RESUMEN
BACKGROUND: Guillain-Barré syndrome is an immune-mediated acute inflammatory polyneuropathy that is associated with various triggers, including certain infections and vaccines. It has been suggested that both SARS-CoV-2 infection and vaccination may be triggering factors for Guillain-Barré syndrome, but evidence remains equivocal. Here, we conducted a population-based incidence study of Guillain-Barré syndrome spanning the 3 years immediately prior to and the 2 years during the pandemic. METHODS: Cases were identified by searching a regional diagnostic database for the ICD-10 code for Guillain-Barré syndrome. Individuals who fulfilled the Brighton criteria for Guillain-Barré syndrome were included. Information on clinical presentation, laboratory values, and vaccination status were retrieved from medical records. We calculated the incidence immediately prior to and during the pandemic. RESULTS: The Guillain-Barré syndrome incidence rate was 1.35/100,000 person-years for the pre-pandemic period and 0.66/100,000 person-years for the pandemic period (incidence rate ratio: 0.49; p = 0.003). Three cases were temporally associated with SARS-CoV-2 infection and 1 case each to the AstraZeneca and Pfizer-BioNTech COVID-19 vaccines. CONCLUSIONS: Our results show that the incidence of Guillain-Barré syndrome decreased during the pandemic. This is most likely due to decreased prevalence of triggering infections due to social restrictions. Our findings do not support a causal relationship between Guillain-Barré syndrome and COVID-19.
Asunto(s)
COVID-19 , Síndrome de Guillain-Barré , Vacunas contra la Influenza , Humanos , Síndrome de Guillain-Barré/epidemiología , Estudios Retrospectivos , Incidencia , Pandemias , Vacunas contra la COVID-19 , COVID-19/epidemiología , COVID-19/complicaciones , SARS-CoV-2RESUMEN
OBJECTIVE: The incidence of sudden unexpected death in epilepsy (SUDEP) varies between studies. We determined the incidence of SUDEP in the entire Icelandic population during a 20-year period. METHODS: All individuals in Iceland with epilepsy who died unexpectedly from January 1, 1991 through December 31, 2010 were included. Case ascertainment was based on autopsies, reimbursement for antiepileptic drugs, death certificates, information from neurologists, and medical records. The incidence of SUDEP was calculated according to the total number of residents in Iceland during the study period and an estimated epilepsy population of Iceland. RESULTS: We identified 37 individuals (26 men, 11 women) with definite SUDEP (n = 29), definite SUDEP plus (n = 4), and probable SUDEP (n = 4). Incidence of SUDEP was 0.6 per 100 000 person-years for the general population, and higher among men. The estimated incidence of SUDEP in the epilepsy population was 1.3 per 1000 person-years. SUDEP accounted for 0.1% of all deaths in Iceland during the study period. SIGNIFICANCE: SUDEP is an important cause of death in working-age people. This study provides the incidence of SUDEP in an unselected population of an entire country. The SUDEP incidence in the epilepsy population is comparable to that of previous studies.
