The Danish HD Registry-a nationwide family registry of HD families in Denmark.

The Danish Huntington's Disease Registry (DHR) is a nationwide family registry comprising 14 245 individuals from 445 Huntington's disease (HD) families of which the largest family includes 845 individuals in 8 generations. 1136 DNA and/or blood samples and 18 fibroblast cultures are stored in a local biobank. The birthplace of the oldest HD carrier in each of the 261 families of Danish origin was unevenly distributed across Denmark with a high number of families in the middle part of the peninsula Jutland and in Copenhagen, the capital. The prevalence of HD in Denmark was calculated to be 5-8:100 000. 1451 individuals in the DHR had the size of the HTT CAG repeat determined of which 975 had 36 CAG repeats or more (mean ± SD: 43,5 ± 4,8). Two unrelated individuals were compound heterozygous for alleles ≥36 CAGs, and 60 individuals from 34 independent families carried an intermediate allele.

Integrating EM and Patch-seq data: Synaptic connectivity and target specificity of predicted Sst transcriptomic types.

Neural circuit function is shaped both by the cell types that comprise the circuit and the connections between those cell types 1 . Neural cell types have previously been defined by morphology 2, 3 , electrophysiology 4, 5 , transcriptomic expression 6-8 , connectivity 9-13 , or even a combination of such modalities 14-16 . More recently, the Patch-seq technique has enabled the characterization of morphology (M), electrophysiology (E), and transcriptomic (T) properties from individual cells 17-20 . Using this technique, these properties were integrated to define 28, inhibitory multimodal, MET-types in mouse primary visual cortex 21 . It is unknown how these MET-types connect within the broader cortical circuitry however. Here we show that we can predict the MET-type identity of inhibitory cells within a large-scale electron microscopy (EM) dataset and these MET-types have distinct ultrastructural features and synapse connectivity patterns. We found that EM Martinotti cells, a well defined morphological cell type 22, 23 known to be Somatostatin positive (Sst+) 24, 25 , were successfully predicted to belong to Sst+ MET-types. Each identified MET-type had distinct axon myelination patterns and synapsed onto specific excitatory targets. Our results demonstrate that morphological features can be used to link cell type identities across imaging modalities, which enables further comparison of connectivity in relation to transcriptomic or electrophysiological properties. Furthermore, our results show that MET-types have distinct connectivity patterns, supporting the use of MET-types and connectivity to meaningfully define cell types.

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.

Five novel mutations in fourteen patients with Fabry Disease.

Fabry disease is an X-linked disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A. The mutations responsible for Fabry disease are diverse and include large rearrangements as well as single base substitutions, and they are dispersed throughout the seven exons of the gene. In this study, we found five novel mutations in four different exons. We have detected the mutations by the PCR-SSCP method and then analysed them by direct sequencing. Three of the novel mutations were deletions: 1205delA, 1238del26 and 5236del18. We also found one novel nonsense mutation: W162X. The final novel mutation was an insertion combined with a deletion: 10995ins24del4.

Founder effect in spinal and bulbar muscular atrophy (SBMA) in Scandinavia.

We haplotyped 13 Finnish, 10 Swedish, 12 Danish and 2 Norwegian SBMA (spinal and bulbar muscular atrophy, Kennedy disease) families with a total of 45 patients and 7 carriers for 17 microsatellite markers spanning a 25.2 cM region around the androgen receptor gene on chromosome Xq11-q12 in search of a genetic founder effect. In addition, the haplotypes of 50 Finnish, 20 Danish and 22 Swedish control males were examined. All the Scandinavian SBMA families shared the same 18 repeat allele for the intragenic GGC repeat, which was present in only 24% of the controls. Linkage disequilibrium was also seen for the closest microsatellite markers. In addition, extended haplotypes of the Finnish, Swedish and Danish SBMA families revealed country-specific common founder haplotypes, which over time became gradually shortened by recombinations. No common haplotype was found among the controls. The data suggest that the SBMA mutation was introduced into western Finland 20 generations ago. Haplotype analysis implies a common ancestor for the majority of Scandinavian SBMA patients.

Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world.

SBMA (spinal and bulbar muscular atrophy), also called Kennedy disease, is an X-chromosomal recessive adult-onset neurodegenerative disorder caused by death of the spinal and bulbar motor neurones and dorsal root ganglia. Patients may also show signs of partial androgen insensitivity. SBMA is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene on the X-chromosome. Our previous study suggested that all the Nordic patients with SBMA originated from an ancient Nordic founder mutation, but the new intragenic SNP marker ARd12 revealed that the Danish patients derive their disease chromosome from another ancestor. In search of relationships between patients from different countries, we haplotyped altogether 123 SBMA families from different parts of the world for two intragenic markers and 16 microsatellites spanning 25 cM around the AR gene. The fact that different SBMA founder haplotypes were found in patients from around the world implies that the CAG repeat expansion mutation has not been a unique event. No expansion-prone haplotype could be detected. Trinucleotide diseases often show correlation between the repeat length and the severity and earlier onset of the disease. The longer the repeat, the more severe the symptoms are and the onset of the disease is earlier. A negative correlation between the CAG repeat length and the age of onset was found in the 95 SBMA patients with defined ages at onset.

Familial occurrence of migraine without aura and migraine with aura.

