Sven Asger Sørensen

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.

Molecular and behavioral analysis of the R6/1 Huntington's disease transgenic mouse.

Transgenic mice expressing exon 1 of the human Huntingtons disease (HD) gene carrying a 115 CAG repeat (line R6/1) are characterized by a neurologic phenotype involving molecular, behavioral and motor disturbances. We have characterized the R6/1 to establish a set of biomarkers, which could be semi-quantitatively compared. We have measured motor fore- and hindlimb coordination, fore- and hindpaw footprinting, general activity and anxiety, feetclasping, developmental instability. Molecular investigations involved measurements of cannabinoid receptor 1 mRNA, met-enkephalin peptide, dopamine and cyclic AMP-regulated phosphoroprotein 32 kDa and neuronal inclusions. Molecular and behavioral testing was performed on female hemizygotic R6/1 transgenic mice and female wildtype littermates between 6 and 36 weeks of age. We show that the cannabinoid receptor 1 receptor is severely and rapidly downregulated in the R6/1 mouse between the 8(th) to the 10(th) week of age. At 14 weeks of age the first transgenic mice showed a behavioral phenotype measured by feetclasping. However, there was great variation between the individual animals. At 11 weeks of age the mice demonstrated progressively increasing developmental instability as measured by fluctuating asymmetry. Weight differences were evident by 22 weeks of age. Mice tested at 23 and 24 weeks of age showed significant impairments in open field and plus-maze analysis respectively. We observed no significant abnormalities in stride length of the R6/1 mouse model. As the analyzed parameters are easily detected and measured, the R6/1 mouse appears to be a good model for evaluating new drugs or types of therapy for HD.

Chromosome 3 linked frontotemporal dementia (FTD-3)

Background: The authors have identified and studied a large kindred in which frontotemporal dementia (FTD) is inherited as an autosomal dominant trait. The trait has been mapped to the pericentromeric region of chromosome 3. Methods: The authors report on the clinical, neuroimaging, neuropsychological, and pathologic features in this unique pedigree collected during 17 years of study. Results: Twenty-two individuals in three generations have been affected; the age at onset varies between 46 and 65 years. The disease presents with a predominantly frontal lobe syndrome but there is also evidence for temporal and dominant parietal lobe dysfunction. Late in the illness individuals develop a florid motor syndrome with pyramidal and extrapyramidal features. Structural imaging reveals generalized cerebral atrophy; H215O-PET scanning in two individuals relatively early and late in the disease shows a striking global reduction in cerebral blood flow affecting all lobes. On macroscopic pathologic examination, there is generalized cerebral atrophy affecting the frontal lobes preferentially. Microscopically, there is neuronal loss and gliosis without specific histopathologic features. Conclusions: FTD-3 shares clinical and pathologic features with other forms of FTD and fulfills international consensus criteria for FTD. There is involvement of the parietal lobes clinically, radiologically, and pathologically in FTD-3 in contrast to some forms of FTD. This more diffuse involvement of the cerebral cortex leads to a distinctive, global pattern of reduced blood flow on PET scanning.

Reduced regional cerebral blood flow in Huntington's disease studied by SPECT.

Regional cerebral blood flow (rCBF) was studied in 18 patients with Huntingtons disease (HD) and 19 age- and sex-matched controls with high resolution single photon emission computerised tomography (SPECT), using Tc-99m-HMPAO. Significant reductions in tracer uptake were found in the caudate and lentiform nuclei (20 and 8%) and in the cerebral cortex, especially in the frontal and parietal areas (11-13%). No significant reductions were found in the thalamus, mesial temporal cortex, and occipital cortex. Fourteen patients had neuropsychological testing. Relationship between rCBF and cognitive function was tested by regression analysis. A linear relationship was found between test scores of Wisconsin Card Sorting Test, Picture Arrangement Test and blood flow in the caudate nucleus. Other tests of cognitive function (Block Design Test, Face and Word Recognition Test, Street Fragmented Pictures Test, and Similarities Test) correlated better with flow in the cortical regions believed to be involved in solving those particular tests. These findings indicate, that blood flow is reduced in both cortical and subcortical structures in symptomatic HD, and that both reductions in cortical and subcortical blood flow may be related to cognitive function in HD.

Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation

Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD‐HSP) and a complex phenotype with variably expressed co‐existing ataxia, dysarthria, unipolar depression, epilepsy, migraine, and cognitive impairment was investigated. Genetic linkage analysis and sequencing of the SPG4 gene was performed and electrophysiologic investigations were carried out in six individuals and positron emission tomography (PET) in one patient. The disease was linked to the SPG4 locus on chromosome 2p as previously reported for pure HSP. Sequence analysis of the SPG4 (spastin) gene identified a novel 1593 C > T (GLN490Stop) mutation leading to premature termination of exon 12 with ensuing truncation of the encoded protein. However, the mutation was only identified in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia. Other features noted in this kindred including epilepsy, cognitive impairment, depression, and migraine did not segregate with the HSP phenotype or mutation, and therefore the significance of these features to SPG4 is unclear. Electrophysiologic investigation showed increased central conduction time at somatosensory evoked potentials measured from the lower limbs as the only abnormal finding in two affected individuals with the SPG4 mutation. Moreover, PET of one patient showed significantly relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations.