Asunto(s)
Electroencefalografía/mortalidad , Vigilancia de la Población , Muerte Súbita e Inesperada en la Epilepsia/epidemiología , Muerte Súbita e Inesperada en la Epilepsia/prevención & control , Adolescente , Adulto , Anticonvulsivantes/uso terapéutico , Niño , Preescolar , Certificado de Defunción , Electroencefalografía/tendencias , Femenino , Humanos , Islandia/epidemiología , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Vigilancia de la Población/métodos , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
OBJECTIVE: Studies in children have shown an increased frequency of central hypothyroidism (CH) with long-term use of antiepileptic drugs (AEDs). The aim of this study was to search for CH in adults treated with AEDs and find whether the type of AEDs used matters. MATERIALS AND METHODS: Adult epileptic patients treated at the neurology outpatient clinic at Landspitali University Hospital (LSH) from 1998 to 2011 were included. Patients were invited for a blood test if serum levels for TSH (s-TSH) or free-T4 (s-fT4 ) had not already been obtained. CH was defined as s-fT4 below the reference range (12-22 pmol/L) and normal s-TSH levels (0.30-4.20 mIU/L). Data were analyzed using logistic regression and Mann-Whitney test. RESULTS: We identified 165 patients (92 women), mean age 45.6 (±15.5, range: 20-92) years. The mean s-fT4 -level in our group was 14.2 (±2.9, range: 8.1-24.4) pmol/L compared with 16.9 (±6.1) pmol/L in a sample of 13248 measurements at LSH during one year (LSH-group) (P < 0.001). The difference in s-fT4 -level between men and the LSH-group was significant and also for women (P < 0.001 and P < 0.001, respectively). Thirty-five patients (21%) had CH. A significant association with the use of carbamazepine or oxcarbazepine was found, odds ratio for women 15.0 (95% CI: 4.6-49.5) and 1.8 (95% CI: 0.4-8.3) for men. CONCLUSION: 21% of patients treated with AEDs had CH, more often patients taking carbamazepine or oxacarbazepine, and more often women. The s-fT4 -level was lower among patients treated with AEDs.
Asunto(s)
Anticonvulsivantes/efectos adversos , Epilepsia/tratamiento farmacológico , Hipotiroidismo/inducido químicamente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: In this study, we examined multiple sclerosis (MS) point prevalence in the well-defined island population of Iceland. METHODS: This study included all registered residents of Iceland with MS on the prevalence day, December 31, 2007. All included patients met at least one of the following criteria: McDonald criteria; Poser criteria for clinically definite MS, laboratory-supported definite MS, clinically probable MS; or criteria for primary progressive MS. The patients' medical records were reviewed, including all available MRI data acquired prior to the prevalence day. RESULTS: We identified 526 patients, of whom 73% (382) were women. The crude point prevalence of MS was 167.1 per 100,000 population on the prevalence day. With age adjustment made to the 2000 U.S. population, the prevalence was 166.5 per 100,000 population. The mean patient age on the prevalence day was 47 years(range 13-89) for both men and women. The mean age at diagnosis was 36 years (range 13-77): 35 years for women and 36 years for men. CONCLUSION: MS prevalence was high in Iceland compared to the prevalence mentioned in reports from most of the world, and was similar to prevalence rates in other Nordic countries.
Asunto(s)
Esclerosis Múltiple/epidemiología , Adolescente , Adulto , Anciano , Femenino , Humanos , Islandia/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Sistema de Registros , Adulto JovenRESUMEN
OBJECTIVE: In this study, we determine the incidence and outcomes of Guillain-Barré syndrome (GBS) in Iceland over a 20-year period. METHOD: Cases were identified from the records of both referral hospitals in the country. All cases met the Brighton Criteria for GBS. Disability was assessed at diagnosis, peak of symptoms, discharge, and follow-up using the Guillain-Barré Disability Scale. RESULTS: Sixty-three individuals fulfilled the diagnostic criteria with an average age of onset of 46 years (range 1-89 years) and a male:female ratio of 1. The average annual incidence was 1.1 per 100 000 person-years. Nerve conduction studies were consistent with demyelinating polyneuropathy in 87% of cases, acute motor axonal neuropathy (AMAN) in 4%, and were normal in 9%. Treatment was received by 89% of patients and included IVIG (84%), plasmapheresis (8%), or both treatments (3%). Mechanical ventilation was required by 22% of patients. Long-term follow-up with an average length of 6.5 years was available for 98% of patients, and the average GBS disability score at follow-up was 0.9. Four deaths related to GBS (6%) were observed. CONCLUSION: We believe we have identified all patients diagnosed with GBS in Iceland during the study period, with an incidence comparable to recent studies from well-defined populations around the world. Our reported mortality is similar to or higher than other population-based studies. At follow-up, 13% of patients still required a walking aid, but most survivors (74%) had minor or no symptoms.
