Functional characterization of rare RAB12 variants and their role in musician’s and other dystonias

Mutations in RAB (member of the Ras superfamily) genes are increasingly recognized as cause of a variety of disorders including neurological conditions. While musician’s dystonia (MD) and writer’s dystonia (WD) are task-specific movement disorders, other dystonias persistently affect postures as in cervical dystonia. Little is known about the underlying etiology. Next-generation sequencing revealed a rare missense variant (c.586A>G; p.Ile196Val) in RAB12 in two of three MD/WD families. Next, we tested 916 additional dystonia patients; 512 Parkinson’s disease patients; and 461 healthy controls for RAB12 variants and identified 10 additional carriers of rare missense changes among dystonia patients (1.1%) but only one carrier in non-dystonic individuals (0.1%; p = 0.005). The detected variants among index patients comprised p.Ile196Val (n = 6); p.Ala174Thr (n = 3); p.Gly13Asp; p.Ala148Thr; and p.Arg181Gln in patients with MD; cervical dystonia; or WD. Two relatives of MD patients with WD also carried p.Ile196Val. The two variants identified in MD patients (p.Ile196Val; p.Gly13Asp) were characterized on endogenous levels in patient-derived fibroblasts and in two RAB12-overexpressing cell models. The ability to hydrolyze guanosine triphosphate (GTP), so called GTPase activity, was increased in mutants compared to wildtype. Furthermore, subcellular distribution of RAB12 in mutants was altered in fibroblasts. Soluble Transferrin receptor 1 levels were reduced in the blood of all three tested p.Ile196Val carriers. In conclusion, we demonstrate an enrichment of missense changes among dystonia patients. Functional characterization revealed altered enzyme activity and lysosomal distribution in mutants suggesting a contribution of RAB12 variants to MD and other dystonias

Learning volition: A longitudinal study of developing intentional awareness in Tourette syndrome

Tourette syndrome (TS) is characterized by the presence of involuntary movements (tics) which are, at least partly, generated within ‘voluntary’ motor pathways. Here we reassess 16 TS patients (age 19 ± 2.3 years) who participated in a mental chronometry study of volition 5.5 years previously (Ganos C et al. Cortex. 2015 Mar.; 64:47–54), and 16 age-matched controls. Participants estimated the time of their own voluntary movements (Libet's M judgement), or of conscious intention to make voluntary movements (Libet's W judgement), in separate blocks. We considered M judgement as a control condition. Therefore, the experience of an intention to move occurring prior to actual movement onset, as measured by the W-M gap, was taken as the cardinal feature of volition. Time estimates of the TS group did not differ significantly from controls, for either M or W judgement. Further, M and W time estimates in the TS group had not changed significantly between the two assessments. However, exploratory analyses revealed a strong relation between disease duration and the development of M- and W-judgements: the longer was the disease duration, the less was the developmental increase in the W-M gap (linear regression, p = .003). In conclusion, our results suggest compromised development of experience of volition in developing TS patients. The developmental difficulty in processing internal premotor signals for voluntary actions could reflect the chronic persistence of tics from adolescence to adulthood

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Application of Multivariate Analysis to Gas-Phase Spectroscopy at 245 GHz

This paper describes the application of multivariate analysis (MVA) techniques to terahertz (THz) gas-phase absorption spectra at around 245 GHz. The THz spectra of gaseous volatile organic compounds (VOCs) and their complex mixtures at pressures between 10 and 5000 Pa were acquired with a vector network analyzer (VNA) and an absorption cell. With the subsequent MVA our experiment shows the feasibility of qualitative and quantitative substance identification. Since the tested VOCs are biomarkers and/or can be found on the EPA (US Environmental Protection Agency) list of harmful substances there is a potential for application in medicine and security. In particular because our measurements show that there is no need of measuring in the Doppler limit

Terahertz Gas-Sensors: Gas-Phase Spectroscopy and Multivariate Analysis for Medical and Security Applications

We developed a terahertz (THz) gas-phase spectrometer based on transmitter(TX)- and subharmonic receiver(RX)-chips fabricated in SiGe BiCMOS. A tunable TX and TX-array for 245 GHz with output powers of Pout=0dBm and 7dBm and a 500 GHz TX-array with Pout=-7dBm acts as tunable narrow band radiation sources. The THz beam is detected by the heterodyne RX. The high-resolution 2f-spectra were obtained by TX-frequency modulation and lock-in amplification of the RXs’ intermediate frequency (IF). The fingerprint-like spectra support a substance detection with absolute specifity, which we confirmed in our foregoing study by using multivariate algorithms (MVA) like principal components analysis (PCA) and partial least squares regression (PLS). We tested volatile organic compounds (VOCs) known as biomarkers and/or are classified as harmful by the EPA. We found a 100% qualitative substance detection and 2% mass fraction accuracy for the components in mixtures we prepared

