Genome sequencing reanalysis increases the diagnostic yield in dystonia.

PURPOSE: We investigated the contribution of genomic data reanalysis to the diagnostic yield of dystonia patients who remained undiagnosed after prior genome sequencing. METHODS: Probands with heterogeneous dystonia phenotypes who underwent initial genome sequencing (GS) analysis in 2019 were included in the reanalysis, which was performed through gene-specific discovery collaborations and systematic genomic data reanalysis. RESULTS: Initial GS analysis in 2019 (n = 111) identified a molecular diagnosis in 11.7 % (13/111) of cases. Reanalysis between 2020 and 2023 increased the diagnostic yield by 7.2 % (8/111); 3.6 % (4/111) through focused gene-specific clinical correlation collaborative efforts [VPS16 (two probands), AOPEP and POLG], and 3.6 % (4/111) by systematic reanalysis completed in 2023 [NUS1 (two probands) and DDX3X variants, and a microdeletion encompassing VPS16]. Seven of these patients had a high phenotype-based dystonia score ≥3. Notable unverified findings in four additional cases included suspicious variants of uncertain significance in FBXL4 and EIF2AK2, and potential phenotypic expansion associated with SLC2A1 and TREX1 variants. CONCLUSION: GS data reanalysis increased the diagnostic yield from 11.7 % to 18.9 %, with potential extension up to 22.5 %. While optimal timing for diagnostic reanalysis remains to be determined, this study demonstrates that periodic re-interrogation of dystonia GS datasets can provide additional genetic diagnoses, which may have significant implications for patients and their families.

High Degree of Genetic Heterogeneity for Hereditary Cerebellar Ataxias in Australia.

Genetic testing strategies such as next-generation sequencing (NGS) panels and whole genome sequencing (WGS) can be applied to the hereditary cerebellar ataxias (HCAs), but their exact role in the diagnostic pathway is unclear. We aim to determine the yield from genetic testing strategies and the genetic and phenotypic spectrum of HCA in Australia by analysing real-world data. We performed a retrospective review on 87 HCA cases referred to the Neurogenetics Clinic at the Royal North Shore Hospital, Sydney, Australia. Probands underwent triplet repeat expansion testing; those that tested negative had NGS-targeted panels and WGS testing when available. In our sample, 58.6% were male (51/87), with an average age at onset of 37.1 years. Individuals with sequencing variants had a prolonged duration of illness compared to those with a triplet repeat expansion. The detection rate in probands for routine repeat expansion panels was 13.8% (11/80). NGS-targeted panels yielded a further 11 individuals (11/32, 34.4%), with WGS yielding 1 more diagnosis (1/3, 33.3%). NGS panels and WGS improved the overall diagnostic rate to 28.8% (23/80) in 14 known HCA loci. The genetic findings included novel variants in ANO10, CACNA1A, PRKCG and SPG7. Our findings highlight the genetic heterogeneity of HCAs and support the use of NGS approaches for individuals who were negative on repeat expansion testing. In comparison to repeat disorders, individuals with sequencing variants may have a prolonged duration of illness, consistent with slower progression of disease.

Impact of COX-2 rs5275 and rs20417 and GPIIIa rs5918 polymorphisms on 90-day ischemic stroke functional outcome: a novel finding.

We hypothesized that polymorphisms in 5 genes related to thrombolytic and inflammation pathways will independently influence occurrence, severity, and 3-month functional outcome in patients with ischemic stroke. This was a case-control design with ischemic stroke patients recruited from 4 public hospitals (n = 640) and community controls (n = 627). Baseline clinical data were collected, and follow-up telephone interviews were conducted with 520 patients at 90 days postevent to determine stroke outcome using the Barthel Index (BI), Modified Rankin Scale (mRS) and Glasgow Outcome Scale (GOS). Blood samples were collected and genotyped for polymorphisms in platelet glycoprotein Ibα (GPIbα) rs224309 and rs6065, glycoprotein IIIa (GPIIIa) rs5918, tissue plasminogen activator (tPA) rs63020761, plasminogen activating inhibitor (PAI-1) rs72578597, and cyclooxygenase-2 (COX-2) rs5275 and rs20417. COX-2 polymorphism rs5275 demonstrated a significant association with poststroke mRS, with a dominant genetic model demonstrating the best fit (CC + TC) (adjusted odds ratio [aOR] = 1.61; P = .026). The COX-2 rs20417 C allele showed an association with GOS (aOR = 1.95; P = .012), and again a dominant genetic model demonstrated the best fit (CC + GC). GPIIIa rs5918 (A1A2) was associated with poststroke BI, with a dominant model demonstrating the best fit (A1A2 + A2A2) (aOR = 0.56; P = .014). There was a significant association between stroke severity and tPA rs63020761 TT allele (aOR = 1.96; 95% CI = 1.03-3.72; P = .040). This is the first study to demonstrate associations between stroke functional outcome and 2 COX-2 variants (rs20417 and rs5275) and a GPIIIa variant (rs5918).