Molecular Genetic Characterisation of Frontotemporal Dementia on Chromosome 3

We have previously localized a locus causing familial nonspecific dementia to the centromeric region of chromosome 3 in a pedigree from the Jutland area of Denmark. This pedigree shows anticipation. Here we present further analysis of these anticipation data which are suggestive of trinucleotide repeat expansion involvement. We also outline our strategies to clone the mutant gene via its putative associated trinucleotide repeat sequence.

Autosomal dominant pure spastic paraplegia: a clinical, paraclinical, and genetic study

OBJECTIVES At least three clinically indistinguishable but genetically different types of autosomal dominant pure spastic paraplegia (ADPSP) have been described. In this study the clinical, genetic, neurophysiological, and MRI characteristics of ADPSP were investigated. METHODS Sixty three at risk members from five families were clinically evaluated. A diagnostic index was constructed for the study. Microsatellite genotypes were determined for chromosomes 2p, 14q, and 15q markers and multipoint linkage analyses were performed. Central motor conduction time studies (CMCT), somatosensory evoked potential (SSEP) measurement, and MRI of the brain and the total spinal cord were carried out in 16 patients from four families. RESULTS The clinical core features of ADPSP were homogeneously expressed in all patients but some features were only found in some families and not in all the patients within the family. In two families non-progressive “congenital” ADPSP was seen in some affected members whereas adult onset progressive ADPSP was present in other affected family members. As a late symptom not previously described low backache was reported by 47%. Age at onset varied widely and there was a tendency for it to decline in successive generations in the families, suggesting anticipation. Genetic linkage analysis confined the ADPSP locus to chromosome 2p21-p24 in the five families. The lod scores obtained by multipoint linkage analysis were positive with a combined maximum lod score of Z=8.60. The neurophysiological studies only showed minor and insignificant prolongation of the central motor conduction time and further that peripheral conduction and integrity of the dorsal columns were mostly normal. Brain and the total spinal cord MRI did not disclose any significant abnormalities compared with controls. CONCLUSIONS ADPSP linked to chromosome 2p21-p24 is a phenotypic heterogeneous disorder characterised by both interfamilial and intrafamilial variation. In some families the disease may be “pure” but the existence of “pure plus” families is suggested in others. The neurophysiological and neuroimaging investigations did not show any major abnormalities.

Platelet serotonin transporters and the transporter gene in control subjects, unipolar patients and bipolar patients

Objective: The purpose of the present study was to relate the number of platelet serotonin transporters in unipolar and bipolar patients and in control subjects to two polymorphisms in the serotonin transporter gene: a VNTR in intron 2 and a deletion/insertion in the promoter region.

Crime in Huntington’s disease: a study of registered offences among patients, relatives, and controls

OBJECTIVES Criminal behaviour has been described as a problem in Huntington’s disease, but systematic studies including control groups have been missing. Based on information from Danish registries, rates and types of crime committed by patients with Huntington’s disease, non-affected relatives, and controls were studied. METHODS 99 males and 151 females with Huntington’s disease were compared with 334 non-affected first degree relatives (134 men and 200 women) and to matched control groups as to frequencies and types of registered criminal convictions. Due to specific age criteria, the group of relatives comprised only about 9% carriers of the gene coding for Huntington’s disease. RESULTS In male patients, crime rates were significantly increased compared with first degree relatives (RR=2.8) and controls (RR=2.3). All types of crime occurred more often in male patients; more severe crimes (murder, rape, arson) were not reported. Rates of drunken driving were significantly increased compared with relatives (RR=3.8) and controls (RR=7.1). Crime rates were neither increased in female patients nor in male and female first degree relatives. CONCLUSION The results indicate increased prevalence of criminal behaviour in males carrying the gene for Huntington’s disease. The crimes committed seem to be of relatively minor severity and are probably closely linked to the personality changes often seen as a result of the disease process, although depressive reactions to the disease, with secondary alcohol misuse, may also play a part. Environmental and familial factors shared by patients and non-affected at risk persons seem to be of less aetiological importance.

Antisense downregulation of mutant huntingtin in a cell model

Huntingtons disease (HD) is an inherited neurodegenerative disorder which is caused by an expansion of a CAG repeat sequence in the HD gene. The repeat encodes an expanded polyglutamine tract in the protein huntingtin. The still unknown pathological mechanisms leading to death of specific neurons in the brains of HD patients correlate with the expression of mutant huntingtin. Therefore, we have studied whether mutant huntingtin expression can be downregulated by antisense technique.