-year intermission of surveillance because of insufficient compliance, the patient presented in a severe clinical condition caused by metastatic colorectal cancer. He died after a short palliative therapy at the age of 31. Based on the family tree, all of his living adult first-degree relatives were subsequently examined and juvenile polyposis syndrome was also diagnosed in his older brother. Genetic testing revealed a mutation in the BMPR1A gene in the clinically affected brother, one of his daughters, and also in the deceased proband's child. CONCLUSION - Genetic testing made it possible to relieve the mutation-free relatives of the anxiety and particularly of a number of unnecessary, mainly invasive examinations, while mutation carriers can be given the best possible clinical surveillance.]

Lege Artis Medicinae

MARCH 21, 2009

[THE REAL FACE OF JUVENILE POLYPOSIS SYNDROME - MALIGNANCY IN A DISEASE PREVIOUSLY THOUGHT TO BE BENIGN]

TAM Beatrix, SALAMON Ágnes, BAJTAI Attila, NÉMETH Annamária, KISS János, SIMON László

[INTRODUCTION - The majority of colorectal cancer cases is sporadic, but familial and autosomal dominant forms should also be considered. Juvenile polyposis syndrome is an autosomal dominant condition caused by mutations in the SMAD4 or the BMPR1A gene. Typically, numerous hamartomatous polyps develop in the upper gastrointestinal and the colorectal area. In contrast to earlier opinions, some of these polyps may transform malignantly, like in the case presented here, at the age of 34-35 years on average. CASE REPORT - During the eighteen-year continuous care of the young man treated for juvenile polyposis, more than a hundred polyps were resected from the gastrointestinal tract. After an eigth-year intermission of surveillance because of insufficient compliance, the patient presented in a severe clinical condition caused by metastatic colorectal cancer. He died after a short palliative therapy at the age of 31. Based on the family tree, all of his living adult first-degree relatives were subsequently examined and juvenile polyposis syndrome was also diagnosed in his older brother. Genetic testing revealed a mutation in the BMPR1A gene in the clinically affected brother, one of his daughters, and also in the deceased probands child. CONCLUSION - Genetic testing made it possible to relieve the mutation-free relatives of the anxiety and particularly of a number of unnecessary, mainly invasive examinations, while mutation carriers can be given the best possible clinical surveillance.]

Clinical Neuroscience

JULY 10, 2005

[Frontotemporal dementia - Part II Differential diagnosis, genetics, molecular pathomechanism and pathology]

GALARIOTIS Vasilis, BÓDI Nikoletta, JANKA Zoltán, KÁLMÁN János

[This is a comprehensive paper in three parts covering history, prevalence, clinical forms, differential diagnosis, genetics, molecular pathomechanism, pathology, clinical diagnosis and treatment of frontotemporal dementia (FTD). The second part focuses on the differential diagnosis, genetics, molecular pathomechanism and pathology. The clinical diagnosis of frontotemporal dementia is based on the presence of a prominent disturbance of the executive function and of frontal lobe syndrome or a progressive aphasic syndrome without severe global cognitive impairment. Of other dementias, it is primarily Alzheimer’s disease that it should be differentiated from, but other psychiatric disorders must also be ruled out. The disease has familial and sporadic forms. Recent identification of mutations in the gene encoding the microtubule-associated tau protein in the inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has demonstrated that various tau dysfunctions can lead to neurodegeneration. Tau gene mutations have varied effects on the biology and function of the protein. This heterogeneous pathomechanism explains the wide range of clinical and neuropathological features observed in the FTDP-17. Tau and ubiquitin antibodies can be detected by sensitive immunohistochemical methods. The diagnosis of FTD should be based on neuropathological examination, and this is also the only method by which it can be definitely differentiated from other types of dementias.]

