A KMT2B Frameshift Variant Causing Focal Dystonia Restricted to the Oromandibular Region After Long-Term Follow-up

KMT2B-linked dystonia (DYT-KMT2B) is a childhood-onset dystonia syndrome typically beginning in the lower limbs and progressing caudocranially to affect the upper limbs with eventual prominent craniocervical involvement. Despite its recent recognition, it now appears to be one of the more common monogenic causes of dystonia syndromes. Here, we present an atypical case of DYT-KMT2B with oromandibular dystonia as the presenting feature, which remained restricted to this region three decades after symptom onset. This appears to be the first reported case of DYT-KMT2B from Southeast Asia and provides further supporting evidence for the pathogenic impact of the KMT2B c.6210_6213delTGAG variant.

GBA1 Variants and Parkinson’s Disease: Paving the Way for Targeted Therapy

Glucosylceramidase beta 1 (GBA1) variants have attracted enormous attention as the most promising and important genetic candidates for precision medicine in Parkinson’s disease (PD). A substantial correlation between GBA1 genotypes and PD phenotypes could inform the prediction of disease progression and promote the development of a preventive intervention for individuals at a higher risk of a worse disease prognosis. Moreover, the GBA1-regulated pathway provides new perspectives on the pathogenesis of PD, such as dysregulated sphingolipid metabolism, impaired protein quality control, and disrupted endoplasmic reticulum-Golgi trafficking. These perspectives have led to the development of novel disease-modifying therapies for PD targeting the GBA1-regulated pathway by repositioning treatment strategies for Gaucher’s disease. This review summarizes the current hypotheses on a mechanistic link between GBA1 variants and PD and possible therapeutic options for modulating GBA1-regulated pathways in PD patients.

COVID-19 vaccine-associated cerebral venous thrombosis in Germany: a descriptive study

ObjectiveReports of cerebral sinus and venous thrombosis (CVT) after ChAdOx1 vaccination against SARS-CoV-2 have raised safety concerns. We aimed to estimate the incidence of CVT within one month from first dose administration and the frequency of vaccine-induced immune thrombotic thrombocytopenia (VITT) as the underlying mechanism after vaccination with BNT162b2, ChAdOx1, and mRNA-1273, in Germany. MethodsA web-based questionnaire was e-mailed to all Departments of Neurology. We asked to report cases of CVT within one month of a COVID-19 vaccination. Other cerebral events could also be reported. Incidence rates of CVT were calculated by using official statistics of nine German States. ResultsA total of 45 CVT cases were reported. In addition, 9 primary ischemic strokes, 4 primary intracerebral hemorrhages, and 4 other neurological events were recorded. Of the CVT patients, 35 (77.8%) were female, and 36 (80.0%) were below the age of 60 years. Fifty-three events were observed after vaccination with ChAdOx1 (85.5%), 9 after BNT162b2 (14.5%), and none after mRNA-1273 vaccination. After 7,126,434 first vaccine doses, the incidence rate of CVT within one month from first dose administration was 6.5 (95% CI, 4.4-9.2) per 100,000 person-years for all vaccines and 17.9 (11.8-26.1) for ChAdOx1 (after 2,320,535 ChAdOx1 first doses). The adjusted incidence rate ratio was 9.68 (3.46-34.98) for ChAdOx1 compared to mRNA-based vaccines and 3.14 (1.22-10.65) for women compared to non-women. In 26/45 patients with CVT (57.8%), VITT was graded highly probable. ConclusionsGiven an incidence of 0.22-1.75 per 100,000 person-years for CVT in the general population, these findings point towards a higher risk for CVT after ChAdOx1 vaccination, especially for women.

Cohort-based surveillance of SARS-CoV2 transmission mirrors infection rates at the population level: a one-year longitudinal study

BackgroundMore than one year into the COVID-19 pandemic, important data gaps remain on longitudinal prevalence of SARS-CoV-2 infection at the population level and in defined risk groups, efficacy of specific lockdown measures, and on (cost-)effective surveillance. MethodsThe ELISA (Lubeck Longitudinal Investigation of SARS-CoV-2 Infection) study invited adult inhabitants (n=[~]300,000) from the Lubeck area (Northern Germany) and enrolled 3051 participants ([~]1%); 1929 population-matched and 1645 with high-exposure based on profession. The one-year study period (03/2020-02/2021) spanned massive influx of tourism in the summer, rise of infection rates in the fall/winter 2020/2021, and two lockdowns. Participants were screened seven times for SARS-CoV-2 infection using PCR and antibody testing and monitored with an app-based questionnaire (n=[~]91,000). ResultsCohort (56% female; mean age: 45.6 years) retention was 75%-98%; 89 persons (3.5%) were antibody- and/or PCR-positive. Seropositivity was almost 2-fold higher in men and increased risk detected in several high-exposure groups (highest for nurses, followed by police, army, firemen, and students). In May 2020, 92% of the infections were missed by PCR testing; by February 2021, only 29% remained undiagnosed. "Contact to COVID-19-affected" was the most relevant risk factor. Other factors, such as frequent use of public transportation, shopping, close contacts at work, and extensive tourism in the summer did not impact infection rates. ConclusionsWe i) provide a model for effective, regional surveillance; ii) identify infection risk factors informing public health measures; iii) demonstrate that easing of lockdown measures appears safe at times of low prevalence in the presence of continuous monitoring.

Metabolic markers distinguish COVID-19 from other intensive care patients and show potential to stratify for disease risk

Coronavirus disease 2019 (COVID-19) is a viral infection affecting multiple organ systems of great significance for metabolic processes. Thus. there is increasing interest in metabolic and lipoprotein signatures of the disease and early analyses have demonstrated metabolic pattern typical for atherosclerotic and hepatic damage in COVID-19 patients. However, it remains unclear whether these are specific for COVID-19 or a general marker of critical illness. To answer this question, we have analyzed 276 serum samples from 92 individuals using NMR metabolomics, including longitudinally collected samples from 5 COVID-19 and 11 cardiogenic shock intensive care patients, 18 SARS-CoV-2 antibody-positive individuals, and 58 healthy controls. COVID-19 patients showed a distinct metabolic serum profile, including changes typical for severe dyslipidemia and a deeply altered metabolic status compared to healthy controls. Specifically, VLDL parameters, IDL particles, large-sized LDL particles, and the ApoB100/ApoA1 ratio were significantly increased, whereas HDL fractions were decreased. Moreover, a similarly perturbed profile was apparent, even when compared to other ICU patients suffering from cardiogenic shock, highlighting the impact of COVID-19 especially on lipid metabolism and energy status. COVID-19 patients were separated with an AUROC of 1.0 when compared to both healthy controls and cardiogenic shock patients. Anti-SARS-CoV-2 antibody-positive individuals without acute COVID-19 did not show a significantly perturbed metabolic profile compared to age- and sex-matched healthy controls, but SARS-CoV-2 antibody-titers correlated significantly with metabolic parameters, including levels of glycine, ApoA2, and small-sized LDL and HDL subfractions. Our data suggest that NMR metabolic profiles are suitable for COVID-19 patient stratification and post-treatment monitoring.

A Novel APTX Variant and Ataxia with Oculomotor Apraxia Type 1

No abstract available.