Enhanced geographically restricted surveillance simulates sporadic Creutzfeldt-Jakob disease cluster.

Spatio-temporal clustering of sporadic Creutzfeldt-Jakob disease (sCJD) has been recognized and investigated previously in various global settings including Australia. Generally, despite often extensive investigation, explanations such as point source outbreaks and plausible case-to-case transmission links have not been identified to explain the apparently higher case rates than expected. In the context of national surveillance during the period 1993-2006, an increased number of cases of sCJD were recognized in a circumscribed coastal region of eastern Australia. To assess the significance of this apparent clustering, the Spatial Scan Statistic was used to examine for geographic excess of CJD mortality at spatial and temporal combined, spatial only and temporal only levels. A significant spatial cluster was confirmed, encompassing three contiguous statistical local areas within the state of New South Wales (NSW). Detailed epidemiological analysis did not reveal a plausible cross-over or point source transmission event. Further evaluation prompted the conclusion that vigilant and motivated managing clinicians in this geographically circumscribed area of NSW evinced a sustained higher level of clinical awareness for the broad phenotypic spectrum of CJD with reliable referral of suspect cases for further investigation. In addition, these physicians established and maintained a well-coordinated and active approach to suspect CJD autopsy. This combination of factors translated into a higher intensity of surveillance at approximately twice the rate per population observed in the entire state, culminating in twice the incidence of sCJD at around 2.28 cases/million population/year. The hypothesis that intensity of surveillance for rare disorders can be objectively measured and that this can positively correlate with disease incidence deserves further exploration. It may prove to be an important insight into the varying incidence rates over periods of time within individual nations and between different countries.

Polymorphisms in platelet glycoprotein 1balpha and factor VII and risk of ischemic stroke: a meta-analysis.

BACKGROUND AND PURPOSE: Platelets and components of the coagulation cascade are known to be instrumental in the pathogenesis of arterial occlusive disorders. The aim of this meta-analysis is to test the hypothesis that genetic variation in the platelet glycoprotein 1balpha and Factor VII genes influence the occurrence of ischemic stroke. All genetic association studies that examined the R353Q (rs6046) polymorphism of the Factor VII gene and 2 polymorphisms of the platelet glycoprotein (1balpha) gene (Thr/Met rs6065 and Kozak sequence -5 C/T rs2243093) in relation to ischemic stroke were examined. METHODS: Electronic databases Embase, Medline, and HuGEnet were searched for all years up until June 2006 for all studies that evaluated any of these candidate genes and stroke. RESULTS: Pooled ORs were calculated with 95% CIs using both fixed and random effects models. Meta-analysis for Factor VII (R353Q) did not detect any effect on ischemic stroke risk. Further estimation resulted in pooled OR(1) QQ versus RR=0.9 (95% CI: 0.4 to 1.9) and pooled OR(2) for RQ versus RR=0.9 (95% CI: 0.6 to 1.4). These results were robust and homogeneous. Pooling ORs for the platelet glycoprotein 1balpha Kozak variant -5 T/C polymorphism showed extreme heterogeneity with differing effect directions across studies. Fisher's method of pooling was therefore used to calculate a combined probability value, which was highly significant (P<0.001). The pooled OR for platelet glycoprotein 1balpha Met/Met v Thr/Thr was 1.0 to 2.0, depending on the sensitivity analyses, and for Thr/Met versus Thr/Thr, the pooled OR was between 1.3 and 1.4. These results were consistent, reasonably robust, and implied a dominant genetic effect. CONCLUSIONS: This analysis provides strong evidence that the Factor VII R353Q gene polymorphism is not associated with ischemic stroke, that the Thr/Met polymorphism of GP1balpha is associated with ischemic stroke in a dominant genetic model, and that the Kozak sequence polymorphism of GP1balpha may be close to another causative locus that is associated with ischemic stroke.

Community-dwelling stroke survivors: function is not the whole story with quality of life.