Lege Artis Medicinae

OCTOBER 18, 2006

[CHEMOPREVENTION OF COLORECTAL CANCER]

LAKATOS Péter László

[Colorectal cancer is the second leading cause of cancer mortality in developed countries; in Hungary, the mortality has almost tripled in the past four decades. A decrease in mortality can only be expected from a consistently applied diagnostic and management strategy, including preventive measures. Primary prevention is defined as dietary, medicinal and lifestyle actions that can reduce the risk of developing cancer in people with average risk. Secondary prevention is the prophylactic treatment of high-risk patients or praecancerous lesions; tertiary prevention is the prevention of recurrence in patients cured of colorectal cancer. Drugs or dietary supplements used for chemoprevention block, delay or reverse the process of carcinogenesis. The most important drugs used for chemoprevention are aspirin and nonsteroidal anti-inflammatory drugs. Long-term administration of these drugs reduces the risk of developing colorectal cancer or adenoma both in the high-risk and in the average-risk population. The risk-lowering effect seems to be in positive correlation with the dose and the duration of use. Other chemoprophylactic drugs such as calcium, folate, oestrogen and antioxidants, as well as 5-aminosalicylates in patients with ulcerative colitis are also discussed in this review. Based on the current knowledge, chemoprophylaxis of colorectal cancer is recommended as secondary prevention in patients at high risk (e.g., familial adenomatous polyposis, extensive ulcerative colitis). In contrast, based on adverse event profile and cost-effectiveness analysis, primary prevention with chemopreventive drugs is currently not recommended in the averagerisk population.]

Lege Artis Medicinae

NOVEMBER 20, 2009

[The role of double-balloon endoscopy in the diagnosis and treatment of small intestinal disease compared with capsule endoscopy]

LAKATOS Péter László, HORVÁTH Henrik Csaba, ZUBEK László, PÁK Gábor, NÉMETH Artúr, RÁCZ István, PÁK Péter, FUSZEK Péter, NAGYPÁL Anna, GEMELA Orsolya, PAPP János

[INTRODUCTION - Until recently, only the proximal small bowel was accessible for diagnostic or therapeutic endoscopy. A new method, doubleballoon enteroscopy (DBE), provides high-resolution imaging and enables both diagnostic and therapeutic interventions in all segments of the gastrointestinal tract. Our aim was to report our experiences with the Fujinon EN-450 T5 therapeutic double-balloon endoscope and compare our findings with the results of earlier capsule endoscopy where this was available. METHODS - Between August 2005 and July 2009, 150 DBE procedures were conducted in 139 consecutive patients (M/F: 67/72, age: 51.1±18.6 years) who presented at our tertiary referral hospital. The examination was performed via the oral route in 112 patients, via the anal route in 16 patients, and via both routes in 11 patients. DBE was indicated due to obscure gastrointestinal bleeding in most cases (83), due to diagnosis or complication of IBD in 29 cases and due to polyposis syndrome or suspected neoplasia in 25 patients. In one patient we performed endoscopic retrograde cholangiopancreatography (ERCP). All procedures were performed using i.v. anaesthesia at our outpatient clinic. After the procedure, the patients were monitored in a recovery room for at least four hours. The results of previous capsule endoscopy were available in 27 patients. RESULTS - Small-bowel abnormalities ? mostly angiodysplasias, minor erosions or ulcers ? were detected in 50 (60.2%) of the patients with obscure gastrointestinal bleeding. Malignancy was found in 7,2% (6/83) of the patients who were examined because of bleeding (three gastrointestinal stoma tumour, one non-Hodgkin lymphoma, one previously undetected melanoma metastasis and one pancreatic adenomacarcinoma that involved the duodenum) Intervention was performed in 24 patients. IBD was diagnosed in five (38.5%) of the 13 patients in whom the disease was suspected. In patients with known Crohn-disease, DBE was indicated on the basis of the extent, behaviour and activity of the disease. Polypectomy was performed in eight patients with Peutz-Jeghers syndrome or familial adenomatous polyposis syndrome, whereas small-bowel adenocarcinoma was diagnosed in four patients. The concordance between the findings of capsule endoscopy and DBE was 51.8% (14/27), and in one patient DBE revealed malignancy that has not been detected by endoscopy. The average insertion length during the procedure was approximately 213 cm (range 50-480 cm, SD 111). CONCLUSIONS - On the basis of our results, DBE is a safe and useful method for assessing and treating small bowel disease, even if capsule endoscopy is contraindicated due to suspected strictures.]

