‘Essential Tremor’ Phenotype in FMR1 Premutation/Gray Zone Sibling Series: Exploring Possible Genetic Modifiers

Fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in carriers of fragile X mental retardation 1 (FMR1) X-linked small CGG expansion (gray zone [GZ] and premutation [PM]) alleles, containing 41–200 repeats. Major features comprise kinetic tremor, gait ataxia, cognitive decline and cerebellar peduncular white matter lesions, but atypical/incomplete FXTAS may occur. We explored the possibility of polygenic effects modifying the FXTAS spectrum phenotypes. We used three motor scales and selected cognitive tests in a series of three males and three females from a single sibship carrying PM or GZ alleles (44 to 75 repeats). The molecular profiles from these siblings were determined by genomewide association study with single-nucleotide polymorphism (SNP) genotyping by Illumina Global Screening Array. Nonparametric linkage analysis was applied and Parkinson’s disease (PD) polygenic risk scores (PRSs) were calculated for all the siblings, based on 107 known risk variants. All male and female siblings manifested similar kinetic tremor phenotypes. In contrast to FXTAS, they showed negligible gait ataxia, and few white matter lesions on MRI. Cognitive functioning was unaffected. Suggestive evidence of linkage to a broad region of the short arm of chromosome 10 was obtained, and median PD PRS for the sibship fell within the top 30% of a sample of over 500,000 UK and Australian controls. The genomewide study results are suggestive of modifying effects of genetic risk loci linked to PD, on the neurological phenotype of FMR1-CGG small expansion carriers, resulting in an oligosymptomatic kinetic tremor seen in FXTAS spectrum, but also consistent with essential tremor.

Tremor

Tremor is broadly classified into physiological tremor and pathological tremor. Depending on the clinical features and the predominant pattern of production, tremor is classified into resting tremor, postural tremor, and kinetic tremor. Tremor is associated with rhythmic contraction of agonist and antagonist muscles, either alternately or simultaneously. Tremor involving muscles in the resting condition is called resting tremor and is seen most commonly in Parkinson disease. Tremor involving muscles during isometric contraction is called postural tremor, and it is most commonly seen in essential tremor. Tremor involving muscles during intended movements (isotonic contraction) is called kinetic tremor, and it is most commonly seen in a lesion of the cerebellar efferent pathway.

A Multimodal Approach to the Quantification of Kinetic Tremor in Parkinson’s Disease

Parkinson’s disease results in motor impairment that deteriorates patients’ quality of life. One of the symptoms negatively interfering with daily activities is kinetic tremor which should be measured to monitor the outcome of therapy. A new instrumented method of quantification of the kinetic tremor is proposed, based on the analysis of circles drawn on a digitizing tablet by a patient. The aim of this approach is to obtain a tremor scoring equivalent to that performed by trained clinicians. Models are trained with the least absolute shrinkage and selection operator (LASSO) method to predict the tremor scores on the basis of the parameters computed from the patients’ drawings. Signal parametrization is derived from both expert knowledge and the response of an artificial neural network to the raw data, thus the approach was named multimodal. The fitted models are eventually combined into model ensembles that provide aggregated scores of the kinetic tremor captured in the drawings. The method was verified with a set of clinical data acquired from 64 Parkinson’s disease patients. Automated and objective quantification of the kinetic tremor with the presented approach yielded promising results, as the Pearson’s correlations between the visual ratings of tremor and the model predictions ranged from 0.839 to 0.890 in the best-performing models.

Quantitative Analysis of Parkinsonian Tremor in a Clinical Setting Using Inertial Measurement Units

Background. Parkinson’s disease (PD) is a neurodegenerative disorder that affects human voluntary movements. Tremor is one of the most common symptoms of PD and is expressed as involuntary oscillation of the body. Tremors can be analysed in the frequency domain. Objective. The aim of the current study was to examine selected tremor parameters (frequency, root mean square, and approximated entropy) in order to quantify the characteristics of patients diagnosed with PD, compared to a healthy control group, and to compare the parameters by dividing the subjects according to UPDRS assessment. Methods. The subjects were divided into two groups: a group of people diagnosed with PD (n = 19) and a control group consisting of healthy volunteers (CO = 12). Each subject performed motor tasks specific to certain tremors: the finger-to-nose test. Each subject performed a motor task three times. A nine degree of freedom (DOF) wireless inertial measurement unit was used for the measurement of upper limb motor tasks. For the quantitative estimation of kinetic and postural tremors, dominant frequency, root means square, and approximation entropy were selected and calculated from the measured angular velocity and linear acceleration signals. A one-way ANOVA with a significance level of α = 0.05 was used to test the null hypothesis that the means of the tremor metrics were the same between the PD and CO groups. Results. Statistically significant differences between PD patients and control groups were observed in ApEn acceleration signal of kinetic tremor, ApEn angular velocity signal of kinetic tremor, ApEn angular velocity of postural tremor, frequency acceleration signal of postural tremor, and RMS angular speed kinetic tremor. Conclusion. Application of inertial measurement units for clinical research of patients and PD tremor evaluation allows providing quantitative information for diagnostic purposes, during screening in a clinical setting that differentiates between PD patients and controls.

Movement Disorders 1: Tourette’s Syndrome, Essential Tremor, and Parkinson’s Disease (DRAFT)

The video in this chapter explores movement disorders, and focuses on Tourette’s Syndrome, Essential tremor, and Parkinson’s Disease. It outlines the characteristics of each, such as motor and vocal tics in Tourette’s Syndrome, postural or kinetic tremor in Essential tremor, and the four hallmark features of Parkinson’s Disease (bradykinesia, resting tremor, cogwheel rigidity, and postural instability).