Kirsten Fenger

Migraine without aura and migraine with aura are distinct clinical entities: a study of four hundred and eighty‐four male and female migraineurs from the general population

The clinical characteristics of migraine without aura (MO) and migraine with aura (MA) were compared in 484 migraineurs from the general population. We used the criteria of the International Headache Society. The lifetime prevalence of MO was 14.7% with a M:F ratio of 1:2.2; that of MA was 7.9% with a M:F ratio of 1:1.5. The female preponderance was significant in both MO and MA. The female preponderance was present in all age groups in MA, but was first apparent after menarche in MO, suggesting that female hormones are an initiating factor in MO, but not likely so in MA. The age at onset of MO followed a normal distribution, whereas the age at onset of MA was bimodally distributed, which could be explained by a composition of two normal distributions. The estimated separation between the two groups of MA was at age 26 years among the females and age 31 years among the males. The observed number of persons with co-occurrence of MO and MA was not significantly different from the expected number. The specificity and importance of premonitory symptoms are questioned, but prospective studies are needed. Bright light was a precipitating factor in MA, but not in MO. Menstruation was a precipitating factor in MO, but not likely in MA. Both MO and MA improved during pregnancy. The clinical differences indicate that MO and MA are distinct entities.

Significantly lower incidence of cancer among patients with Huntington disease

The authors of this study have previously observed that cancer is rarely reported on the death certificates of patients with Huntington disease. This study was undertaken to investigate whether this disorder is associated with a lower incidence of cancer.

The prevalence and characteristics of migraine in twins from the general population.

We examined whether prevalence, age at onset, and cessation of migraine without aura and migraine with aura are different among twins and singletons.

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.

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.

Frequency of the C282Y and H63D mutations of the hemochromatosis gene (HFE) in 2501 ethnic Danes

The aim of the study was to assess the frequency of the C282Y and H63D mutations of the hemochromatosis gene (HFE) in ethnic Danes. The series comprised 2501 subjects (1284 men) of Danish heritage who were drawn at random from the Census Registry in age cohorts of 30, 40, 50, and 60 years. The frequency of the C282Y and H63D mutations was assessed on blood samples by genotyping using a polymerase chain reaction (PCR) technique. The HFE genotype distribution was in Hardy–Weinberg equilibrium (p=0.85). C282Y mutation: 9 subjects (0.36%) were homozygous and 265 subjects (10.6%) were heterozygous. H63D mutation: 40 subjects (1.6%) were homozygous and 584 subjects (23.4%) were heterozygous. C282Y/H63D compound heterozygosity was found in 36 subjects (1.4%). The C282Y allele frequency was 5.7% [95% confidence interval (CI) 5.0–6.3%] and the H63D allele frequency was 13.3% (95% CI 12.3–14.2%). In conclusion, the C282Y frequency is relatively high in the Danes, being close to the frequency in other Scandinavian countries, i.e., Iceland 5.1%, the Faroe Islands 6.6%, and Sweden 5.7%, but significantly lower than in Norway 6.6% (p=0.02). Also, the H63D frequency in Danes is close to and not significantly different from the frequency in Iceland 10.9%, Norway 11.2%, and Sweden 12.4%, but significantly lower than in the Faroe Islands 15.4% (p=0.046).

Cellular mitochondrial heterogeneity in cultured astrocytes as demonstrated by immunogold labeling of α-ketoglutarate dehydrogenase

In brain cells, various metabolites and metabolic pathways, largely of mitochondrial origin, have been shown to be compartmentalized. Attention has therefore been focused on the possible existence of mitochondrial heterogeneity in the brain at the cellular level. To determine whether mitochondria in cultured cortical and cerebellar astrocytes are heterogeneous at the single cell level, immunogold electron microscopy and an antibody against the α‐ketoglutarate dehydrogenase component of the α‐ketoglutarate dehydrogenase complex, a marker enzyme for the tricarboxylic acid (TCA) cycle, were employed. The number of gold particles was counted in the mitochondria of 36 and 42 cells from cultured cerebellar and cortical astrocytes, respectively. A test for random distribution (Poisson distribution) of mitochondria according to the number of gold particles was subsequently performed for every one of the 36 and 42 cells as the ratio variance/mean (= index of dispersion). This should be approximately distributed as χ2/degrees of freedom (df) = n − 1, n = number of mitochondria), if the observations obeyed a Poisson distribution. For 26 of the 36 (cerebellar astrocytes) distributions and for 28 of the 42 (cortical astrocytes) distributions a random distribution had to be rejected. These findings therefore strongly indicate that α‐ketoglutarate dehydrogenase is heterogeneously distributed in mitochondria within individual astrocytes originating either from cerebellum or cerebral cortex. In conclusion, this study underlines the probability that mitochondrial heterogeneity at the single cell level might be extended to involve other metabolic pathways and metabolites.

Frequency of the hemochromatosis HFE mutations C282Y, H63D, and S65C in blood donors in the Faroe Islands

The aim of the study was to assess the frequencies of the hereditary hemochromatosis HFE mutations C282Y, H63D, and S65C in the population in the Faroe Islands. The series comprised 200 randomly selected blood donors of Faroese heritage. The frequency of the C282Y, H63D, and S65C mutations on the HFE gene was assessed by genotyping using the polymerase chain reaction (PCR) technique and calculated from direct allele counting. We found no C282Y homozygous subjects; 28 (14.0%) subjects were C282Y heterozygous and four subjects were C282Y/H63D compound heterozygous (2.0%). The C282Y allele frequency was 8.0% (95% CI 5.3–10.7%). The series contained three (1.5%) H63D homozygous subjects and 60 (30.0%) H63D heterozygous subjects. The H63D allele frequency was 17.5% (95% CI 13.8–21.2%). There were four (2.0%) S65C heterozygous subjects. The S65C allele frequency was 1.0% (95% CI 0.3–2.5%). The frequency of the C282Y mutation is high in Faroese blood donors, being close to and not significantly different from the frequencies reported in other Scandinavian countries: Denmark 5.7%, Norway 6.6%, Iceland 5.1%, and Sweden 6.1%. The frequency of the H63D mutation in Faroese subjects is significantly higher than the frequency in Denmark 12.8% (p=0.007), Iceland 10.9% (p=0.003), and Sweden 12.4% (p=0.015), but not from the frequency in Norway 11.2% (p=0.063). The frequency of the S65C mutation in Faroese subjects is not significantly different from the frequencies in Denmark 1.5% and Sweden 1.6%. Screening of larger groups of the Faroese population for HFE mutations especially C282Y should be considered in order to establish the penetrance.

Correlation between magnitude of CAG repeat length alterations and length of the paternal repeat in paternally inherited Huntington's disease

An increasing number of diseases are being found to be due to elongation of specific trinucleotide repeat sequences. Inverse correlation between the age at onset and the length of the repeat has been found in most of these. The elongated CAG repeat causing Huntingtons disease is highly unstable when inherited from an affected father. In this study we found an average parent‐to‐offspring difference of +0.08 repeat units in maternally inherited repeats, significantly less than the average difference of +2.92 repeat units with paternal transmission. Large repeat expansions, of more than 5 repeat units, were seen only in paternally inherited cases. With paternal transmission the magnitude of repeat length alterations was directly correlated to increasing paternal repeat length. Increasing variation in repeat length among siblings was correlated to increasing average repeat length in the sibship in both maternally and paternally inherited HD. Comparison of the magnitude of repeat length alterations to parental age at the time of birth of the offspring showed no correlation.