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Clinical Neuroscience

JULY 30, 2019

Cerebral cavernous malformation type 1 with retinal blood vessel tortuosity and KRIT1 gene mutation

KALMÁR Tibor, MARÓTI Zoltán, VADVÁRI Árpád, HALMOSI Ágnes, KÁLOVITS Ferenc, KÁLMÁN Bernadette

Cerebral cavernous malformations (CCMs) represent a relatively rare and heterogeneous clinical entity with mutations identified in three genes. Both sporadic and familial forms have been reported. We present a young female patient with episodic paresthesia and headaches, but without acute neurological deficits. Her mother had a hemorrhaged cavernoma surgically removed 21 years ago. Cranial magnetic resonance imaging revealed multiple cavernous malformations in the size of a few millimeters and the ophthalmologic exam detected retinal blood vessel tortuosity in the proband. Targeted exome sequencing analysis identified a nonsense mutation in exon 16 of the KRIT1 gene, which resulted in a premature stop codon and a truncated protein underlying the abnormal development of cerebral and retinal blood vessels. This mutation with pathogenic significance has been reported before. Our case points to the importance of a thorough clinical and molecular work up despite the uncertain neurological complaints, since life style recommendations, imaging monitoring and genetic counseling may have major significance in the long term health of the patient.

Clinical Neuroscience

JULY 30, 2016

[Transthyretin familial amyloid polyneuropathy - three Hungarian cases with rare mutations (His88Arg and Phe33Leu)]

CSILLIK Anita, POZSONYI Zoltán, SOÓS Krisztina, BALOGH István, BODÓ Imre, ARÁNYI Zsuzsanna

[Introduction - Transthyretin familial amyloid polyneuropathy is a rare autosomal dominant progressive systemic disesase of adults caused by endoneural amyloid deposition due to point mutations of the transthyretin gene. It is the most severe form among hereditary polyneuropathies, being fatal within 10 years if left untreated. The disease is underdiagnosed, the late onset forms (above the age of 50) being probably more widespread than previously thought. Early diagnosis is essential as the early introduction of causal therapy (tafamidis) slows progression and prolongs survival. Patients - We report here three non-related Hungarian cases of transthyretin familial amyloid polyneuropathy with non- Val30Met mutations (His88Arg in two cases, Phe33Leu in one case). They were all characterized by late-onset, progressive, length-dependent, axonal, sensorimotor polyneuropathy and the simultaneous presentation of severe restrictive cardiomyopathy. In all three cases, clinical and electrophysiological signs of myopathy were also present, suggesting the involvement of skeletal muscles as well. In two cases, high resolution ultrasound of the peripheral nerves was also performed, which showed segmental structural alterations (change or loss of fascicular structure) and some increase of echogenicity of the interfascicular epineurium, without substantial enlargement of the nerves. Conclusion - In Hungary, mainly the rare, non-Val30Met mutation forms of transthyretin familial amyloid polyneuropathy are encountered, as in our cases. As opposed to the Val30Met forms, these mutations are characterized by late onset and simultaneous presentation of severe cardiomyopathy. Our report highlights the importance of considering transthyretin familial amyloid polyneuropathy in the differential diagnosis of late-onset, progressive, axonal polyneuropathies of unknown etiology, particularly if associated with cardiac disease.]

Clinical Oncology

DECEMBER 05, 2014

[Bone metastases - Current treatment strategy]

BOÉR Katalin, NÉMETH Zsuzsanna

[Bone is the most common site of metastatic disease in many solid tumours, mainly in breast, prostate and lung cancer. Patients with bone metastases are at risk for skeletal-related events such as bone pain, pathological fractures requiring surgery and/or radiation to bone lesions, hypercalcemia, and spinal cord compression. Skeletal-related events are major source of morbidity for cancer patients and may be associated with negative impact on quality of life and survival. Bisphosphonates inhibit osteoclast function and are widely used in the treatment of malignant bone disease, as preventive therapy against skeletal-related events. Recently, the NF-κappa B-ligand (RANKL)-mediated osteoclast activity and this pathway in bone metabolism became a prime target for the treatment of bone metastases. The fi rst drug targeting the RANK-RANKL pathway is denosumab, a fully monoclonal human antibody which binds to RANKL and inhibits osteoclast activity. Nowadays optimal treatment of bone metastases requires multidisciplinary management of patients including the administration of bone-modifying agents such bisphosphonates or denosumab. The use of bone-targeted agents is a valuable additional treatment in the fi ght against bone metastases and multiple, randomised trials have demonstrated the effectivity of these drugs in reducing skeletal morbidity caused by advanced cancer.]

Lege Artis Medicinae

FEBRUARY 05, 2016

[Effect of rosuvastatin therapy’s introduction on lipid levels and on proportion of target values reaching in patients with familial hypercholesterolemia and familiarity]

SZTANEK Ferenc

[Familial hypercholesterolemia (FH) is a genetically heterogeneous disorders characterized by very high total cholesterol and low-density lipoprotein (LDL) cholesterol levels, and it accelerates the development of atherosclerosis and early cardiovascular disease. FH is most commonly caused by mutations in low-density lipoprotein receptor (LDLR) or apolipoprotein B-100 (APOB) genes. In rest of the cases the mutation is in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene. Previous studies have shown that rosuvastatin significantly reduces major cardiovascular events in high risk patients. The goal of our study was to investigate the lipid-altering efficacy of simvastatin or atorvastatin therapy compared with high-intensity rosuvastatin therapy in patients with FH and familiarity. Recent work has demonstrated the efficacy of high-intensity rosuvastatin therapy in enabling high-risk and very high-risk patients in lowering significantly plasma levels of total and LDL-cholesterol, which can subtantially affect major cardiovascular events in familial hypercholesterolemia.]

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.]