Terahertz gas-phase spectroscopy: chemometrics for security and medical applications

We describe a spectrometer consisting of a vector network analyser, a gas absorption cell, and a quasi-optical bench that acquires terahertz spectra of gaseous substances and mixtures. We tested volatile organic compounds that are medical biomarkers or chemicals which can be found on the US Environment Protection Agency list of harmful substances. Absorption spectra at gas pressures between 10 Pa and 5000 Pa were recorded. A subsequent multivariate data analysis demonstrated excellent qualitative and quantitative identification of pure substances and complex mixtures. The applied multivariate algorithms are Principal Components Analysis, Partial Least Square regression and Soft Independent Modelling of Class Analogy

Tunable 245 GHz transmitter and receiver in SiGe technology for gas spectroscopy

A 245 GHz sensor system for gas spectroscopy is presented, which includes an integrated SiGe transmitter (TX) and receiver (RX), and a 0.6 m-long gas absorption cell between the TX and RX modules. The integrated local oscillators (LOs) of TX and RX chips are controlled by two external phase-locked loops (PLLs), whose reference frequencies are swept with constant frequency offset for a low intermediate frequency of the RX. The RX consists of a differential low-noise amplifier, an integrated 122 GHz LO with a 1/64 divider, a 90° differential hybrid and an active subharmonic mixer. The TX consists of an integrated 122 GHz LO with a 1/64 divider, and a frequency doubler. The TX and RX chips are fabricated in 0.13 μm SiGe BiCMOS technology with fT/fmax of 300 GHz/500 GHz. Using external dielectric lenses for the TX and RX modules, the gas absorption spectra were measured for acetonitrile and methanol

245 GHz Transmitter and Receiver in SiGe for Gas Spectroscopy

A 245 GHz sensor system for gas spectroscopy is presented, which includes a SiGe transmitter (TX) and a receiver (RX). The integrated local oscillators of TX- and RX-chips are controlled by two external phase-locked loops (PLL), whose reference frequencies are swept with constant frequency offset. The reference frequency of the TX-PLL is modulated for frequency-modulation spectroscopy. The performance of the sensor system is demonstrated by the 2f absorption spectrum (second harmonic detection) of methanol

Gas Spectroscopy System at 245 and 500 GHz using Transmitters and Receivers in SiGe BiCMOS

A compact gas spectroscopy system is demonstrated, which contains a transmitter (TX) and a receiver (RX) in SiGe BiCMOS, as well as a gas absorption cell. The sensitivity of this spectroscopy system is demonstrated by measuring the high-resolution 2f absorption spectrum (second harmonic detection) of gaseous methanol (CH3OH) at 238 – 252 GHz, and at 495 – 497 GHz. The 245 GHz TX consists of a 120 GHz local oscillator (LO) and a frequency doubler, and the 245 GHz RX includes a low noise amplifier (LNA), a LO, and an active subharmonic mixer. A 245 GHz TX-array increases significantly the sensitivity of the sensor system. The 500 GHz system includes a TX-array, and a subharmonic RX with a transconductance mixer. The 500 GHz TX contains a frequency quadrupler, and the RX uses a frequency doubler for the LO. The LOs of the RX and the TX are controlled by two external phase-locked loops (PLLs)

Gas Spectroscopy System for Breath Analysis at mm-wave/THz Using SiGe BiCMOS Circuits

The unique fingerprint spectra of volatile organic compounds for breath analysis and toxic industrial chemicals make an mm-wave (mmW)/THz gas sensor very specific and sensitive. This paper reviews and updates results of our recent work on sensor systems for gas spectroscopy based on integrated transmitter (TX) and receiver (RX), which are developed and fabricated in IHP’s 0.13 µm SiGe BiCMOS technology. In this paper, we present an mmW/THz spectroscopic system including a folded gas absorption cell of 1.9 m length between the TX and RX modules. We discuss the results and specifications of our sensor system based on integrated TX and RX. We demonstrate TXs and RXs with integrated antennas for spectroscopy at 238-252 GHz and 494-500 GHz using integer-N phase-locked loops (PLLs). We present a compact system by using fractional-N PLLs allowing frequency ramps for the TX and RX, and for TX with superimposed frequency shift keying or reference frequency modulation. In another configuration, the voltage controlled oscillators of the TX and RX local oscillator are tuned directly without PLLs by applying external voltages. Further developments of our system are aimed at realizing an even wider frequency span by switching between frequency bands, and to use a more compact gas absorption cell