Co-occurrence of major depression or suicide attempt with migraine with aura and risk for unprovoked seizure

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldWe hypothesized and found that the co-occurrence of migraine with aura (MA) with major depression (MD) or with suicide attempt (SA) increases the risk for developing unprovoked seizure more than these conditions alone. Number of conditions showed a linear relationship to seizure risk. This may reflect a new condition cluster defined by MA, MD, SA and unprovoked seizures. Identifying the biological underpinnings this cluster may affect clinical diagnosis and treatment

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.</p

Population-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadPredicting the pathogenicity of biallelic missense variants can be challenging. Here, we use a deficit of observed homozygous carriers of missense variants, versus an expected number in a set of 153,054 chip-genotyped Icelanders, to identify potentially pathogenic genotypes. We follow three missense variants with a complete deficit of homozygosity and find that their pathogenic effect in homozygous state ranges from severe childhood disease to early embryonic lethality. One of these variants is in CPSF3, a gene not previously linked to disease. From a set of clinically sequenced Icelanders, and by sequencing archival samples targeted through the Icelandic genealogy, we find four homozygous carriers. Additionally, we find two homozygous carriers of Mexican descent of another missense variant in CPSF3. All six homozygous carriers of missense variants in CPSF3 show severe intellectual disability, seizures, microcephaly, and abnormal muscle tone. Here, we show how the absence of certain homozygous genotypes from a large population set can elucidate causes of previously unexplained recessive diseases and early miscarriage.Sacchi Foundatio

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Publisher Copyright: © 2023, The Author(s).Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.Peer reviewe

Autism spectrum disorders in children with a history of infantile spasms: a population-based study.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldThe objective of this article is to describe autistic spectrum disorders in children diagnosed with infantile spasms in the first year of life. The source of data was the records of all 3 pediatric departments in Iceland. Twenty children born between 1981 and 1998 who had infantile spasms were invited to participate. When appropriate, the parents of these children were asked to complete the Social Communication Questionnaire. Children scoring 10 points or higher on the questionnaire were selected for further examination using the Autism Diagnostic Interview- Revised and either the Autism Diagnostic Observation Schedule or the Childhood Autism Rating Scale. All participants were given appropriate cognitive tests or measures of adaptive behavior. The parents of 17 children (10 boys, 7 girls) agreed to participate in the study. Age at assessment ranged from 5 to 19 years with a mean age of 11 years and 6 months. Fourteen children had at least one neurodevelopmental disorder. Six (6/17), or 35.3%, were diagnosed with autism spectrum disorder (3 boys, 3 girls), five of these had a history of symptomatic infantile spasms, and four were profoundly mentally retarded (IQ/DQ<20). If the diagnosis of autism spectrum disorder was restricted to children with a developmental age of 24 months or more (3 cases), the prevalence was 17.6%. The estimates found in this study exceed the estimated prevalence of autism spectrum disorder in the general population

Prevalence of symptomatic Charcot-Marie-Tooth disease in Iceland: a study of a well-defined population

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldBACKGROUND/AIM: To determine the prevalence and clinical spectrum of Charcot-Marie-Tooth disease (CMT) in Iceland. METHODS: We identified all individuals with symptomatic CMT, based on information from all practicing neurologists, both neurophysiology laboratories and the only neurology department in the country. The diagnosis was based on clinical features and neurophysiological testing. DNA testing was regarded as confirmatory. RESULTS: We identified 37 individuals in 18 families, which were not linked by identifying 5 generations of ancestors. The point prevalence (January 1, 2007) for all CMT subtypes in Iceland was 12.0/10(5), 10.1/10(5) for CMT1 and 2.0/10(5) for CMT2. The clinical features include lower limb weakness (95%), impaired gait (68%), decreased or absent deep tendon reflexes (86%), pes cavus (70%) and hammer toes (46%). Clinical symptoms were similar for the 2 main CMT subtypes. CONCLUSION: We report the prevalence and clinical spectrum of CMT, which is comparable to the results of other prevalence studies, in a well-defined, total population sample

Autism spectrum disorders in children with seizures in the first year of life - a population-based study

