M. Wessman

Subclinical vestibulocerebellar dysfunction in migraine with and without aura

Objective: In patients with migraine, neurotologic symptoms and signs occur commonly. The authors’ aim was to determine whether neurotologic findings are in accordance with the type of migraine and whether test findings differ from those of healthy controls. Methods: The authors examined 36 patients with various types of migraine classified by International Headache Society criteria. Comprehensive neurotologic tests were performed between attacks: video-oculography (VOG), electronystagmography, static posturography, and audiometry on 12 patients with migraine with aura (MA) and 24 patients with migraine without aura (MO). Results were compared to those of test-specific nonmigrainous control groups. Only eight migraineurs (six with MA and two with MO) had vertigo or dizziness. Results: Despite the absence of clinical neurotologic symptoms, most of the patients with migraine (83%) showed abnormalities in at least one of these tests. Both migraine types differed significantly from the control group (in VOG, in saccadic accuracy, and in static posturography). Vestibular findings tended to be more severe in MA than in MO. Conclusions: These data suggest that interictal neurotologic dysfunction in MA and MO share similar features and that the defective oculomotor function is mostly of vestibulocerebellar origin.

Assignment of a Novel Locus for Autosomal Recessive Congenital Ichthyosis to Chromosome 19p13.1-p13.2

Autosomal recessive congenital ichthyosis (ARCI) is a rare, clinically and genetically heterogeneous genodermatosis. One gene (transglutaminase 1, on 14q11) and one additional locus (on 2q33-35, with an unidentified gene) have been shown to be associated with a lamellar, nonerythrodermic type of ARCI. We performed a genomewide scan, with 370 highly polymorphic microsatellite markers, on five affected individuals from one large Finnish family with nonerythrodermic, nonlamellar ARCI. The only evidence for linkage emerged from markers in a 6.0-cM region on chromosome 19p13.1-2. The maximum two-point LOD score of 7.33 was obtained with the locus D19S252, and multipoint likelihood calculations gave a maximum location score of 5.2. The affected individuals share two common core haplotypes, which makes compound heterozygosity possible. The novel disease locus is the third locus linked to ARCI, supporting previous evidence for genetic heterogeneity of ARCI. This is also the first locus for a nonlamellar, nonerythrodermic phenotype of ARCI.

Treatment of hemiplegic migraine with triptans

The objective of this study was to investigate the efficacy, safety and tolerability of triptans in patients who suffer from familial or sporadic hemiplegic migraine. Seventy‐six subjects had used triptans at least once as an abortive treatment. Average triptan response was 6.9 (SD ±3.1) and adverse event severity 4.9 (SD ±3.3) on a scale from 0 to 10 (no response or side effect 0, excellent response or unbearable side effects 10). None of the patients had an ischaemic stroke or a heart attack. One patient reported prolonged neurological symptoms, related to a single dose of rizatriptan, but there were no pathological findings in several MRI‐scans. Triptans seem to be safe and effective treatment for most hemiplegic migraine patients.

Glu298Asp and NOS4ab polymorphisms in diabetic nephropathy.

Background and aims. The risk of diabetic nephropathy (DN) increases with increase in intraglomerular pressure, which may partly be regulated by nitric oxide (NO). NO‐production can be affected by polymorphisms in the endothelial NO‐synthase gene (NOS3), hyperglycaemia and smoking. We therefore studied association between DN and two polymorphisms in NOS3, Glu298Asp and NOS4ab, in Caucasian type 1 diabetes (T1D) patients. Patients and methods. A total of 1510 Finnish and Swedish T1D patients were included in a cross‐sectional case‐control study. Incipient DN was defined as an albumin excretion rate (AER) of 20–200 µg/min (n = 336). Overt DN = AER>200 µg/min or renal replacement therapy (n = 619). All patients with DN were considered as cases. The controls were T1D patients with diabetes duration ⩾20 years, AER<20 µg/min and without antihypertensive treatment (n = 555). The genetic markers studied were a 27 bp repeat (NOS4ab) and Glu298Asp (rs1799983). Results. Age at onset of diabetes, male sex, duration of diabetes, HbA1c, blood pressure and smoking were assessed as possible confounders in the logistic regression analysis, which showed that homozygosity for the Glu‐allele of the Glu298Asp‐polymorphism was independently associated with increased risk of DN (OR = 1.46; 95% CI = 1.12–1.91). The variables smoking (OR = 2.13; 95% CI = 1.63–2.78), male sex (OR = 1.61; 95% CI = 1.23–2.10), HbA1c (OR per % increase above upper limit of the normal reference range = 1.02; 95% CI = 1.02–1.03), systolic (OR = 1.05; 95% CI = 1.04–1.06) and diastolic blood pressure (OR = 1.04; 95% CI = 1.02–1.05) also significantly and independently increased the risk of DN when taking age at diabetes onset and diabetes duration into account. The NOS4 a‐allele was not associated with DN. Conclusions. The Glu/Glu‐genotype of the NOS3 Glu298Asp polymorphism may increase the risk of developing DN independently of other known risk factors.