OBJECTIVE: To compare function and quality of life in community-dwelling stroke survivors at 1, 3, and 5 years after stroke. DESIGN: A community-based, cross-sectional study of 3 retrospective cohorts. SETTING: Community-dwelling stroke survivors in Australia. PARTICIPANTS: The 3 cohorts comprised 30 participants each at 1, 3, and 5 years poststroke discharge from a tertiary referral hospital. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Stroke severity, comorbidity, medications used, and demographic information were recorded. Poststroke function was assessed using the Modified Rankin Scale, Mini-Mental State Examination, Stroke Impact Scale, and Multidimensional Scale of Perceived Social Support. RESULTS: This cross-sectional study provides insights into trends in stroke survivors over time. A high proportion of stroke survivors use community services, even those who are independent with activities of daily living. Although there was little attrition in medication use over time except for warfarin, this was from a baseline of suboptimal compliance and adherence with stroke preventive therapies. Stroke survivors report high levels of perceived social support; however, emotional well-being was low overall. The data suggest that those who are independent at 1 year tend to remain independent, although this was an extrapolation from serial cross-sections and needs to be explored in a longitudinal study. CONCLUSIONS: Stroke survivors' function does not change significantly over time. A high proportion of survivors require community services. The development of needs-related effective long-term service delivery models is required.

Perimetric homonymous visual field loss post-stroke.

Post-stroke homonymous visual field (PSHVF) loss has functional and driving implications for patients. Automated, as opposed to confrontational, assessment of PSHVF loss has the potential to provide a more reliable indicator for field loss and thus ability to drive. Sixty-one consecutive stroke admissions were assessed at 9 months post-stroke. Driving status and the patient's awareness of any visual field loss was ascertained. Patients underwent formal perimetric visual field testing using a Humphrey Visual Field Analyser II. A separate, blinded, confrontational assessment of visual fields was made using the National Institutes of Health Stroke Scale (NIHSS) technique. Homonymous field defects were found in 10 (16%) patients, with 50% of these being hemianopia and 50% quadrantanopia. Right-sided field loss was more common (70%). No patients with PSHVF loss were aware of their loss, and only two were detected using NIHSS assessment. One patient was thought to have PSHVF loss on NIHSS assessment but this was not confirmed on perimetry. Of those with significant PSHVF loss at 9 months, 30% were driving. The prevalence of PSHVF loss is relatively high and is underestimated by confrontational testing. Stroke patients are often unaware of their field loss, with up to 5% driving with significantly affected visual fields at 9 months. Perimetric testing may be useful in decision-making regarding driving eligibility post-stroke.

Stroke or encephalitis?

Viral encephalitis is associated with significant morbidity and mortality, particularly when appropriate management is omitted as a result of delayed diagnosis. A case of herpes simplex virus type 1 (HSV-1) encephalitis is presented, demonstrating that the presentation of confusion, speech difficulties and fever with non-specific early brain CT appearances can easily be misdiagnosed as pneumonia with stroke. This case highlights the need for increased awareness of HSV-1 encephalitis among emergency physicians and radiologists, given that the early spectrum of clinical and CT findings can mimic the more common diagnoses of sepsis and stroke.

Quinine associated blindness.

BACKGROUND: Quinine is commonly prescribed to the elderly for the treatment of benign nocturnal cramps, yet its use is not without complications. OBJECTIVE: This article presents a case of quinine toxicity producing bilateral blindness, followed by a review of the adverse reactions associated with quinine use and its efficacy in treating benign nocturnal muscular cramps. DISCUSSION: Visual loss has been associated with quinine serum concentrations above 10 microg/mL (therapeutic range 2-5 microg/mL). Other adverse reactions include neurological symptoms, haemolysis, acute renal failure and arrhythmia. There is conflicting evidence for the efficacy of quinine for leg cramps in randomised controlled studies, however, meta-analysis of these studies suggests some benefit. Although severe side effects are rare at therapeutic doses, the possibility of overdose needs to be considered when prescribing and an individual risk benefit analysis needs to be made. Benefits and adverse reactions should be closely monitored and medication ceased if appropriate.

Laboratory results in the elderly: the Sydney Older Persons Study.

BACKGROUND: The use of laboratory intervals based on younger and healthier populations is of questionable validity in older populations. The aim of this study was to examine haematological and biochemical profiles in a sample of community-dwelling older people and to study the impact of age, disease, disability and medications. METHODS: Basic haematological and biochemical values were obtained for 338 survivors of a random sample of community-living people aged 75 years or over at time of recruitment. These values were compared to the laboratory reference intervals and the effects of age, disease, medication and disability examined. RESULTS: The distribution of the 35 parameters measured differed from those described by the laboratory reference intervals in all but four of the variables. The values showed few significant age associations but did show associations with disease, disability and drug use. CONCLUSIONS: Abnormalities identified in haematological and biochemical testing are not due to age but to age-related illnesses. This is contrary to previous studies reporting a change in haematological and biochemical parameters purely on the basis of age. In the presence of abnormalities, identification and clarification of disease states should be made.