Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects.

Squamous cell carcinoma antigen recognized by T cells 3 (SART3) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in SART3 in nine individuals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Knockdown of the Drosophila orthologue of SART3 reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelic SART3 variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome (Intellectual disability, Neurodevelopmental defects and Developmental delay with 46,XY GONadal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for individuals born with this condition.

Procedural learning in Tourette syndrome, ADHD, and comorbid Tourette-ADHD: Evidence from a probabilistic sequence learning task.

Procedural memory, which is rooted in the basal ganglia, plays an important role in the implicit learning of motor and cognitive skills. Few studies have examined procedural learning in either Tourette syndrome (TS) or Attention Deficit Hyperactivity Disorder (ADHD), despite basal ganglia abnormalities in both of these neurodevelopmental disorders. We aimed to assess procedural learning in children with TS (n=13), ADHD (n=22), and comorbid TS-ADHD (n=20), as well as in typically developing children (n=21). Procedural learning was measured with a well-studied implicit probabilistic sequence learning task, the alternating serial reaction time task. All four groups showed evidence of sequence learning, and moreover did not differ from each other in sequence learning. This result, from the first study to examine procedural memory across TS, ADHD and comorbid TS-ADHD, is consistent with previous findings of intact procedural learning of sequences in both TS and ADHD. In contrast, some studies have found impaired procedural learning of non-sequential probabilistic categories in TS. This suggests that sequence learning may be spared in TS and ADHD, while at least some other forms of learning in procedural memory are impaired, at least in TS. Our findings indicate that disorders associated with basal ganglia abnormalities do not necessarily show procedural learning deficits, and provide a possible path for more effective diagnostic tools, and educational and training programs.

Tourette syndrome-associated psychopathology: roles of comorbid attention-deficit hyperactivity disorder and obsessive-compulsive disorder.

OBJECTIVE: Individuals with Tourette syndrome (TS) often display comorbid symptoms of attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD), as well as externalizing and internalizing behaviors. This study was aimed to examine the impacts of tic severity, ADHD symptoms, and OCD on internalizing (e.g., anxiety) and externalizing (e.g., aggression) psychopathology. METHODS: Using linear regressions, we examined how tics, ADHD, and OCD symptoms predicted the externalization and internalization behaviors measured by the Child Behavior Checklist in a clinical sample of children and adolescents with TS. In addition, Child Behavior Checklist scales were compared among children with TS without ADHD, TS and ADHD, ADHD without TS, and unaffected control group. RESULTS: In the TS group, externalizing behaviors were predicted by tic severity, inattention, and hyperactivity/impulsivity but not by OCD symptoms, whereas internalizing behaviors were predicted by inattention and OCD symptoms but not by tic severity or hyperactivity/impulsivity. Comparison among different clinical groups revealed main effects of TS and ADHD on both externalizing and internalizing behaviors. CONCLUSION: These findings suggest that tics, ADHD, and OCD symptoms differentially explain the variance in externalizing and internalizing behavioral problems in individuals with TS. In addition, the data support the notion that TS is itself a risk factor for behavioral problems, mandating that children with TS even without ADHD and OCD still need to be assessed and treated for psychopathology.

Factors influencing diagnosis delay in children with Tourette syndrome.