Birth Weight Is Inversely Correlated to Adult Systolic Blood Pressure and Pulse Pressure in Type 1 Diabetes

In the general population, there is an inverse relationship between birth weight and adult systolic blood pressure. Because blood pressure in diabetic patients at least in part seems to be regulated by different mechanisms than in nondiabetic subjects, it is not known whether a similar correlation exists in diabetic individuals. Therefore, we obtained data on birth weight from original birth certificates in 1543 type 1 diabetic patients. Blood pressure was measured auscultatorily on a single occasion. In the 1225 patients born at term (after 37 weeks of gestation), the age- and sex-adjusted regression coefficients between systolic blood pressure and birth weight was −1.90 mm Hg/kg (95% confidence interval [CI], −3.71 to −0.09). The finding remained unchanged after adjustment for body mass index, current smoking, duration of diabetes, social class, antihypertensive therapy, glomerular filtration rate, glycemic control, and elevated albuminuria. The regression coefficient between birth weight and pulse pressure was of a similar magnitude. The age-adjusted regression coefficient between systolic blood pressure and birth weight seemed stronger in females (−3.34 mm Hg/kg; 95% CI, −6.06 to −0.62) than in males (−0.42 mm Hg/kg; 95% CI, −2.80 to 1.95), although this difference was not statistically significant. As a new finding, we report an inverse relationship between weight at birth and systolic blood pressure and pulse pressure in adult type 1 diabetic patients. Given the deleterious effects of elevated arterial blood pressure in diabetes, the impact of intrauterine growth retardation on the development of end-organ damage needs to be clarified.

Comorbidity in Finnish migraine families

The objective of the study was to investigate comorbidity of migraine in Finnish migraine families. One thousand consecutive participants in the Finnish Migraine Gene Project reported their medical illnesses in addition to migraine and headache. Migraine patients (n=678) reported significantly more hypotension (OR 1.43, CI 95% 1.02–2.01), allergy (OR 1.83, CI 95% 1.34–2.51) and psychiatric disorders (OR 4.09, CI 95% 2.11–7.92) compared to their family members without migraine (n=322). Subgroup analyses demonstrated that especially women and the group fulfilling the criteria for both migraine with and without aura were likely to have additional disorders besides their migraine. Interestingly, male migraineurs with aura reported a significant association with stroke and epilepsy. Familial migraine is comorbid with hypotension, allergy and psychiatric disorders. The association between migraine with aura and stroke and epilepsy among men of the studied families warrants further study. Clinical, pathophysiological and genetic implications of these results are discussed.

Shared loci for migraine and epilepsy on chromosomes 14q12-q23 and 12q24.2-q24.3

Objectives: To describe clinical characteristics and to identify susceptibility loci for epilepsy and migraine in a Finnish family with a complex phenotype. Methods: Participating family members were interviewed and medical files were reviewed. The seizure classification was made according to International League Against Epilepsy criteria. Migraine diagnosis was made using the validated Finnish Migraine Specific Questionnaire for Family Studies and criteria according to the current International Classification of Headache Disorders-II. DNA samples were obtained from 56 family members and nonparametric genome-wide linkage analyses were performed using 382 polymorphic microsatellite markers. The most promising loci were fine-mapped with additional microsatellite markers. Results: Clinical data were obtained from 60 family members of whom 12 (20%) had idiopathic epileptic seizures. Eight of those 12 (67%) also had migraine. Altogether 33 of the 60 family members (55%) had migraine. Significant evidence of linkage was found between a locus on 14q12-q23 and migraine (p = 0.0001). Suggestive evidence of linkage in this region was also found for epilepsy with generalized tonic-clonic seizures (p = 0.0034). In addition, significant evidence of linkage was found at a locus on 12q24.2-q24.3 (p < 0.001) for migraine alone and for the combined phenotype of migraine and epilepsy. Conclusions: Our data suggest the occurrence of common susceptibility loci for epilepsy and migraine on chromosomes 14q12-q23 and 12q24.2-q24.3, implicating a shared genetic etiology for these 2 diseases.

