Mutation Frequency of the Major Frontotemporal Dementia Genes, MAPT, GRN and C9ORF72 in a Turkish Cohort of Dementia Patients

‘Microtubule-associated protein tau’ (MAPT), ‘granulin’ (GRN) and ‘chromosome 9 open reading frame72’ (C9ORF72) gene mutations are the major known genetic causes of frontotemporal dementia (FTD). Recent studies suggest that mutations in these genes may also be associated with other forms of dementia. Therefore we investigated whether MAPT, GRN and C9ORF72 gene mutations are major contributors to dementia in a random, unselected Turkish cohort of dementia patients. A combination of whole-exome sequencing, Sanger sequencing and fragment analysis/Southern blot was performed in order to identify pathogenic mutations and novel variants in these genes as well as other FTD-related genes such as the ‘charged multivesicular body protein 2B’ (CHMP2B), the ‘FUS RNA binding protein’ (FUS), the ‘TAR DNA binding protein’ (TARDBP), the ‘sequestosome1’ (SQSTM1), and the ‘valosin containing protein’ (VCP). We determined one pathogenic MAPT mutation (c.1906C>T, p.P636L) and one novel missense variant (c.38A>G, p.D13G). In GRN we identified a probably pathogenic TGAG deletion in the splice donor site of exon 6. Three patients were found to carry the GGGGCC expansions in the non-coding region of the C9ORF72 gene. In summary, a complete screening for mutations in MAPT, GRN and C9ORF72 genes revealed a frequency of 5.4% of pathogenic mutations in a random cohort of 93 Turkish index patients with dementia

A novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family

Triggering receptor expressed on myeloid cells 2 (TREM2) homozygous mutations cause Nasu-Hakola disease, an early-onset recessive form of dementia preceded by bone cysts and fractures. The same type of mutations has recently been shown to cause frontotemporal dementia (FTD) without the presence of any bone phenotype. Here, we further confirm the association of TREM2 mutations with FTD-like phenotypes by reporting the first compound heterozygous mutation in a Turkish family

Peripheral GRN mRNA and Serum Progranulin Levels as a Potential Indicator for Both the Presence of Splice Site Mutations and Individuals at Risk for Frontotemporal Dementia

Progranulin (GRN) gene mutations are a major cause of frontotemporal dementia (FTD). Most mutations identified to date are null mutations, which are predicted to cause the pathology via haploinsufficiency. Decreased peripheral progranulin protein (PGRN) levels are associated with the presence of GRN null mutations and are accepted as reliable biomarkers. In this study, our aim was to test whether the presence of specific GRN splice site mutations (c.– 8+2T>G and c.708+6_9del), could be predicted by peripheral mRNA or protein GRN levels, by studying affected and asymptomatic individuals from FTD families. We also tested four missense GRN variants to assess if altered GRN levels depended on the type of mutation. Our results confirmed a reduction in both mRNA and protein PGRN levels in the splice site mutation carriers, which is consistent with previous reports for null mutations. Our results also suggested that both decreased peripheral GRN mRNA and serum PGRN levels indicate the presence of pathogenic mutations in affected individuals, and identify the asymptomatic individuals at risk, without previous knowledge of genetic status. Both inferences suggest a potential use of peripheral GRN mRNA or serum PGRN levels as biomarkers for families with FTD

Mutations in TYROBP are not a common cause of dementia in a Turkish cohort

Mutations in TYROBP and TREM2 have been shown to cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. Recently, variants in TREM2 were also associated with frontotemporal dementia and Alzheimer's disease. Given the functional proximity between these 2 genes, we investigated the genetic variation of TYROBP in a Turkish cohort of 103 dementia patients. No mutations or copy number variants predicted to be pathogenic were identified. These results indicate that mutations in TYROBP are not a common cause of dementia in this Turkish cohort

Paraneoplastic limbic encephalitis with immature ovarian teratoma - A case report

Paraneoplastic limbic encephalitis (PLE) is a remote, nonmetastatic complication of carcinoma. Neuropsychiatric symptoms usually predate the diagnosis of cancer by 3 months to 6 years and very rarely the symptoms develop after the diagnosis of malignancy. We report the first case of limbic encephalitis associated with an immature ovarian teratoma. Within the month following the diagnosis of the tumor with pathologic stage Ia, somewhat acutely she developed neuropsychiatric symptoms that was exclusively a limbic disorder with impairments in almost every realm of limbic function. This case may show us that it is important to recognize the neuropsychiatric symptoms of PLE as the first manifestation of a very small malignant ovarian tumor and to aggressively try to identify the underlying cancer

Clozapine Treatment in Oromandibular Dystonia

Oromandibular dystonia (OMD) is a form of focal dystonias, which can be associated with substantial disability and is frequently refractory to all antidystonic therapies. Clozapine is a dibenzodiazepin derivative atypical neuroleptic that has been reported to be effective in the treatment of primary or symptomatic dystonia. We report here two patients with severe OMD refractory to other antidystonic therapies, who had substantial improvement with clozapine. We suggest that clozapine should be considered in patients with OMD who fail to response to other treatments

Modelling the Stroop effect: A connectionist approach

A connectionist model, which simulates the operation of prefrontal circuits during Stroop task is proposed. The Stroop test has traditionally been used as a measure of cognitive inhibition. The task is to inhibit an over-learned, habitual response (i.e., reading color words) in favor of an unusual, novel requirement (i.e., naming incongruously printed colors of color words). The longer durations in completing the task indicate an inability to inhibit habitual but contextually inappropriate response tendencies, which is suggestive of a prefrontal dysfunction. The connectionist model is designed adapting artificial neural networks (ANNs) in such a way that each ANN corresponds to a particular neuroanatomic component of the prefrontal circuit which is likely to take part in the execution of the Stroop task. The ability of the proposed model to simulate the normal and the abnormal performance on the Stroop task is tested. The simulation results show that the model is consistent with the clinical data. (c) 2006 Elsevier B.V. All rights reserved