Asunto(s)
Evaluación de la Discapacidad , Síndrome de Guillain-Barré/epidemiología , Recuperación de la Función , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Islandia/epidemiología , Incidencia , Lactante , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Hereditary cystatin C amyloid angiopathy (HCCAA) is a genetic disease caused by a mutation in the cystatin C gene. Cystatin C is abundant in cerebrospinal fluid and the most prominent pathology in HCCAA is cerebral amyloid angiopathy due to mutant cystatin C amyloid deposition with associated cerebral hemorrhages, typically in young adult carriers. Analyses of post-mortem brain samples shows that pathological changes are limited to arteries and regions adjacent to arteries. The severity of pathological changes at post-mortem has precluded the elucidation of the evolution of histological changes. Mutant cystatin C deposition in carriers is systemic and has, for example, been described in the skin, suggesting similar pathological mechanisms both in the brain and outside of the central nervous system. The aim of this study was to use skin biopsies from asymptomatic and symptomatic carriers to study intermediate events in HCCAA pathogenesis. We found that cystatin C deposition in minimally affected samples was limited to the basement membrane (BM) between the dermis and epidermis. When the deposits were more advanced, they extended to other BM regions in the skin. Our results showed that the immunoreactivity of the BM protein COLIV was increased to a similar extent in all carrier biopsies and cystatin C deposits were in close association with COLIV. The density of fibroblasts in the upper dermis of carrier skin was increased, whereas the distribution of other cell types examined did not differ compared with control biopsies. COLIV and cystatin C immunoreactivity in carrier biopsies was closely associated with the fibroblasts. The results of this study, in conjunction with our previous results regarding pathological BM changes in leptomeningeal arteries of patients, suggest that BM changes are early and important events in HCCAA pathogenesis that could facilitate cystatin C deposition and aggregation.
Asunto(s)
Membrana Basal/metabolismo , Angiopatía Amiloide Cerebral/metabolismo , Tejido Conectivo/metabolismo , Cistatina C/metabolismo , Piel/metabolismo , Adulto , Anciano , Membrana Basal/patología , Angiopatía Amiloide Cerebral/genética , Colágeno Tipo IV/metabolismo , Tejido Conectivo/patología , Cistatina C/genética , Dermis/metabolismo , Dermis/patología , Epidermis/metabolismo , Epidermis/patología , Femenino , Heterocigoto , Humanos , Inmunohistoquímica , Masculino , Microscopía Fluorescente , Persona de Mediana Edad , Mutación , Piel/patología , Adulto JovenRESUMEN
BACKGROUND AND AIM: We report a population-based study conducted in Iceland to determine the incidence, clinical characteristics and prognosis of idiopathic chronic inflammatory demyelinating polyneuropathy (CIDP) during a 21-year period. METHODS: Cases were identified from the records of all practicing neurologists in the country, the only neurology department in the country and both neurophysiology laboratories. All index cases met the 2010 European Federation of Neurological Societies/Peripheral Nerve Society criteria for CIDP. RESULTS: Nineteen individuals fulfilled the diagnostic criteria during the study period. The average annual incidence was 0.3/100,000 (95% CI 0.04-2.47). There were 14 men (74%) in a gender ratio of 1:2.8. The mean age at diagnosis was 57 (range 19-81 years): women, 36 years and men, 63 years; p = 0.0006. The disease course was remitting-relapsing in 21% and chronic progressive or monophasic in 79%. The average length of follow-up was 6.9 years. The standardized mortality ratio for the 21-year study period was 0.9 (95% CI 0.3-2.2). CONCLUSION: We believe we have identified all diagnosed with CIDP in Iceland during a 21-year period. Many had no or only limited disease progression over the years and mortality is not increased compared with the general population.
