CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants

Purpose To expand the recent description of a new neurodevelopmental syndrome related to alterations in CDK19. Methods Individuals were identified through international collaboration. Functional studies included autophosphorylation assays for CDK19 Gly28Arg and Tyr32His variants and in vivo zebrafish assays of the CDK19(G28R) and CDK19(Y32H). Results We describe 11 unrelated individuals (age range: 9 months to 14 years) with de novo missense variants mapped to the kinase domain of CDK19, including two recurrent changes at residues Tyr32 and Gly28. In vitro autophosphorylation and substrate phosphorylation assays revealed that kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein. Injection of CDK19 messenger RNA (mRNA) with either the Tyr32His or the Gly28Arg variants using in vivo zebrafish model significantly increased fraction of embryos with morphological abnormalities. Overall, the phenotype of the now 14 individuals with CDK19-related disorder includes universal developmental delay and facial dysmorphism, hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%). Conclusion CDK19 de novo missense variants are responsible for a novel neurodevelopmental disorder. Both kinase assay and zebrafish experiments showed that the pathogenetic mechanism may be more diverse than previously thought.Peer reviewe

Functional Visual Acuity of Early Presbyopia.

PURPOSE:To evaluate visual function in patients with early presbyopia using the functional visual acuity (FVA) test. METHODS:This study included 27 eyes of 27 healthy older volunteers (mean age, 44.1 ± 2.6 years) and 14 eyes of 14 healthy young volunteers (mean age, 28.4±4.8 years). The distance-corrected visual acuity (DCVA), distance-corrected near VA (DCNVA), subjective amplitude of accommodation (AA), and distance and near pupillary diameters were measured. The distance FVA and distance-corrected near FVA (DCNFVA) were measured using the FVA Measurement System. The standard Schirmer test and standard tear break-up time measurement also were performed. RESULTS:The logarithm of the minimum angle of resolution (logMAR) DCVA was better than 0 in all subjects. The percentages of subjects with logMAR DCNVA below 0 was significantly lower in the presbyopia group than in the young group. The DCNFVA in the presbyopia group was significantly (P < 0.001) poorer than the DCNVA in that group. Significant linear negative correlations were seen between the DCNVA and AA (r = -0.507, P < 0.001) and the DCNFVA and AA (r = -0.681, P < 0.001) in the older subjects. Stepwise regression analysis showed that only the AA was a significant factor predictive of the DCNFVA in the presbyopia group. Tear function parameters were not adopted in the regression model. CONCLUSIONS:Measurement of the DCNFVA can detect decreased AA in early presbyopia better than measurement of the conventional near VA. The DCNFVA is a good index for early presbyopia

Reducing Short-Wavelength Blue Light in Dry Eye Patients with Unstable Tear Film Improves Performance on Tests of Visual Acuity

<div><p>Purpose</p><p>To investigate whether suppression of blue light can improve visual function in patients with short tear break up time (BUT) dry eye (DE).</p><p>Methods</p><p>Twenty-two patients with short BUT DE (10 men, 12 women; mean age, 32.4 ± 6.4 years; age range, 23–43 years) and 18 healthy controls (10 men, 8 women; mean age, 30.1 ± 7.4 years; age range, 20–49 years) underwent functional visual acuity (VA) examinations with and without wearing eyeglasses with 50% blue light blocked lenses. The functional VA parameters were starting VA, functional VA, and visual maintenance ratio.</p><p>Results</p><p>The baseline mean values (logarithm of the minimum angle of resolution, logMAR) of functional VA and the visual maintenance ratio were significantly worse in the DE patients than in the controls (<i>P</i> < 0.05), while no significant difference was observed in the baseline starting VA (<i>P</i> > 0.05). The DE patients had significant improvement in mean functional VA and visual maintenance ratio while wearing the glasses (<i>P</i> < 0.05), while there were no significant changes with and without the glasses in the control group (<i>P</i> > 0.05),</p><p>Conclusions</p><p>Protecting the eyes from short-wavelength blue light may help to ameliorate visual impairment associated with tear instability in patients with DE. This finding represents a new concept, which is that the blue light exposure might be harmful to visual function in patients with short BUT DE.</p></div

Mechanism of the effect of the blue light blocked lens on visual function.

<p>Red and blue lines represent red and blue light, respectively. a. Unstable tear film without blue light blocked lens. The blue light is scattering. b. Unstable tear film with blue light blocked lens. The lens is blocking the blue light.</p

Functional visual acuity (VA) parameters with and without blue light blocked glasses.

<p>Functional visual acuity (VA) parameters with and without blue light blocked glasses.</p

Rayleigh scattering phenomenon.

<p>a. The red light passes through the skim milk in a glass. b. The blue light scatters and little of it passes through the skim milk in a glass.</p

Characteristics.

<p>Characteristics.</p

Correlations between the distance-corrected near visual acuity (DCNVA) and amplitude of accommodation (AA), the distance-corrected near functional visual acuity (DCNFVA), and AA in each group.

<p>The vertical axis shows the VA and the horizontal axis shows the AA. Significant linear correlations are seen in both of the presbyopia group’s combinations, and the slope of the linear regression between the DCNFVA and AA is steeper than between the DCNVA and AA. D, diopters.</p

A representative printout of typical functional visual acuity (VA) testing.

<p>The blue line denotes the Landolt corrected VA. The red line shows the time-wise changes in the VA during testing. The green line denotes the mean logarithm of the minimum angle of resolution (logMAR) over 60 seconds, defined as the functional VA. The yellow dots show the number of correct responses; the blue triangles indicate spontaneous blinks.</p