Next-generation genetic sequencing (NGS) technologies facilitate the screening of multiple genes linked to neurodegenerative dementia, but there are few reports about their use in clinical practice. ...Which patients would most profit from testing, and information on the likelihood of discovery of a causal variant in a clinical syndrome, are conspicuously absent from the literature, mostly for a lack of large-scale studies. We applied a validated NGS dementia panel to 3241 patients with dementia and healthy aged controls; 13,152 variants were classified by likelihood of pathogenicity. We identified 354 deleterious variants (DV, 12.6% of patients); 39 were novel DVs. Age at clinical onset, clinical syndrome and family history each strongly predict the likelihood of finding a DV, but healthcare setting and gender did not. DVs were frequently found in genes not usually associated with the clinical syndrome. Patients recruited from primary referral centres were compared with those seen at higher-level research centres and a national clinical neurogenetic laboratory; rates of discovery were comparable, making selection bias unlikely and the results generalisable to clinical practice. We estimated penetrance of DVs using large-scale online genomic population databases and found 71 with evidence of reduced penetrance. Two DVs in the same patient were found more frequently than expected. These data should provide a basis for more informed counselling and clinical decision making.
Techniques for clinical genetic testing in dementia disorders have advanced rapidly but remain to be more widely implemented in practice. A positive genetic test offers a precise molecular diagnosis, ...can help members of an affected family to determine personal risk, provides a basis for reproductive choices and can offer options for clinical trials. The likelihood of identifying a specific genetic cause of dementia depends on the clinical condition, the age at onset and family history. Attempts to match phenotypes to single genes are mostly inadvisable owing to clinical overlap between the dementias, genetic heterogeneity, pleiotropy and concurrent mutations. Currently, the appropriate genetic test in most cases of dementia is a next-generation sequencing gene panel, though some conditions necessitate specific types of test such as repeat expansion testing. Whole-exome and whole-genome sequencing are becoming financially feasible but raise or exacerbate complex issues such as variants of uncertain significance, secondary findings and the potential for re-analysis in light of new information. However, the capacity for data analysis and counselling is already restricting the provision of genetic testing. Patients and their relatives need to be given reliable information to enable them to make informed choices about tests, treatments and data sharing; the ability of patients with dementia to make decisions must be considered when providing this information.
Abstract Introduction Mutations in the TANK-binding kinase 1 ( TBK1 ) gene have recently been shown to cause frontotemporal dementia (FTD). However, the phenotype of TBK1 -associated FTD is currently ...unclear. Methods We performed a single case longitudinal study of a patient who was subsequently found to have a novel A705fs mutation in the TBK1 gene. He was assessed annually over a 7-year period with a series of clinical, cognitive, and magnetic resonance imaging assessments. His brain underwent pathological examination at postmortem. Results The patient presented at the age of 64 years with an 18-month history of personality change including increased rigidity and obsessiveness, apathy, loss of empathy, and development of a sweet tooth. His mother had developed progressive behavioral and cognitive impairment from the age of 57 years. Neuropsychometry revealed intact cognition at first assessment. Magnetic resonance imaging showed focal right temporal lobe atrophy. Over the next few years his behavioral problems progressed and he developed cognitive impairment, initially with anomia and prosopagnosia. Neurological examination remained normal throughout without any features of motor neurone disease. He died at the age of 72 years and postmortem showed TDP-43 type A pathology but with an unusual novel feature of numerous TAR DNA-binding protein 43 (TDP-43)–positive neuritic structures at the cerebral cortex/subcortical white matter junction. There was also associated argyrophilic grain disease not previously reported in other TBK1 mutation cases. Discussion TBK1 -associated FTD can be associated with right temporal variant FTD with progressive behavioral change and relatively intact cognition initially. The case further highlights the benefits of next-generation sequencing technologies in the diagnosis of neurodegenerative disorders and the importance of detailed neuropathologic analysis.
Apolipoprotein E (ApoE) is the most important genetic risk factor for Alzheimer's disease (AD), with ApoE4 thought to enhance and accelerate amyloid-β (Aβ) pathology. ApoE4 has recently been ...described to increase neurodegeneration in a mouse model of frontotemporal dementia (FTD), in vitro, and in patients, demonstrating that ApoE4 modifies tauopathy independently of Aβ. This raises the question whether ApoE genotype also modifies the clinical phenotype in patients with FTD with tau pathology.
We analyzed 704 patients with FTD, including a genetically and neuropathologically confirmed subset, and 452 healthy elderly controls. We compared ApoE4 genotype frequency and age at onset in tau+ or TDP43+ FTD patients with or without Aβ copathology.