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldPURPOSE: To describe autistic spectrum disorders (ASDs) in a cohort of children with history of unprovoked seizures other than infantile spasms in the first year of life. METHODS: The source of data was computer records from all the three pediatric departments in Iceland. Children diagnosed 1982-2000 with unprovoked seizures with onset between 28 days and 12 months of age (N = 102) were invited to participate in a study. Children with known developmental disorders and those whose parents had concerns regarding their child's development or behavior were investigated for possible ASD. Parents were asked to complete the Social Communication Questionnaire and children scoring 10 points or higher were further examined with the Autism Diagnostic Interview-Revised and observational measures. RESULTS: Eighty-four children (82.4%), 28 boys and 56 girls, participated in the study and 36.9% (31/84) were investigated for possible ASD. Twenty-four (28.6%) had at least one neurodevelopmental disorder, 14.3% had mental retardation (MR), and six (7.1%) were diagnosed with ASD, all of whom also had MR and three of whom had congenital brain abnormalities. CONCLUSION: These results suggest that the estimated prevalence of ASD is higher in children with history of seizure in the first year of life than it is in the general population. There are indications that support the view that children with ASD and history of seizure in the first year of life have higher prevalence of congenital brain abnormalities and are more often female, than other children with ASD

Prevalence of recurrent symptoms and their association with epilepsy and febrile seizure in school-aged children: a community-based survey in Iceland.

We determined the prevalence of common recurrent symptoms in a community-based study of children and investigated whether these symptoms were associated with epilepsy and febrile seizure. A questionnaire was developed and sent to parents of all children attending school in the Reykjavik school district, grades 1-10. The questions assessed personality traits, headache, epilepsy, febrile seizure, and recurrent symptoms. Of the 13,044 questionnaires distributed, 10,578 were returned (81%). We analyzed the subset of 9679 (91%) questionnaires with complete information on relevant factors. The prevalence of epilepsy was 7.7/1000; febrile seizures were reported in 5.1% of children. Prevalence estimates of recurrent symptoms were similar to the published literature. In our cohort, recurrent dizzy spells and recurrent visual disturbances were associated with epilepsy after adjustment for age, migraine and febrile seizure. This association could reflect, only in part, the occurrence of auras in children with epilepsy.GSK (GlaxoWellcome) Icelandic General Practitioners Scientific Fun

Migraine with aura is a risk factor for unprovoked seizures in children

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldOBJECTIVE: Migraine is associated with epilepsy, but the time order and nature of the relationship are unclear. We conducted a population based case control study to clarify the time order to determine whether migraine is a risk factor for epilepsy. METHODS: Migraine symptoms were evaluated in a population-based case-control study of all incident epilepsy in Icelandic children and in matched controls (next two same sex births in the country). RESULTS: Migraine was associated with a fourfold increased risk for developing epilepsy, an association explained by migraine with aura (odds ratio, 8.1; 95% confidence interval, 2.7-24.3). Migraine without aura did not increase risk for epilepsy. INTERPRETATION: Children with migraine with aura have a substantial increased risk to develop subsequent epilepsy. This finding is consistent with the hypothesis that migraine with aura and migraine without aura may be different disorders

Depression and suicide attempt as risk factors for incident unprovoked seizures

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldMajor depression has been shown to increase the risk for development of epilepsy, but prior studies have not evaluated whether this is due to specific symptoms of depression. We conducted a population-based case-control study of all newly diagnosed unprovoked seizures among Icelandic children and adults aged 10 years and older to test the hypothesis that major depression is a risk factor for developing unprovoked seizure and epilepsy, and to address whether specific symptoms of depression account for this increased risk. Cases were matched to the next two same sex births from the population registry. Using standardized interviews, we ascertained symptoms of major depression to make a Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) diagnosis. A history of major depression was 1.7-fold more common among cases than among controls (95% confidence interval, 1.1-2.7). A history of attempted suicide was 5.1-fold more common among cases than among controls (95% confidence interval, 2.2-11.5). Attempted suicide increased seizure risk even after adjusting for age, sex, cumulative alcohol intake, and major depression or number of symptoms of depression. Major depression and attempted suicide independently increase the risk for unprovoked seizure. These data suggest that depression and suicide attempt may be due to different underlying neurochemical pathways, each of which is important in the development of epilepsy