Jørgen E. Nielsen

Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia.

We have previously reported a large Danish pedigree with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 3 (FTD3). Here we identify a mutation in CHMP2B, encoding a component of the endosomal ESCRTIII complex, and show that it results in aberrant mRNA splicing in tissue samples from affected members of this family. We also describe an additional missense mutation in an unrelated individual with FTD. Aberration in the endosomal ESCRTIII complex may result in FTD and neurodegenerative disease.

Alzheimer disease-like clinical phenotype in a family with FTDP-17 caused by a MAPT R406W mutation.

We report clinical, molecular, neuroimaging and neuropathological features of a Danish family with autosomal dominant inherited dementia, a clinical phenotype resembling Alzheimer’s disease and a pathogenic mutation (R406W) in the microtubule associated protein tau (MAPT) gene. Pre‐symptomatic and affected family members underwent multidisciplinary (clinical, molecular, neuroimaging and neuropathological) examinations. Treatment with memantine in a family member with early symptoms, based on the clinical phenotype and the lack of specific treatment, appears to stabilize the disease course and increase the glucose metabolism in cortical and subcortical areas, as determined by serial [F18]FDG‐PET scanning before and after initiation of treatment. Neuropathological examination of a second affected and mutation‐positive family member showed moderate atrophy of the temporal lobes including the hippocampi. Microscopy revealed abundant numbers of tau‐positive neurofibrillary tangles in all cortical areas and in some brainstem nuclei corresponding to a diagnosis of frontotemporal lobe degeneration on the basis of a MAPT mutation. The clinical and genetic heterogeneity of autosomal dominant inherited dementia must be taken into account in the genetic counselling and genetic testing of families with autosomal dominantly inherited dementia in general.

A novel mutation in the HSPD1 gene in a patient with hereditary spastic paraplegia

AbstractA mutation in thenHSPD1 gene has previously beennassociated with an autosomalndominant form of spastic paraplegianin a French family. HSPD1nencodes heat shock protein 60, anmolecular chaperone involved innfolding and quality control ofnmitochondrial proteins. In thenpresent work we have investigatedn23 Danish index patients withnhereditary spastic paraplegian(HSP) for mutations in the HSPD1ngene. One patient was found to benheterozygous for a c.1381C > Gnmissense mutation encoding thenmutant heat shock protein 60np.Gln461Glu. The mutation wasnalso present in two unaffectednbrothers, but absent in 400 unrelatednDanish individuals. Wenfound that the function of thenp.Gln461Glu heat shock protein 60nwas mildly compromised. Thenc.1381C > G mutation likelynrepresents a novel low-penetrancenHSP allele.

Reduced ceramide synthase 2 activity causes progressive myoclonic epilepsy.

Ceramides are precursors of complex sphingolipids (SLs), which are important for normal functioning of both the developing and mature brain. Altered SL levels have been associated with many neurodegenerative disorders, including epilepsy, although few direct links have been identified between genes involved in SL metabolism and epilepsy.

4p16.3 haplotype modifying age at onset of Huntington disease

Huntington disease (HD) is caused by an expanded CAG repeat sequence in the HD gene. Although the age at onset is correlated to the CAG repeat length, this correlation only explains approximately half of the variation in onset age. Less variation between siblings indicates that the variation is, in part, explained by genetic modifiers. We analyzed polymorphic loci within or close to the HD gene on the HD chromosome in Danish HD patients. We found one specific haplotype segregating with later age at onset, compared with patients with similar CAG repeat length and another haplotype. The nine Danish families in the study carrying this haplotype most likely have a common founder. Several of the polymorphic loci displayed alleles that may be specific to the late‐onset haplotype, implicating that from this study we cannot determine which of the loci tested (or other polymorphic loci in this chromosomal area) do in fact contain genetic modifiers of age at onset.

Presymptomatic Generalized Brain Atrophy in Frontotemporal Dementia Caused by CHMP2B Mutation

Background/Aims:CHMP2B mutations are a rare cause of familial frontotemporal dementia (FTD). The clinical syndrome is dominated by personality change and behavioural symptoms, but language, memory, calculation and praxis impairments are also seen early in the course of the disease. There are no detailed studies of brain imaging in CHMP2B mutation-associated FTD. This study aimed to investigate whether there were early or presymptomatic changes in this group of patients. Methods: Subjects comprised 16 members of a Danish family with CHMP2B mutation-associated FTD. Nine subjects were presymptomatic mutation carriers with a control group of 7 mutation-negative family members. Volumetric MRI brain scans were performed on all subjects at two time points, and rates of volume change were compared between the two groups. Results: We demonstrate that generalized atrophy occurs presymptomatically in CHMP2B gene mutation carriers. Conclusions: This finding suggests that mutations in CHMP2B have widespread effects throughout the brain, leading to a neuro-anatomical signature distinct from other diseases in the frontotemporal lobar degeneration spectrum.

