Copyright © 2019-2020, the authors.
AH: ORCiD 0000-0002-0335-984X
YW: ORCiD 0000-0001-5903-9370

Abstract

This is the sixth yearly article in the Tourette Syndrome Research Highlights series, summarizing research from 2019 relevant to Tourette syndrome and other tic disorders. The highlights from 2020 is being drafted on the Authorea online authoring platform; readers are encouraged to add references or give feedback on our selections comments feature on this page. After the calendar year ends, this article is submitted as the annual update for the Tics collection F1000Research.

Introduction

This article is meant to disseminate recent scientific progress on Gilles de la Tourette Syndrome (TS).

Methods

We searched PubMed from time to time during 2019 using the search strategy “("Tic Disorders"[MeSH] OR Tourette NOT Tourette[AU]) AND 2019[PDAT] NOT 1950:2018[PDAT]”.  Colleagues also recommended articles, and we attended selected medical conferences. We selected material for this review subjectively, guided by our judgment of possible future impact on the field.

Results

Phenomenology and natural history

\citet{30661132} present a stimulating argument based on data that demonstrate a severity continuum between chronic tics and TS using a database regrouping 1018 subjects. They thus conclude that TS and chronic tics do not represent distinct diagnostic categories. Accordingly, they suggest the introduction of the the term "tic spectrum disorders" (in analogy to autism spectrum disorders) which might present the added benefit of decreased social stigma related to TS.  
Martino and Hedderly provide an excellent review on the differences between tics and stereotypies, and their clinical management \citep*{30773283}
A useful resource is the video atlas of various vocalizations that includes tics and helps with differential diagnosis \citep{31651053}.

Epidemiology

Several good epidemiological studies and meta-analyses on the childhood prevalence of TS have been published over the past years, with most figures ranging between 0.5 to 0.8%, but they could be much higher. However, prevalence in adulthood remains unknown. Levine et al. analyzed three studies (published 1986, 2011 and 2016) involving 2,356,485 participants \citep{31220521}. Overall prevalence of TS in adulthood was estimated to be 118 cases of TS per million adults, that is  0.0118%. This appears very low, even factoring in remission in two thirds to three quarters of childhood cases during adulthood (which, in itself, is debatable). Clearly, more research is needed on this important topic, preferably using current DSM-5 criteria. 

Tic suppression

Forty-five children with tics starting on average only 3-4 months ago were assessed with clinical and psychological methods and reassessed at the 12-month anniversary of their first tic \citep{31241402}. Children who were less able at the first visit to suppress tics while given immediate rewards for 10-second tic-free intervals had worse clinical status (higher YGTSS total tic score) at the follow-up visit 6 to 9 months later. This finding adds to the meager prognostic clues available for Provisional Tic Disorder a simple, clinically relevant test.

Sensory phenomena and premonitory urges

Rae and colleagues provide a very thoroughly discussed computational model of how tics and premonitory sensations may be generated \citep{30890965}. The model links premonitory phenomena and tics to a hypothesized overly precise internal estimate of sensory information and predicted movement, and has the key advantage of generating some testable hypotheses. 

Other

David Mataix-Cols’ group continue their epidemiological exploration of patients with Tourette syndrome (TS) and chronic tic disorders (CTD) using the Swedish National Patient Register. This time, they looked for metabolic and cardiovascular disorders in these patients, and find that the risk is doubled compared to the general population, especially with regard to obesity, type 2 diabetes and circulatory system diseases. With regard to co-morbidities, the presence of attention-deficit / hyperactivity disorder significantly increased the risk (however, excluding ADHD does not normalize the risk, still 50% higher than in the general population). Most surprisingly, use of antipsychotic medication for more than one year was associated with a significantly decreased risk for metabolic and cardiovascular disorders in patients with TS or CTD. This counterintuitive finding, given antipsychotics’ propensity to induce metabolic syndrome, requires further clarification. For now, the authors speculate that patients with TS or CTD receiving medication benefit from frequent follow ups and better monitoring of their general health. In any case, this is a further demonstration, after papers on suicide and educational attainment in patients with TS or CTD, that chronic tic disorders are far from benign and require correct diagnosis, then regular care and follow up \citep{30640363}.

Etiology

Genetics

2019 has seen the publication of a variety of studies using whole exome sequencing. Depienne et al. \citep{Depienne2019} investigated 120 TS patients and identified disrupting variants of OPRK1, encoding the opioid kappa receptor, in a significant subset of subjects compared to controls. This result points to a role, discussed since the 1980s, of the opioid system as involved in the pathophysiology of TS and also suggest a new potential therapeutic target. 
After whole exome sequencing of 100 trios (TS patients and their parents), point mutations in ASH1 Like Histone Lysine Methyltransferase (ASH1L) causing defects in its enzymatic activity were identified as a susceptibility gene for TS \citep{31673123}, previously associated  with mental retardation and autism. A transgenic mouse line (Ash1l heterozygous mice) indeed displayed tic-like motor and compulsive behaviors, and dopaminergic hyperinnervation was observed in the dorsal striatum, demonstrating good construct validity for this model. 
Two more genes, chromodomain helicase DNA binding protein 8 (CHD8) and Signal Peptide, CUB Domain And EGF Like Domain Containing 1 (SCUBE1), were identified by whole exome sequencing in a cohort of 222 OCD parent-child trios, and it was further shown that these genes overlap with genes previously implicated in TS \citep{31771860}. Of note, Katayama et al. (2016) demonstrated that mice heterozygous for Chd8 mutations manifest ASD-like behavioral characteristics including increased anxiety, repetitive behavior, and altered social behavior behavior \citep{Katayama2016}.
Using the Swedish National Registry, it was shown that maternal polycystic ovary syndrome (PCOS), as a model for investigating the role of prenatal androgen exposure, is a risk for TS, ADHD and ASD \citep{30857571}. These results support a potential causal influence of prenatal androgen exposure on the development of male-predominant neuropsychiatric disorders in female offspring of women with PCOS.