Ólafur Thorarensen

OBJECTIVE: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. METHODS: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. RESULTS: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. CONCLUSIONS: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.

Activated protein C resistance caused by an Arg506Gln mutation in the factor V gene (factor V Leiden mutation) is the most common cause of familial thrombosis. This mutation is associated with arterial and venous thromboembolic disease in neonates, infants, and children, but is not a significant risk factor for ischemic stroke in adults. We report on 3 babies with different neonatal cerebrovascular disorders including ischemic infarction and hemorrhagic stroke who are heterozygous for factor V Leiden mutation. One infant had multiple thrombi in the fetal placental vasculature. This is the first reported association between hemiplegic cerebral palsy, placental thrombosis, and factor V Leiden mutation. We suspect that activated protein C resistance may be an important cause of in utero cerebrovascular disease and hemiplegic cerebral palsy.

AIM: To describe trends in cerebral palsy (CP) prevalence, severity, and associated impairments among 139 Icelandic children (65 males, 74 females) born from 1990 to 1996 (period one) and 1997 to 2003 (period two). METHOD: A population-based study using systematically collected data on motor functioning and associated impairments of children with CP. Mean age at assessment was 5 years 5 months (SD 7.68 mo) in period one and 5 years 5 months (SD 10.44 mo) in period two. Infants with postneonatal CP were excluded. RESULTS: Prevalence of CP per 1000 live births was 2.2 in period one and 2.3 in period two (p=0.862); it decreased from 1.5 to 0.9 for children born at term, was stable for preterm births, but increased from 33.7 to 114.6 for very preterm births (p=0.002). Concurrently, neonatal and infant mortality rates decreased in Iceland. The proportion of children born preterm increased over time (p=0.002), whereas improvements in gross motor function assessed with the Gross Motor Function Classification System were confined to term births (p=0.009). The proportion of children with diplegia increased, accompanied by a decrease in the proportion with quadriplegia (p=0.047). Furthermore, among term births there was a significant reduction over time in the proportion of children with epilepsy (p=0.030) and in the proportion with two or more associated impairments (p=0.030). INTERPRETATION: Although CP prevalence remained stable over 14 years, we observed a decrease in prevalence and severity of the disability among term births.