We report a study of 121 probands (patients) with migraine without aura (MO) and 72 probands with migraine with aura (MA), diagnosed according to the operational diagnostic criteria of the International Headache Society and selected from 35 general practices in Denmark. The probands were interviewed about the presence of MO and MA among their first-degree relatives. Compared with the general population, the first-degree relatives of probands with MO had a threefold increase of MO, and only one first-degree relative of one proband with MO had MA. First-degree relatives of probands with MA had a twofold increase of both MA and MO. Compared with the general population, few spouses had MO and MA. This threefold and twofold increase in family risk of MO and MA, combined with the lack of increased risk in spouses, strongly suggests that MO and MA are genetically determined.

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; H2 15 O-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.

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

Transgenic mice expressing exon 1 of the human Huntington's 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.

Genetic characterization of a familial non-specific dementia originating in Jutland, Denmark.

Dementias with non-specific pathological changes are a relatively common but under diagnosed form of presenile dementia. A high proportion of reported cases are familial. We report on molecular genetic findings in the largest known pedigree with this syndrome. We have excluded the mutations known to cause familial prion disease, APP-linked familial Alzheimer's disease and candidate regions for Huntington's disease, other forms of Alzheimer's disease and motor neuron disease. We have demonstrated that familial non-specific dementia is a novel genetic dementia.

Machado-Joseph disease in three Scandinavian families.

Machado-Joseph disease (MJD) is an autosomal dominantly inherited neurodegenerative disorder characterized by varying age of onset and pronounced phenotypic heterogeneity. The clinical core features include gait ataxia, external ophthalmoplegia, nystagmus, and bulging eyes. Recently, Kawagushi et al. (1994) cloned the MJD1 gene on chromosome 14 and MJD turned out to be the fifth neurodegenerative disease caused by an unstable CAG repeat expansion. We have studied two large Danish families and one Norwegian family with MJD. Three features not previously associated with MJD are reported: dementia, generalized muscle and joint pain, and in one case neuropathological examination revealed atrophy of the inferior olives. We found a significant inverse correlation between age of onset and the length of the CAG repeat expansion, and anticipation is described through four succeeding generations. Instability of the CAG repeat expansion was most pronounced at paternal transmission.

ADOXI-PLOT: a computer program for plotting pedigrees illustrating autosomal dominant and X-linked inheritance.

A FORTRAN program ADOXI-PLOT (Autosomal Dominant Or X-linked Inheritance Plot) has been developed. Different symbols are used to characterize individual family members. Depending on the size of the kindred, the pedigree automatically obtains a rectangular or circular appearance. The program can be used alone, or be connected to a register of families from which the input information for the plot program is obtained.

Siting criteria based on the prevention of deterministic effects from plutonium inhalation exposures.

Siting criteria are established by regulatory authorities to evaluate potential accident scenarios associated with proposed nuclear facilities. The 0.25 Sv (25 rem) siting criteria adopted in the United States has been historically based on the prevention of deterministic effects from acute, whole-body exposures. The Department of Energy has extended the applicability of this criterion to radionuclides that deliver chronic, organ-specific irradiation through the specification of a 0.25 Sv (25 rem) committed effective dose equivalent siting criterion. A methodology is developed to determine siting criteria based on the prevention of deterministic effects from inhalation intakes of radionuclides which deliver chronic, organ-specific irradiation. Revised siting criteria, expressed in terms of committed effective dose equivalent, are proposed for nuclear facilities that handle primarily plutonium compounds. The analysis determined that a siting criterion of 1.2 Sv (120 rem) committed effective dose equivalent for inhalation exposures to weapons-grade plutonium meets the historical goal of preventing deterministic effects during a facility accident scenario. The criterion also meets the Nuclear Regulatory Commission and Department of Energy Nuclear Safety Goals provided that the frequency of the accident is sufficiently low.

Safety significant class determination of continuous air monitors at facilities handling alpha-emitting radionuclides.

The role and use of continuous air monitors typically fall under the responsibility of institutional radiation protection programs established to maintain stochastic effects to workers at acceptable levels. This practice has led to a general perception that acute serious worker injury is not credible even with high intakes of alpha-emitting radionuclides. Using data derived from animal studies, release masses potentially causing serious worker injury are estimated. Serious pulmonary injuries to unprotected individuals are credible from airborne alpha-emitting transuranic release levels ranging between 0.1 and 10 GBq (2.7 to 270 mCi). Safety-significant designation of continuous air monitor systems should be considered at facilities where releases of these magnitudes are possible. Such designations should enhance the formality of continuous air monitor usage and ultimately improve the reliability of these systems. Serious pulmonary injuries are not considered possible from airborne releases of 235U, 238U, and 232Th due to airborne mass-loading limitations.

[X-linked recessive bulbospinal neuropathy (Kennedy syndrome)]. / X-bunden recessiv bulbospinal neuronopati (Kennedys syndrom).

A case of X-linked recessive bulbospinal neuronopathy is reported. Neurophysiological findings were consistent with chronic partial denervation (motor axonopathy) and large fibre sensory axonopathy. DNA analysis showed an abnormal increased size of tandem CAG repeats.

[Hereditary dystonias]. / Hereditaere dystonier.

Dystonia is a heterogeneous, neurological disease characterized by involuntary, sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. The patients are often difficult to diagnose, and the treatment is almost always only symptomatic. It is believed that about 75% of all patients with dystonia have primary dystonia, and 25-85% of these are hereditary. Seven gene loci for autosomal, dominant inherited dystonia and two for X-linked, recessive inherited dystonia are known at present, but the underlying genes are known only for DYT1 and DYT5. Testing is possible for these two in Denmark. Growing molecular genetic knowledge will lead to earlier and correct diagnosing, including prognosis, and may elucidate the pathogenesis, making better treatment possible.