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.

GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis.

Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson's disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.

Frailty assessment tools and associated postoperative outcomes in older patients undergoing elective surgery: A prospective pilot study.

BACKGROUND: There is a need for a feasible tool to assess the risk of frailty prior to surgery. We aimed to identify the ratio of abnormal results for three clinically applicable screening tools to assess the risk of frailty, and their association with adverse outcomes in a cohort of elderly surgical patients. METHODS: In this prospective pilot study, patients ≥65 years undergoing preoperative evaluation for elective surgery were included and subjected to three frailty screening tests; Program of Research to Integrate Services for the Maintenance of Autonomy 7-item questionnaire (PRISMA7), Timed Up and Go (TUG), and Clock Drawing Test (CDT). The primary outcome was the incidence of abnormal testing, and secondary outcomes were the association between abnormal tests and mortality, readmission, delirium, surgical complications and non-home discharge. RESULTS: Out of 99 patients, 41%, 37%, and 43% had abnormal PRISMA7, TUG, and CDT screening, respectively. Postoperative delirium was more likely to occur in patients with abnormal TUG screening (19% vs. 3%, p = .011) and CDT (17% vs. 2%, p = .019). When analyzing screening tool combinations, patients with abnormal PRISMA7 and TUG had a higher rate of non-home discharge (38% vs. 17%, p = .029); and patients with abnormal TUG and CDT had a higher rate of postoperative delirium (25% vs. 3%, p = .006) and any surgical complication (58% vs. 38%, p = .037); and patients with abnormal results from all three tools had a higher rate of postoperative delirium (21% vs. 5%, p = .045) and non-home discharge (42% vs. 18%, p = .034). CONCLUSION: Approximately 40% of elderly surgical patients have abnormal PRISMA7, TUG, and CDT screening tests for frailty, and they are associated individually or in combination with increased risk of adverse postoperative outcomes. The results will aid in designing studies to further risk-stratify patients at risk of frailty and attempt to modify associated outcomes.

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.

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.

Isolated pseudoabducens palsy in acute thalamic stroke.

Oculomotor abnormalities are rarely noted in thalamic strokes. We describe isolated right pseudoabducens palsy in a young patient with acute left thalamic infarction revealed by diffusion-weighted magnetic resonance imaging. The patient's horizontal diplopia and oculomotor palsy resolved within 3days. This case supports the hypothesis that a lesion can cause isolated esotropia by interrupting descending inhibitory convergence pathways that traverse the paramedian thalamus and decussate in the subthalamic region to innervate the contralateral third oculomotor nucleus. Esotropia contralateral to the thalamic lesion results from tonic activation of the medial rectus, producing pseudoabducens palsy.

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.

Community implementation of PMTO(™): impacts on referrals to specialist services and schools.

In 2000, the city of Hafnarfjörður, Iceland, implemented Parent Management Training--Oregon Model (PMTO(™)) to prevent and treat behavioral problems among children. This paper describes the implementation and findings regarding impacts in the community. As hypothesized, findings showed that the number of referrals to specialist services decreased in Hafnarfjörður following PMTO implementation and increased in two comparison communities not implementing the method. Within the Hafnarfjörður community, recorded instances of behavior problems reduced in elementary schools working in line with PMTO. The results presented are the first such findings in Iceland and suggest the kinds of systematic changes communities may experience following the implementation of an evidence-based program.