No association between VAPB mutations and familial or sporadic ALS in Sweden, Portugal and Iceland.

Linkage analysis in Brazilian families with amyotrophic lateral sclerosis (ALS) revealed that a missense mutation p.Pro56Ser in a conserved gene VAMP-associated protein type B and C (VAPB) cosegregates with disease. Blood samples were studied from 973 Swedish, 126 Portuguese and 19 Icelandic ALS patients, and from 644 control subjects. We identified five VAPB mutations, two of which are novel, in 14 Swedish ALS patients and in nine control individuals from Sweden and Portugal. The 14 patients with VAPB mutations all carried a diagnosis of sporadic ALS. Mutations were also found in healthy adult relatives. The p.Asp130Glu VAPB mutation was also found in two patients from an Icelandic ALS family, but the mutation did not cosegregate with disease. All patients were instead found to be heterozygous for a p.Gly93Ser SOD1 mutation. There were no clinical differences between them, suggesting that the p.Asp130Glu VAPB mutation is unrelated to the disease process. In conclusion, the VAPB mutations were as frequent in control individuals as in patients. This observation, in combination with the finding of several healthy relatives carrying the VAPB mutations and no ancestors with ALS disease, suggests that it is unlikely that these VAPB mutations are pathogenic.

Incidence and prevalence of multiple system atrophy: a nationwide study in Iceland.

BACKGROUND: Multiple system atrophy (MSA) is a neurodegenerative disorder characterised by autonomic dysfunction with parkinsonism (MSAp) or cerebellar (MSAc) symptoms. At autopsy, α-synuclein inclusions in glial cells of the brain are needed to confirm a definite diagnosis. We determined the 10 year incidence of MSA, point prevalence and survival in a well defined population with a high number of neurologists. METHODS: Cases were identified from the only neurology department and all practising neurologists in Iceland, over a 10 year period. The diagnosis of MSA was in accordance with the Second Consensus Criteria of MSA. FINDINGS: 19 incidence cases were diagnosed with MSA (11 women, eight men) during the study period, giving an average annual incidence of 0.7:100 000 (95% CI 0.4 to 1.1). Ten cases were alive on the prevalence day, giving a point prevalence of 3.4:100 000 (95% CI 1.6 to 6.3). 16 of the cases had probable and three possible MSA; 16 had MSAp and three had MSAc. Mean age at symptom onset was 65 years and mean age at diagnosis was 68 years. Patients were followed for an average of 31 months, and 15 died during the follow-up period. Survival from symptom onset was mean 5.7 years. The 1 and 5 year survival rates from diagnosis were 74% and 28%, respectively. INTERPRETATION: We reported on the incidence of MSA (both MSAp and MSAc) in a nationwide study where a definite diagnosis of MSA was confirmed in four out of five patients autopsied. We found survival to be shorter than reported in other studies.

Case-control studies on ceruloplasmin and superoxide dismutase (SOD1) in neurodegenerative diseases: a short review.

This short review describes a series of case-control studies on the concentration and oxidative activity of ceruloplasmin (CP) in serum and the activity of superoxide dismutase (SOD1) in erythrocytes in patients with Alzheimer's disease (AD), Parkinson's disease (PD) and Down's syndrome (DS). The same parameters were re-examined in the PD patients 5 years later. The specific oxidative activity (oxidative activity related to mass) of CP was calculated in PD and DS. In AD and PD the oxidative activity of CP and SOD1 activity was significantly lower in patients than controls. The specific oxidative activity of CP was also significantly lower in PD patients. The difference in all parameters determined was still present 5 years later in PD patients. There was no difference in the concentration or activity of CP in patients with DS and controls. Because of the gene-dose effect (the gene for SOD1 is located on chromosome 21); the SOD1 activity was 50% higher in the patients than the controls. The CP specific oxidative activity and SOD1 activity were found to be significantly lower in the older (>40 years) than the younger DS patients. Whether changes in CP and SOD1 in AD, PD and DS are primary changes or a result of prolonged disease burden needs to be examined.

Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1.

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10⁻9, odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10⁻¹¹ (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10⁻5, permuted threshold for genome-wide significance 7.7 × 10⁻5. To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

Ceruloplasmin and superoxide dismutase (SOD1) in heterozygotes for Wilson disease: A case control study.

At the time of this study, there were five known patients with Wilson disease (WD) in Iceland. The mutation, a 7-bp deletion in exon 7 on chromosome 13 for WD, is only known in Iceland. In twenty healthy Icelandic heterozygotes for WD and their age- and gender-matched controls, copper concentration in plasma, ceruloplasmin (CP) concentration, CP oxidative activity and CP-specific oxidative activity in serum and superoxide dismutase (SOD1) activity in erythrocytes were determined. The same determinations were done on the five WD patients. There was no significant difference in these parameters between the heterozygotes and the controls, although an inclination toward lower CP determinations and higher SOD1 activity in the heterozygotes was noted. As expected the WD patients were low on the copper and CP parameters, but their SOD1 activity was within the upper normal range. In conclusion, the CP parameters and SOD1 activity are within the normal range in Icelandic heterozygotes for WD, although with a trend toward mild dyshomeostasis. This may indicate subclinical copper retention in the heterozygotes, but a bigger study group is needed to confirm this.

Localization of a gene for migraine without aura to chromosome 4q21.

Migraine is a common form of headache and has a significant genetic component. Here, we report linkage results from a study in Iceland of migraine without aura (MO). The study group comprised patients with migraine recruited by neurologists and from the registry of the Icelandic Migraine Society, as well as through the use of a questionnaire sent to a random sample of 20,000 Icelanders. Migraine diagnoses were made and confirmed using diagnostic criteria established by the International Headache Society. A genome-wide scan with multipoint allele-sharing methods was performed on 289 patients suffering from MO. Linkage was observed to a locus on chromosome 4q21 (LOD=2.05; P=.001). The locus reported here overlaps a locus (MGR1) reported elsewhere for patients with migraine with aura (MA) in the Finnish population. This replication of the MGR1 locus in families with MO indicates that the gene we have mapped may contribute to both MA and MO. Further analysis indicates that the linkage evidence improves for affected females and, especially, with a slightly relaxed definition of MO (LOD=4.08; P=7.2 x 10(-6)).