Asunto(s)
Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Islandia/epidemiología , Incidencia , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Iceland is an island in the North Atlantic with ≈319 000 inhabitants. The study determines the incidence of first stroke in the adult population of Iceland during 12 months, which has not been previously reported in the entire Icelandic population. METHODS: The study population consisted of all residents of Iceland, aged ≥ 18 years, during the 12-month study period. Cases were identified by multiple overlapping approaches. Medical records were reviewed to verify diagnosis, to determine stroke subtype and to determine selected risk factors. RESULTS: A total of 343 individuals, aged ≥ 18 years, had a first stroke during the study period. Incidence was 144 per 100 000 person years; 81% ischemic infarction; 9% intracerebral hemorrhage; 7% subarachnoid hemorrhage; and 3% unknown. Fifty percent of the individuals were men. Mean age for ischemic infarction and intracerebral hemorrhage was 71 years for men and 73 years for women. Atrial fibrillation was previously known in 18% with first ischemic stroke or intracerebral hemorrhage and another 6% were diagnosed on routine admission ECG. Long-term ECG study (24 hours) found that 12% (18/154) of the remaining individuals had paroxysmal atrial fibrillation. CONCLUSIONS: Incidence of first stroke in Iceland is similar to other Western countries. The high number of paroxysmal atrial fibrillation found during the 24-hour ECG suggests that atrial fibrillation may be underdiagnosed in patients with stroke.
Asunto(s)
Accidente Cerebrovascular/clasificación , Accidente Cerebrovascular/epidemiología , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/complicaciones , Fibrilación Atrial/epidemiología , Femenino , Humanos , Islandia/epidemiología , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico , Adulto JovenRESUMEN
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.
Asunto(s)
Atrofia de Múltiples Sistemas/epidemiología , Atrofia de Múltiples Sistemas/mortalidad , Edad de Inicio , Anciano , Anciano de 80 o más Años , Encéfalo/metabolismo , Femenino , Humanos , Islandia/epidemiología , Incidencia , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/complicaciones , Atrofia de Múltiples Sistemas/diagnóstico , Atrofia de Múltiples Sistemas/metabolismo , Prevalencia , Tasa de Supervivencia , alfa-Sinucleína/metabolismoRESUMEN
Introduction: Mortality is an important feature of the natural history of multiple sclerosis (MS). We report the mortality of all individuals with MS in Iceland, identified in a nationwide population-based study. Patients and Methods: The results are based on a prevalence cohort and an incidence cohort. The prevalence cohort consisted of all patients with MS (n = 526) living in Iceland on the 31 December 2007. The incidence cohort consisted of all residents of Iceland (n = 222) diagnosed with MS during 2002 to 2007. Mortality was determined by following both the incidence cohort (from diagnosis) and the prevalence cohort (from the prevalence day) until death or 31 December 2020. The mortality, associated with MS, was compared with that expected in the Icelandic population (standardized mortality ratio (SMR)). Results: (a) Prevalence cohort (n = 526). The mean follow up was 12.0 years (range 0.3-13.0). The SMR was 1.6 (95% confidence interval (CI) 1.3-2.0). (b) Incidence cohort (n = 222). The mean follow up was 15.4 years (range 3.7-18.5). The SMR was 1.2 (95% CI 0.6-2.2). Conclusion: During the follow-up period, there was a substantial increase in mortality among the patients with MS, compared with the general population. There was no increase in mortality among the incidence cohort, when followed for up to 18.5 years following diagnosis.
RESUMEN
OBJECTIVES: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by involuntary movements and psychiatric disturbances, found worldwide, with a variable prevalence. The purpose of this study was to determine the history of HD in Iceland and determine the prevalence and incidence of HD. MATERIALS AND METHODS: Clinical information was obtained from general, neurologic, and psychiatric hospitals, practicing neurologists, general practitioners, and family members of affected individuals. RESULTS: Twenty-seven individuals were identified with typical symptoms of HD from the 1850s to 2007. All but one sporadic case are descendants of a husband and wife living in the early and mid-19th century. The point prevalence of HD in Iceland is 1.0 per 100,000 individuals. CONCLUSIONS: The prevalence of HD in Iceland is markedly lower than in the neighboring countries (Norway and the British Isles), where Icelanders originate from.