Ca&Bone

NOVEMBER 20, 2004

[A de novo heterozygous R551K point mutation and an A986S polymorphism in a patient with neonatal severe primary hyperparathyroidism]

CSÁKVÁRY Violetta, TÓTH Miklós, PATÓCS Attila, VARGA Ibolya, OROSZLÁN György, RÁCZ Károly

[INTRODUCTION - Familial hypocalciuric hypercalcemia and neonatal severe primary hyperparathyroidism are caused by inactivating mutations of the calcium-sensing receptor (CaSR) gene. We report the case of a now 9.5 years old boy who presented with the clinical syndrome of neonatal severe hyperparathyroidism. PATIENT AND METHODS - At the age of 2 days the patient developed respiratory distress. Clinical studies revealed increased serum calcium (3.1 mmol/l), non-suppressed serum parathyroid hormone level (48.3 pg/ml) and severe undermineralization of bones, as well as periosteal calcification in the distal part of both femurs suggesting fractures during the intrauterine life. Parathyreoidectomy was not performed.At the age of 6 years normal mental and physical development, persisting hypercalcemia without clinical symptoms, normal skeletal morphology, absence of new bone fractures, and absence of renal stones or nephrocalcinosis were documented, and the patient has remained completely symptom-free until his present age of 9.5 years. Sequence analysis of the entire coding region (exons 2-7) of the CaSR gene in peripheral leukocyte DNA revealed a heterozygous mutation at codon 551 (AGG→AAG) predicting a change of arginine to lysine (R551K). In addition, a known heterozygous polymorphism at codon 986 (GCC→TCC) was found in the proband and in his father. CONCLUSION - Our patient seems to represent the fourth reported case of neonatal severe primary hyperparathyroidism with a heterozygous de novo mutation of the CaSR gene. In addition, this case provides new evidence that with time the disease of neonatal severe hyperparathyroidism may spontaneously turn into a symptomless, benign condition resembling familial hypocalciuric hypercalcemia.]

Clinical Neuroscience

NOVEMBER 30, 2007

[GENETIC BACKGROUND OF HUMAN PRION DISEASES]

KOVÁCS Gábor Géza

[acquired. The human prion protein gene (PRNP) is located to chromosome 20 (20p12-ter). Mutations and polymorphisms in the PRNP are associated with prion disease. Genetic prion diseases are inherited in an autosomal dominant trait, examination of the penetrance is restricted to mutation E200K (59-89%). Mutations can be substitutions or insertions. Genetic prion diseases are classified according to the clinicopathological phenotype and comprise genetic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease and fatal familial insomnia. Base pair insertions may resemble Creutzfeldt-Jakob disease or Gerstmann-Sträussler-Scheinker disease phenotypes, however, their unique clinicopathological presentations are also emphasized. Among the polymorphisms of the PRNP, the one at codon 129 is the most important, where methionine or valine may be encoded. This polymorphism is known to influence the phenotype of disease forms. Molecular classification of sporadic Creutzfeldt-Jakob disease also depends on the codon 129 polymorphisms in addition to the Western blot pattern of the protease resistant prion protein. According to this at least six well characterised forms of sporadic Creutzfeldt-Jakob disease are known. Influence of other genes were also investigated. Contrasting results are reported regarding the role of apolipoprotein E allele ε4, but presence of allele ε2 seems to influence the prognosis. Polymorphisms in the doppel gene or ADAM10 could not be clearly associated with Creutzfeldt-Jakob disease. Polymorphisms in the upstream and intronic regulatory region of the PRNP gene may be a risk factor for Creutzfeldt-Jakob disease. The PRNP codon 129 polymorphism was examined in non-prion diseases. Some studies suggest that this polymorphism may have influence on the cognitive decline and early onset Alzheimer’s disease.]

Clinical Neuroscience

MARCH 20, 2011

[CADASIL and other hereditary small vessel diseases of the brain - Increasingly diagnosed conditions underlying familial ischaemic stroke and dementia]