The ApoE4 genotype lowered age at onset in patients with FTD and tau pathology, particularly once accounting for confounding effects of Aβ pathology.
We conclude that ApoE4 accelerates neurodegeneration in FTD patients with MAPT mutations or FTLD-tau pathology, independent of Aβ.
•A novel PSEN1 mutation (Ile168dup) causes pathologically proven Alzheimer's disease.•PSEN1 Ile168dup can manifest with seizures, myoclonus and pyramidal dysfunction.•Duplication and ...insertion/deletion mutations of PSEN1 can cause young onset dementia.
Mutations in the Presenilin 1 (PSEN1) gene are the most common cause of autosomal dominant familial Alzheimer's disease. We report the clinical, imaging and postmortem findings of kindred carrying a novel duplication mutation (Ile168dup) in the PSEN1 gene. We interpret the pathogenicity of this novel variant and discuss the additional neurological features (pyramidal dysfunction, myoclonus and seizures) that accompanied cognitive decline. This report broadens the clinical phenotype of PSEN1 insertion mutations while also highlighting the importance of considering duplication, insertion and deletion mutations in cases of young onset dementia.
MIC-Resektionen bei Magen-GIST Prinz, C; Bernhardt, J; Schneider-Koriath, S ...
Zeitschrift für Gastroenterologie,
07/2007
Conference Proceeding
Recenzirano
Odprti dostop
Einleitung/Hintergrund:
Gastrointestinale Stromatumore sind in den letzten Jahren in den Mittelpunkt des Interesses gerückt. Sie sind in der Diagnostik mitunter schwierig zu beurteilen.
Für lokal ...begrenzte GIST ohne Nachweis von Metastasen ist die limitierte Resektion eine ideale Indikation für die MIC.
Patienten und Methode:
Zwischen 1994 und 2007 wurde bei 72 Patienten eine minimal-invasive Resektion von nicht karzinomatösen Magentumoren durchgeführt. Darunter befanden sich 48 gastrale GIST. Die präoperative Diagnostik umfasste die primäre Gastroskopie mit Biopsie, die Endosonographie, die extrakorporale Sonographie oder CT-Untersuchung, eine Rö-Thorxaufnahme sowie Laboruntersuchungen. Für die MIC-Resektion kamen nur lokal begrenzte Tumore in Frage. Metastasen waren ein Ausschlusskriterium. Im follow-up erfolgten gastroskopische Kontrollen nach 3 und 12 Monaten sowie alle 3 Monate klinische und sonografische Untersuchungen.
Folgende Op-Techniken wurden angewendet:
Extramuköse laparoskopische Enukleation (LER)
Laparoskopische Vollwandresektion (LVR)
Laparoskopisch intragastrale Resektion (LIR)
Ergebnisse:
Die MIC-Resektion wurde bei 28 Frauen und 20Männern mit einem Durchschnittsalter von 54,5 Jahren (23–81) durchgeführt. Eine präoperative histologische Sicherung gelang bei 29 von 48 Patienten. 39 Resektionen erfolgten in Rendezvousverfahren. Die mittlere Op-Dauer lag bei 54,6min (31–112), wobei sich die LIR am zeitintensivsten erwies. Die durchschnittliche Tumorgröße betrug 3,7cm (0,8–6,5). Alle Resektate wiesen eine R0-Status auf. Die immunhistologische Beurteilung ergab in 37 Fällen benigne, in 7 Fällen Borderline und 4 maligne GIST, welche konventionell organresezierend nach definitiver Histologie behandelt wurden. Bei 2 Patienten (4,1%) kam es zur Perforation im Bereich der Hinterwand im Rahmen einer LIR. In 1 Fall konnte der Defekt laparoskopisch versorgt werden. Im anderen Fall wurde nach Konversion bei pylorusnaher Lokalisation eine distale Magenresektion erforderlich. Bei 1 Patienten (2%) trat postoperativ eine Blutung nach LVR auf. Diese konnte durch Relaparoskopie und Übernähung beherrscht werden. Die Letalität war 0. In einer mittleren Nachbeobachtungszeit von 38,2 Monaten (2–103) wurden bisher keine Lokalrezidive oder Metastasierungen diagnostiziert.
Fazit:
Bei GIST <5cm kann die MIC-Resektion als gut durchführbar eingeschätzt werden, wobei die LER und LVR gegenüber intragastralen Resektionen komplikationsärmere Verfahren darstellen. Die vorliegenden Ergebnisse sind derzeit noch unter Vorbehalt zu werten und müssen weiterhin klinisch entwickelt und evaluiert werden.
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