Asunto(s)
Enfermedad de Huntington/epidemiología , Adulto , Femenino , Historia del Siglo XVI , Humanos , Islandia/epidemiología , Incidencia , Masculino , Persona de Mediana Edad , Prevalencia , Adulto JovenRESUMEN
BACKGROUND: We conducted a study to determine the incidence of multiple sclerosis (MS) among the whole Icelandic population during a 6-year period (2002-2007). METHODS: We included all Icelandic residents diagnosed with MS during the study period. Cases were identified from records of the only neurology department in Iceland, plus the records of all practicing neurologists and all radiology departments. All patients had experienced at least two confirmed MS relapses (i.e. clinically definite MS) or had primary progressive MS as defined by the Poser criteria. RESULTS: We identified 136 individuals who met the inclusion criteria, including 102 (75%) women. The mean age at diagnosis was 36.3 years (women 35.7 years, men 38.3 years). Average annual incidence was 7.6 per 100,000 population. All but one patient (99%) had an MRI study done at diagnosis and 61% of these (83/135) fulfilled the Barkhof criteria for diagnosis of MS; one had a normal MRI. A visual evoked potential test was done in 68% (93/136) at the time of diagnosis and 44% (41/93) were abnormal. Spinal fluid was obtained from 78% (106/136), and 75% (80/106) had oligoclonal bands. CONCLUSION: A total population study is the most reliable method of determining the spectrum of clinical symptoms and the results of investigations in MS patients at diagnosis.
Asunto(s)
Esclerosis Múltiple/epidemiología , Adulto , Distribución por Edad , Potenciales Evocados Visuales , Femenino , Humanos , Islandia/epidemiología , Incidencia , Imagen por Resonancia Magnética , Masculino , Esclerosis Múltiple/diagnóstico , Bandas OligoclonalesRESUMEN
Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disease with high penetrance, manifest by brain hemorrhages in young normotensive adults. In Iceland, this condition is caused by the L68Q mutation in the cystatin C gene, with contemporary carriers reaching an average age of only 30 years. Here, we report, based both on linkage disequilibrium and genealogical evidence, that all known copies of this mutation derive from a common ancestor born roughly 18 generations ago. Intriguingly, the genealogies reveal that obligate L68Q carriers born 1825 to 1900 experienced a drastic reduction in life span, from 65 years to the present-day average. At the same time, a parent-of-origin effect emerged, whereby maternal inheritance of the mutation was associated with a 9 year reduction in life span relative to paternal inheritance. As these trends can be observed in several different extended families, many generations after the mutational event, it seems likely that some environmental factor is responsible, perhaps linked to radical changes in the life-style of Icelanders during this period. A mutation with such radically different phenotypic effects in reaction to normal variation in human life-style not only opens the possibility of preventive strategies for HCCAA, but it may also provide novel insights into the complex relationship between genotype and environment in human disease.
Asunto(s)
Sustitución de Aminoácidos/genética , Cistatinas/genética , Tamización de Portadores Genéticos , Estilo de Vida , Longevidad/genética , Adolescente , Adulto , Anciano , Angiopatía Amiloide Cerebral/genética , Angiopatía Amiloide Cerebral/mortalidad , Cistatina C , Femenino , Glutamina/genética , Humanos , Leucina/genética , Longevidad/fisiología , Masculino , Persona de Mediana Edad , Linaje , Caracteres SexualesRESUMEN
Hereditary cystatin C amyloid angiopathy is a dominantly inherited disease caused by a leucine to glutamine variant of human cystatin C (hCC). L68Q-hCC forms amyloid deposits in brain arteries associated with micro-infarcts, leading ultimately to paralysis, dementia and death in young adults. To evaluate the ability of molecules to interfere with aggregation of hCC while informing about cellular toxicity, we generated cells that produce and secrete WT and L68Q-hCC and have detected high-molecular weight complexes formed from the mutant protein. Incubations of either lysate or supernatant containing L68Q-hCC with reducing agents glutathione or N-acetyl-cysteine (NAC) breaks oligomers into monomers. Six L68Q-hCC carriers taking NAC had skin biopsies obtained to determine if hCC deposits were reduced following NAC treatment. Remarkably, ~50-90% reduction of L68Q-hCC staining was observed in five of the treated carriers suggesting that L68Q-hCC is a clinical target for reducing agents.