GUNDA Bence, HUGUES Chabriat, BERECZKI Dániel

[CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) has recently gained great interest in vascular neurology as the most common heritable cause of stroke and vascular dementia in adults. This autosomal dominant small vessel disease of the brain - unlike the sporadic, hypertensive form - appears already in adult midlife in the absence of vascular risk factors with ischemic episodes and progressive dementia, its first manifestation can be migraine with aura, and is often associated with psychiatric disturbances. The magnetic resonance imaging (MRI) changes showing a characteristic pattern may precede symptoms by more than a decade. The identification of the mautation of the NOTCH 3 gene responsible for the disorder encoding a transmembrane receptor of vascular smooth muscle cells - has given great impetus on research to understand the molecular and vascular pathogenesis of the disease. The special importance of this latter lies in the fact that CADASIL provides a pure genetic model for subcortical cerebral ischemia and vascular dementia without the confounding factors of comorbidities and advanced age. Thus insights into CADASIL may help us better understand the more common sporadic forms as well. Moreover CADASIL is one of the best studied examples of secondary migraine. Currently we have far less knowledge on other forms of hereditary small vessel disease of the brain such as CARASIL, HERNS, CRV, HVR, PXE etc. Neurologists are becoming more and more familiar with CADASIL, and with the wider availability of MRI it is increasingly diagnosed. However the disorder is still probably underrecognised. This review aims to summarize our current knowledge on CADASIL with special emphasis on diagnostic and diffrential diagnostic points for the practising neurologist.]

Ca&Bone

NOVEMBER 20, 2004

[The pathophysiological role of the cell surface calcium-sensing receptor New clinical entities and drugs, potential therapeutic targets]

TÓTH Miklós

[The extracellular calcium-sensing receptor (CaSR) was recognized and cloned a decade ago. It is a G-proteincoupled receptor that plays an essential role in the regulation of extracellular calcium homeostasis. Diseases known as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism and autosomal dominant hypocalcemia are the consequences of naturally occurring mutations of the CaSR. However, the spectrum of the CaSR diseases became more complex with the recognition of both hypo- and hypercalcemic states caused by anti-CaSR autoantibodies. Activating anti-CaSR autoantibodies have been implicated in the pathogenesis of isolated idiopathic hypoparathyroidism and of hypoparathyroidism associated with autoimmune polyglandular syndromes. Inactivating CaSR autoantibodies may cause fluctuating hypercalcemic disorder that resembles primary hyperparathyroidism. The CaSR recently became one of the most intensively investigated target of potential new drugs. Cinacalcet has been approved for the treatment of secondary hyperparathyroidism associated with chronic renal insufficiency and for the management of inoperable or metastatic parathyroid carcinoma.The CaSR may be one of the main molecular target of strontium ranelate, wich is a new antiosteoporotic compound.]

Clinical Neuroscience

JANUARY 20, 2007

[THE FAMILIAL INCIDENCE OF EPILEPSY IN THE GROUP OF EPILEPTIC PATIENTS EXAMINED AFTER THEIR FIRST SEIZURE - PILOT STUDY]

RÓZSAVÖLGYI Margit, RAJNA Péter

[Introduction - It is essential to identify the genetic factors of epilepsy in the every day clinical practice for several reasons. The proof of the genetically defined sub-clusters existing inside the epileptic disease group is significant in diagnoses and therapy. The risk of inheriting epilepsy could influence the patient’s family planning which has a great impact on their quality of life. The aim of the study - To analyse clinical data obtained from patients examined after their first provoked or unprovoked seizure and the observation of the recurrence of seizures. To compare the data obtained with the familial occurrence of epilepsy. Population and methods - Data was obtained from a questionnaire developed by the authors. The epileptic patients with positive familial data underwent to an analysis of their family tree. Results - Of 120 persons who were examined the prevalence of epilepsy in their family was 20.4%. This corresponds to the familial prevalence of generalised epilepsy according to the published clinical data. The recurrence of seizures was experienced by 32% of the patients with a family background affected by epilepsy. The risk of reoccurring seizures was the highest if the familial epilepsy manifested itself in the same generation (among brothers or sisters) and if we were able to register epileptiform activity on the interictal EEG. According to our clinical data the genetic set up can play a role also in the provoked first epileptic seizure. The incidence of familial epilepsy was found high (12.72%) in the presence of incidental epileptic seizures when the EEG was free of epileptiform alterations. Conclusion - 1. The genetic basis for the first epileptic seizure in the population of young adults approaches the data known in idiopathic generalised epilepsy irrespective of the fact whether it was related to the seizure provoking factors or not. 2. The risk of seizure reactivation was higher in non-provoked seizures then at the incidental epileptic symptoms. Seizure reactivation had to be taken into consideration when epileptiform patterns appeared on the patient's EEG and/or epileptic symptoms were experienced by the patient's brother or sister. The probability of reoccurring seizures was lower if the epileptic seizures manifested in parents or earlier generations.]