Loss-of-function variants in ITSN1 confer high risk of Parkinson's disease.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder and its rising global incidence highlights the need for the identification of modifiable risk factors. In a gene-based burden test of rare variants (8647 PD cases and 777,693 controls) we discovered a novel association between loss-of-function variants in ITSN1 and PD. This association was further supported with burden data from the Neurodegenerative Disease Knowledge Portal and the Accelerating Medicines Partnership Parkinson's Disease Knowledge Platform. Our findings show that Rho GTPases and disruptions in synaptic vesicle transport may be involved in the pathogenesis of PD, pointing to the possibility of novel therapeutic approaches.

A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome.

Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (48,843 cases and 1,190,837 controls), we found 53 sequence variants at 50 loci associated with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 × 10-24, OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in bilateral/recurrent/persistent cases than nonrecurrent/nonpersistent cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS.

Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles.

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.

A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo.

Vertigo is the leading symptom of vestibular disorders and a major risk factor for falls. In a genome-wide association study of vertigo (Ncases = 48,072, Ncontrols = 894,541), we uncovered an association with six common sequence variants in individuals of European ancestry, including missense variants in ZNF91, OTOG, OTOGL, and TECTA, and a cis-eQTL for ARMC9. The association of variants in ZNF91, OTOGL, and OTOP1 was driven by an association with benign paroxysmal positional vertigo. Using previous reports of sequence variants associating with age-related hearing impairment and motion sickness, we found eight additional variants that associate with vertigo. Although disorders of the auditory and the vestibular system may co-occur, none of the six genome-wide significant vertigo variants were associated with hearing loss and only one was associated with age-related hearing impairment. Our results uncovered sequence variants associating with vertigo in a genome-wide association study and implicated genes with known roles in inner ear development, maintenance, and disease.

X-linked serotonin 2C receptor is associated with a non-canonical pathway for sudden unexpected death in epilepsy.

Sudden Unexpected Death in Epilepsy is a leading cause of epilepsy-related mortality, and the analysis of mouse Sudden Unexpected Death in Epilepsy models is steadily revealing a spectrum of inherited risk phenotypes based on distinct genetic mechanisms. Serotonin (5-HT) signalling enhances post-ictal cardiorespiratory drive and, when elevated in the brain, reduces death following evoked audiogenic brainstem seizures in inbred mouse models. However, no gene in this pathway has yet been linked to a spontaneous epilepsy phenotype, the defining criterion of Sudden Unexpected Death in Epilepsy. Most monogenic models of Sudden Unexpected Death in Epilepsy invoke a failure of inhibitory synaptic drive as a critical pathogenic step. Accordingly, the G protein-coupled, membrane serotonin receptor 5-HT2C inhibits forebrain and brainstem networks by exciting GABAergic interneurons, and deletion of this gene lowers the threshold for lethal evoked audiogenic seizures. Here, we characterize epileptogenesis throughout the lifespan of mice lacking X-linked, 5-HT2C receptors (loxTB Htr2c). We find that loss of Htr2c generates a complex, adult-onset spontaneous epileptic phenotype with a novel progressive hyperexcitability pattern of absences, non-convulsive, and convulsive behavioural seizures culminating in late onset sudden mortality predominantly in male mice. RNAscope localized Htr2c mRNA in subsets of Gad2+ GABAergic neurons in forebrain and brainstem regions. To evaluate the contribution of 5-HT2C receptor-mediated inhibitory drive, we selectively spared their deletion in GAD2+ GABAergic neurons of pan-deleted loxTB Htr2c mice, yet unexpectedly found no amelioration of survival or epileptic phenotype, indicating that expression of 5-HT2C receptors in GAD2+ inhibitory neurons was not sufficient to prevent hyperexcitability and lethal seizures. Analysis of human Sudden Unexpected Death in Epilepsy and epilepsy genetic databases identified an enrichment of HTR2C non-synonymous variants in Sudden Unexpected Death in Epilepsy cases. Interestingly, while early lethality is not reflected in the mouse model, we also identified variants mainly among male Sudden Infant Death Syndrome patients. Our findings validate HTR2C as a novel, sex-linked candidate gene modifying Sudden Unexpected Death in Epilepsy risk, and demonstrate that the complex epilepsy phenotype does not arise solely from 5-HT2C-mediated synaptic disinhibition. These results strengthen the evidence for the serotonin hypothesis of Sudden Unexpected Death in Epilepsy risk in humans, and advance current efforts to develop gene-guided interventions to mitigate premature mortality in epilepsy.