Asunto(s)
Acetilcisteína/farmacología , Proteínas Amiloidogénicas/metabolismo , Angiopatía Amiloide Cerebral Familiar/dietoterapia , Cistatina C/metabolismo , Cistatinas/metabolismo , Acetilcisteína/administración & dosificación , Acetilcisteína/análogos & derivados , Acetilcisteína/química , Proteínas Amiloidogénicas/química , Proteínas Amiloidogénicas/genética , Biopsia , Angiopatía Amiloide Cerebral Familiar/tratamiento farmacológico , Angiopatía Amiloide Cerebral Familiar/genética , Cistatina C/química , Cistatina C/genética , Cistatinas/química , Cistatinas/genética , Expresión Génica , Glutatión/química , Glutatión/farmacología , Células HEK293 , Humanos , Piel/efectos de los fármacos , Piel/metabolismo , Adulto JovenRESUMEN
BACKGROUND/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.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Niño , Preescolar , Familia , Femenino , Humanos , Islandia/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Adulto JovenRESUMEN
The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10-8, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.
Asunto(s)
Metilación de ADN , Predisposición Genética a la Enfermedad/genética , Cadenas HLA-DRB1/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Células Cultivadas , Estudios de Cohortes , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Factores de Riesgo , Adulto JovenRESUMEN
We 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.
Asunto(s)
Trastorno Depresivo Mayor/complicaciones , Migraña con Aura/complicaciones , Convulsiones/complicaciones , Intento de Suicidio/psicología , Adulto , Consumo de Bebidas Alcohólicas/epidemiología , Análisis por Conglomerados , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/psicología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Migraña con Aura/epidemiología , Migraña con Aura/psicología , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , Riesgo , Factores de Riesgo , Convulsiones/epidemiología , Convulsiones/psicología , Intento de Suicidio/estadística & datos numéricosRESUMEN
A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 × 10-7, 4.3 × 10-9) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.
RESUMEN
BACKGROUND: No population-based incidence studies of epilepsy have studied syndrome classification from the outset. We prospectively studied the incidence of a single unprovoked seizure and epilepsy in the population of Iceland, and applied the syndrome classification endorsed by the International League Against Epilepsy to this population. METHODS: We used a nationwide surveillance system to prospectively identify all residents of Iceland who presented with a first diagnosis of a single unprovoked seizure or epilepsy between December 1995 and February 1999. All cases were classified by seizure type, cause or risk factors, and epilepsy syndrome. RESULTS: The mean annual incidence of first unprovoked seizures was 56.8 per 100,000 person-years, 23.5 per 100,000 person-years for single unprovoked seizures, and 33.3 per 100,000 person-years for epilepsy (recurrent unprovoked seizures). Incidence was similar in males and females. Partial seizures occurred in 40% and a putative cause was identified in 33%. Age-specific incidence was highest in the first year of life (130 per 100,000 person-years) and in those 65 years and older (110.5 per 100,000 person-years). Using strict diagnostic criteria for epilepsy syndromes, 58% of cases fell into non-informative categories. Idiopathic epilepsy syndromes were identified in 14% of all cases. INTERPRETATION: Findings are consistent with incidence studies from developed countries. Although the epilepsy syndrome classification might be useful in tertiary epilepsy centers, it has limited practicality in population studies and for use by general neurologists.