BACKGROUND: Tourette syndrome (TS) is a chronic disorder characterized by motor and vocal tics. Previous studies reported a substantial lag period between disease onset and diagnosis ranging from 3 to 11.9 years. AIMS: To determine the lag period and factors associated with diagnosis delay of TS. METHODS: All files of 185 children with TS attending one neuropediatric unit in Jerusalem were reviewed. Lag time between disease onset, according to DSM criteria, and diagnosis was determined and the contributions of the disease course, comorbidities and epidemiological factors were assessed. RESULTS: A relatively short lag to diagnosis following the onset of diagnosable TS was documented (mean 13.2+/-15.9 months, median 6 months). A relatively longer gap was associated with older age at TS onset (r=0.161, p<0.05) and vocal tics as the first manifestation rather than motor or combined motor and vocal tics (mean=20.3+16.3 months vs 11.9+16.5 and 12.6+15.2, respectively, p<0.05). A relatively shorter gap was associated with tic severity (r=0.13, p<0.05) and presence of comorbid obsessive-compulsive disorder (OCD) (9.5+14.7 months vs. 14.1+16 without OCD, p<0.05). CONCLUSIONS: Lag time to diagnosis is relatively short in our population. Factors associated with a shorter lag (early age of TS onset, motor tics as the first manifestation, greater tics severity and the presence of OCD) may be perceived as disruptive, prompting patient and families to seek medical care. Conversely, vocal tics as the first manifestation, associated with a longer lag, may be misdiagnosed as features of common pediatric conditions, thus delaying diagnosis.

The role of enzyme-linked immunosorbent assay D-dimer in patients with acute coronary syndrome presenting with normal cardiac enzymes.

Plasma D-dimer levels, the primary degradation product of cross-linked fibrin, are elevated in acute coronary syndrome (ACS). However, the role of D-dimer in patients presenting to the Emergency Department with ACS and normal cardiac enzymes is unknown. We conducted a prospective, observational study in the Emergency Department of a major tertiary university-affiliated center. The study included 124 patients presented to the Emergency Department with ACS and normal cardiac enzymes. Blood samples were collected and assayed for D-dimer levels with the enzyme-linked immunosorbent assay (ELISA) test. The D-dimer values were correlated with the clinical, laboratory and electrocardiographic findings on admission, as well as with the catheterization findings and with hospital length of stay. ELISA D-dimer levels positively correlated with sex, hypertension and smoking (r = -0.27, P = 0.002; r = 0.33, P = 0.0002; and r = -0.24, P = 0.007, respectively). Significant correlation was also observed between ELISA D-dimer and cardiac medications including beta-blocker (r = 0.22, P = 0.01), aspirin (r = 0.18, P = 0.04), nitrate (r = 0.20, P = 0.002), acute phase reactants fibrinogen (r = 0.45, P = 0.0001) and C-reactive protein (r = 0.29, P = 0.004), ischemic electrocardiographic changes (r = 0.21, P = 0.02) and length of stay (r = 0.29, P = 0.001). The catheterization findings were also correlated with the ELISA D-dimer levels (r = 0.31, P = 0.02). The ELISA D-dimer test may add important clinical data concerning patients with ACS and normal cardiac enzymes.

A rapid quantitative D-dimer assay at admission correlates with the severity of community acquired pneumonia.

Previous research has shown a link between infectious inflammatory processes and hemostatic abnormalities. No data exist, however, on whether coagulation markers correlate with the severity of community-acquired pneumonia (CAP) at admission. We conducted a prospective, observational study in an Emergency Medicine Department of a primary care hospital. Sixty-eight patients admitted with CAP were included. Blood samples were collected at admission and assayed for D-dimer levels. D-dimers were correlated with the Pneumonia Patient Outcome Research Team (PORT) score and Acute Physiology and Chronic Health Evaluation II score on admission, with length of hospital stay, number of organ failures, time to defervescence and hospital mortality. D-dimer levels were positively correlated with the Acute Physiology and Chronic Health Evaluation II score (r = 0.44, P = 0.0002), the PORT score (r = 0.36, P = 0.002) and the length of hospital stay (r = 0.24, P = 0.046). Mean D-dimer levels of patients for whom hospitalization is recommended, according to PORT guidelines, were significantly higher than D-dimer levels of patients for whom hospitalization is not recommended (1.47 +/- 1.05 microg/ml and 0.71 +/- 0.79 microg/ml respectively; P = 0.006). The correlation between D-dimer levels and time to defervescence, development of organ system failure and outcome was not statistically significant. We conclude that D-dimer levels at admission may predict the severity of CAP.