A meta-analysis uncovers the first sequence variant conferring risk of Bell's palsy.

Bell's palsy is the most common cause of unilateral facial paralysis and is defined as an idiopathic and acute inability to control movements of the facial muscles on the affected side. While the pathogenesis remains unknown, previous studies have implicated post-viral inflammation and resulting compression of the facial nerve. Reported heritability estimates of 4-14% suggest a genetic component in the etiology and an autosomal dominant inheritance has been proposed. Here, we report findings from a meta-analysis of genome-wide association studies uncovering the first unequivocal association with Bell's palsy (rs9357446-A; P = 6.79 × 10-23, OR = 1.23; Ncases = 4714, Ncontrols = 1,011,520). The variant also confers risk of intervertebral disc disorders (P = 2.99 × 10-11, OR = 1.04) suggesting a common pathogenesis in part or a true pleiotropy.

Clinical features of microscopic colitis in a nation-wide follow-up study in Iceland.

OBJECTIVE: The long-term natural history of collagenous colitis (CC) and lymphocytic colitis (LC) is not well known. The few reports available that address these issues have a limited follow-up. The aims of this study were to evaluate the natural history of microscopic colitis (MC), to describe the treatment medications prescribed and to assess the use of non-steroidal anti-inflammatory drugs (NSAIDs) in MC. MATERIAL AND METHODS: This study is based on an earlier epidemiological study conducted in Iceland where 125 patients with MC (71 with CC and 54 with LC) were diagnosed in the period 1995-99. All patients still alive and available were questioned about symptoms, treatment and NSAID use in the 3 months preceding the interview. RESULTS: In a mean follow-up time of 6.4 years from diagnosis, 15% of the patients had diarrhoeal symptoms more than once a week, 30% less than once a week and 55% had no diarrhoea. Abdominal pain was reported in 18% of the patients. There was no statistically significant difference in symptoms of CC and LC patients. Forty-eight patients (50%) were receiving medication for MC, 16% used aminosalicylates and 14% corticosteroids. Patients using medication for MC had significantly more diarrhoeal symptoms compared with those who did not (p = 0.002). Patients using NSAIDs regularly or as required, statistically did not have more symptoms related to MC than non-NSAID users. CONCLUSIONS: Only a minority of patients with MC had diarrhoea more than once a week in a long-term follow-up and the symptom pattern was similar between CC and LC patients. The use of NSAIDs was not associated with more diarrhoeal symptoms.

[Microscopic colitis - review]. / Smásae ristilbólga - yfirlit.

Microscopic colitis (MC) is an encompassing term for two diseases; collagenous colitis and lymphocytic colitis. The colon appears normal by colonoscopy and a diagnosis is only obtained with a biopsy. The histopathology of collagenous colitis is mainly characterized by a thickening of the subepithelial basement membrane of the colonic mucosa with a band of collagen. Lymphocytic colitis is mainly characterized by an intraepithelial lymphocytosis without the collagen thickening. Even though the two diseases have a distinctive pathology their clinical symptoms are characterized by chronic watery diarrhea without bleeding. Microscopic colitis is thought to cause about 4-13% of all chronic diarrhea but their relative frequency is much higher among older people. The mean annual incidence for collagenous and lymphocytic colitis has been increasing. Steroids are the most effective treatment for microscopic colitis and budesonide is the most studied and effective therapy for MC. The aim of this paper is to give a review of two relatively new diseases which are among the most common cause of chronic diarrhea, especially among older people.

[The application of stem cells for research and treatment of neurological disorders]. / Notkun stofnfrumna til rannsókna og laekninga á taugasjúkdómum.

It has long been a common view that neurons in the human central nervous system were not capable of self renewal. But in the mid-1990s scientists discovered that certain areas of the human brain do have the ability generate new neurons, at least under certain circumstances. It was subsecuently confirmed that the human central nervous system contains stem cells similar to the cells which originally give rise to the central nervous sysem during fetal development. The possible use of stem cells in the treatment of various neurological disorders, holds great promise. However, much research needs to be carried out before stem cell therapy can be moved from the bench to the bedside. Now researchers are pursuing two fundamental strategies to exploit the possible application of stem cells. One is to cultivate stem cells in vitro and to design the right differentiation profile of cells suitable for implantation. The other strategy relies on studying endogenous signals that could stimulate the patient s own stem cells and repair mechanisms. Here we give an overview of neural stem cells and their possible future use in the treatment of neural diseases such as Parkinson s disease, motor neuron disease and spinal cord injury.