Proteomic investigations of the ventriculo-lumbar gradient in human CSF

Cerebrospinal fluid (CSF) is an ideal biological material in which to search for new biomarkers for improved diagnosis of neurological diseases. During a lumbar puncture between 5 and 15 mL of CSF are obtained. Previous studies have assessed the ventriculo-lumbar concentration gradient of a number of specific proteins. In the present study we took a proteomics approach to investigate the possible concentration gradient of a panel of proteins and peptides in the CSF of 16 patients with neurodegenerative diseases. Using two different mass spectrometry techniques, matrix assisted laser desorption ionization time of flight (MALDI-TOF) and surface enhanced laser desorption ionization time of flight (SELDI-TOF), we found that only one of the investigated proteins, apolipoprotein CI, was significantly decreased between the 1st and the 10th mL of CSF. Furthermore, we confirmed previous results showing a significant decrease in albumin concentration from the first to the last CSF aliquots. In conclusion, we found a significant gradient effect for only two of the measured proteins. However, a standardized procedure for CSF collection for diagnostic and research purposes is crucial to allow comparisons of results between patient groups and between laboratories. This is especially important since CSF is usually collected at several centres and variation in sampled CSF due to pre-analytical factors could complicate the interpretation of the results.

Behavioral variant of frontotemporal dementia mimicking Huntington's disease

Behavioral changes and cognitive decline are the core clinical manifestations in the behavioral variant of frontotemporal dementia (bv-FTD). The behavioral changes may include characteristic stereotypic movements. These movements, although without clear purpose, are not involuntary. Involuntary movements are usually not seen in FTD.Two patients with involuntary choreoathetoid movements but otherwise presenting a bv-FTD-phenotype were referred and Huntingtons disease (HD) was suspected. The diagnoses of bv-FTD were made after comprehensive assessment and exclusion of other diagnoses, including HD and Huntingtons disease-like (HDL) phenotypes. Although a definite diagnosis will require neuropathological confirmation, we conclude that a HDL phenotype may be part of the clinical spectrum of the bv-FTD phenotype.

Sporadic Creutzfeldt-Jakob Disease in a Woman Married Into a Gerstmann-Sträussler-Scheinker Family: An Investigation of Prions Transmission via Microchimerism

This is the first report of presumed sporadic Creutzfeldt-Jakob disease (sCJD) and Gerstmann-Sträussler-Scheinker disease (GSS) with the prion protein gene c.305C>T mutation (p.P102L) occurring in one family. The father and son were affected with GSS and the mother had a rapidly progressive form of CJD. Diagnosis of genetic, variant, and iatrogenic CJD was ruled out based on the mothers clinical history, genetic tests, and biochemical investigations, all of which supported the diagnosis of sCJD. However, given the low incidence of sCJD and GSS, their co-occurrence in one family is extraordinary and challenging. Thus, a hypothesis for the transmission of infectious prion proteins (PrPSc) via microchimerism was proposed and investigated. DNA from 15 different brain regions and plasma samples of the CJD patient was subjected to PCR and shallow sequencing for detection of a male sex-determining chromosome Y (chr. Y). However, no trace of chr. Y was found. A long CJD incubation period or presumed small concentrations of chr. Y may explain the obtained results. Further studies of CJD and GSS animal models with controlled genetic and proteomic features are needed to determine whether maternal CJD triggered via microchimerism by a GSS fetus might present a new PrPSc transmission route.

P1-314: A novel PSEN2 mutation in early-onset dementia with profound semantic loss

The common apolipoprotein E (APOE) e4 allele is strongly associated with risk of dementia and age at onset, but studies are inconclusive as to whether the e4 allele affects rate of progression or survival in demented patients. Furthermore, previous observations suggest a contribution of two APOE promoter polymorphisms (-491 A/T and -219 G/T) in dementia, but the influence of these two polymorphisms on survival in demented patients have not been evaluated yet.