Fine mapping of Hyplip1 and the human homolog, a potential locus for FCHL.

Abstract. Familial combined hyperlipidemia (FCHL) is a common genetic dyslipidemia predisposing to premature coronary heart disease (CHD). We previously identified a locus for FCHL on human Chromosome (Chr) 1q21-q23 in 31 Finnish FCHL families. We also mapped a gene for combined hyperlipidemia (Hyplip1) to a potentially orthologous region of mouse Chr 3 in the HcB-19/Dem mouse model of FCHL. The human FCHL locus was, however, originally mapped about 5 Mb telomeric to the synteny border, the centromeric part of which is homologous to mouse Chr 3 and the telomeric part to mouse Chr 1. To further localize the human Hyplip1 homolog and estimate its distance from the peak linkage markers, we fine-mapped the Hyplip1 locus and defined the borders of the region of conserved synteny between human and mouse. This involved establishing a physical map of a bacterial artificial chromosome (BAC) contig across the Hyplip1 locus and hybridizing a set of BACs to both human and mouse chromosomes by fluorescence in situ hybridization (FISH). We narrowed the location of the mouse Hyplip1 gene to a 1.5-cM region that is homologous only with human 1q21 and within approximately 5–10 Mb of the peak marker for linkage to FCHL. FCHL is a complex disorder and this distance may, thus, reflect the well-known problems hampering the mapping of complex disorders. Further studies identifying and sequencing the Hyplip1 gene will show whether the same gene predisposes to hyperlipidemia in human and mouse.

Gene-based pleiotropy across migraine with aura and migraine without aura patient groups

Introduction It is unclear whether patients diagnosed according to International Classification of Headache Disorders criteria for migraine with aura (MA) and migraine without aura (MO) experience distinct disorders or whether their migraine subtypes are genetically related. Aim Using a novel gene-based (statistical) approach, we aimed to identify individual genes and pathways associated both with MA and MO. Methods Gene-based tests were performed using genome-wide association summary statistic results from the most recent International Headache Genetics Consortium study comparing 4505 MA cases with 34,813 controls and 4038 MO cases with 40,294 controls. After accounting for non-independence of gene-based test results, we examined the significance of the proportion of shared genes associated with MA and MO. Results We found a significant overlap in genes associated with MA and MO. Of the total 1514 genes with a nominally significant gene-based p value (pgene-based ≤ 0.05) in the MA subgroup, 107 also produced pgene-based ≤ 0.05 in the MO subgroup. The proportion of overlapping genes is almost double the empirically derived null expectation, producing significant evidence of gene-based overlap (pleiotropy) (pbinomial-test = 1.5 × 10–4). Combining results across MA and MO, six genes produced genome-wide significant gene-based p values. Four of these genes (TRPM8, UFL1, FHL5 and LRP1) were located in close proximity to previously reported genome-wide significant SNPs for migraine, while two genes, TARBP2 and NPFF separated by just 259 bp on chromosome 12q13.13, represent a novel risk locus. The genes overlapping in both migraine types were enriched for functions related to inflammation, the cardiovascular system and connective tissue. Conclusions Our results provide novel insight into the likely genes and biological mechanisms that underlie both MA and MO, and when combined with previous data, highlight the neuropeptide FF-amide peptide encoding gene (NPFF) as a novel candidate risk gene for both types of migraine.

Decreased cerebellar total creatine in episodic ataxia type 2: A 1H MRS study

Episodic ataxia type 2 (EA2) affects mainly the cerebellum via mutations in the CACNA1A gene. The authors used proton MR spectroscopy to examine cerebellar and thalamic metabolism of nine mostly nonataxic EA2 family members (all with proven CACNA1A mutation) and nine healthy control subjects. Cerebellar total creatine was lower in the patient group (p = 0.005) than in control subjects, possibly reflecting an early sign of calcium channel dysfunction in EA2.