[Organising Pneumonia - a review and results from Icelandic studies]. / Trefjavefslungnabólga - yfirlitsgrein og helstu niurstöur íslenskra rannsókna.

Organising pneumonia (OP) is a relatively rare interstitial lung disease. It s definition is based on a characteristic histological pattern in the presence of certain clinical and radiological features. Organising pneumonia represents also what has been called Bronchiolitis Obliterans Organising Pneumonia (BOOP). Recently it has been recommended to call OP cryptogenic organising pneumonia (COP) when no definite cause or characteristic clinical context is found and secondary organising pneumonia (SOP) when causes can be identified such as infection or it occurs in a characteristic clinical context such as connective tissue disorder. The most common clinical symptoms are dyspnea, cough, fever and general malaise. It is common that symptoms have been present for some weeks before the diagnosis is made. Patients commonly have lowered PO2 and a mildly restrictive spirometry. Radiographic features are most often patchy bilateral airspace opacities but an interstitial pattern or focal opacities can also be seen. Most of patients respond well to steroids but relapses are quite common. The aim of this paper is to present an overview of the disease and the main results from studies on OP in Iceland. The mean annual incidence for OP in Iceland was 1.97/100,000 inhabitants. Annual incidence for COP was 1.10/100,000 and 0.87/100,000 for SOP. This is higher than in most other studies. In Iceland patients with OP had a higher standardized mortality ratio than the general population despite good clinical responses. No clinical symptoms could separate between SOP and COP.

[Chronic eosinophilic pneumonia in Iceland: clinical features, epidemiology and review]. / Langvinn eósínófíl lungnabólga á Islandi Faraldsfraedi, klínísk einkenni og yfirlit.

OBJECTIVE: The objective of the study was to describe the incidence and clinical features of chronic eosinophilic pneumonia (CEP) in Iceland and review recent literature. MATERIAL AND METHODS: Retrospective study where information was obtained from clinical charts from 1990-2004. Records, imaging studies and histopathology were evaluated. RESULTS: During the study period 10 individuals were diagnosed with CEP, 7 males and 3 females. Mean age was 58 years. None of the patients was a current smoker. The incidence of CEP during the study period was 0.23 per 100,000/year but increased to 0.54 per 100,000/year during the last 5 years of the study period. Clinical symptoms were malaise, cough, dyspnea, sweating and weight loss. Sedimentation rate was 72 mm/h and C-reactive protein (CRP) 125 mg/L. Eight of the ten patients had increase in blood eosinophils. On chest auscultation crackles were heard in seven patients and wheezing in three. Forced vital capacity (FVC) was 75% of predicted value and forced expiratory volume in one second (FEV1) was 73% of predicted. Mean PO2 was 68 mmHg. All the patients had classic diffuse bilateral opacities on chest radiograph that most commonly were peripheral. All patients were treated with corticosteroids and responded well. The average initial dose of Prednisolone was 42.5 mg per day. Seven of the patients relapsed but they all responded well to repeated treatment. CONCLUSIONS: Chronic eosinophilic pneumonia is a rare disorder but it has specific radiologic and histologic features. It is important to think of the disease in patients with diffuse infiltrates that are resistant to antibiotics. CEP responds well to corticosteroids but there is a high relapse rate, which also responds to treatment.

[Organising pneumonia in connection with Amiodarone treatment. Case reports and review]. / Trefjavefslungnabólga tengd notkun lyfsins amíódarón Sjúkratilfelli og yfirlit.

OBJECTIVE: The objective of the study was to describe case reports of organising pneumonia in Iceland induced by the drug amiodarone. MATERIAL AND METHODS: Retrospective study where information was obtained from clinical charts from 1984-2003. Medical records, imaging studies and histopathology were re-evaluated. RESULTS: Described are three case reports of organising pneumonia associated with amiodarone use in two males and one female. Diagnostic methods and treatment are described and current literature is discussed. CONCLUSIONS: It is important for physicians to be aware of lung changes that amiodarone can cause and the importance of monitoring these patients.