Biallelic CDK9 variants as a cause of a new multiple-malformation syndrome with retinal dystrophy mimicking the CHARGE syndrome.

CDK9 has been considered a candidate gene involved in the CHARGE-like syndrome in a pair of cousins. We report an 8-year-old boy with a strikingly similar phenotype including facial asymmetry, microtia with preauricular tags and bilateral hearing loss, cleft lip and palate, cardiac dysrhythmia, and undescended testes. Joint contracture, no finger flexion creases, and large halluces were the same as those of a previously reported patient with homozygous CDK9 variants. The ocular phenotype included blepharophimosis, lacrimal duct obstruction, eyelid dermoids, Duane syndrome-like abduction deficit, and congenital cataracts. Optical coherence tomography and electroretinography evaluations revealed severe retinal dystrophy had developed at an early age. Trio-based whole-exome sequencing identified compound heterozygous variants in CDK9 [p.(A288T) of maternal origin and p.(R303C) of paternal origin] in the patient. Variants' kinase activities were reduced compared with wild type. We concluded that CDK9 biallelic variants cause a CHARGE-like malformation syndrome with retinal dystrophy as a distinguishing feature.

Visual characteristics of children with Down syndrome.

PURPOSE: To analyze long-term visual development in children with Down syndrome who received early ophthalmological intervention. METHODS: A total of 125 children with Down syndrome who were examined before 6 years of age and followed up for more than 5 years were selected. Visual development, refraction, visual acuity testing, and the prescription of spectacles were examined retrospectively. RESULTS: Mean visual acuity by age was as follows: 2 years, 1.13 ± 0.23 logarithm of the minimum angle of resolution (logMAR); 5 years, 0.55 ± 0.25 logMAR; 8 years, 0.27 ± 0.19 logMAR; 11 years, 0.17 ± 0.16 logMAR; and 14 years, 0.10 ± 0.15 logMAR. In 32 children (25.6%), visual acuity reached 0.0 logMAR or better. Hyperopia of +2D or more was observed in 132 eyes (52.8%), and astigmatism of 2D or more was observed in 153 eyes (61.2%). Subjective testing was difficult in many children prior to 4.5 years of age, and grating acuity testing was necessary. Spectacles were prescribed at a mean age of 3.5 ± 1.6 years in 120 children (96.0%). The average duration until the spectacles were worn constantly was 9.0 ± 9.3 months. CONCLUSION: Early ophthalmological intervention and longitudinal care is important for children with Down syndrome.

Eyelash line resection for cilial entropion in patients with Down's syndrome.

AIM: To describe a surgical procedure for excising the eyelash line to treat cilial entropion in patients with Down's syndrome. METHODS: 24 Down's patients with cilial entropion and medial epiblepharon underwent eyelash line resection bilaterally. The area and density of fluorescein staining of the superficial punctate keratopathy (SPK; 0=none to 3=wide or severe) and the frequency of spectacle wear (0=no wear to 2=all day wear) were evaluated prospectively. RESULTS: The postoperative area and density of the SPK improved significantly in both eyes (p<0.001, p<0.001). The score of spectacle wear was 1.3 ± 0.8 preoperatively which improved significantly to 1.7 ± 0.5 after surgery (p=0.018). Five patients had a partial recurrence of misdirected eyelashes adjacent to the site of the excision. Two patients had extended excisions of the misdirected eyelashes 3 years after the initial surgery, and they did not have any further recurrences. Three other patients were followed without additional treatment because lacrimation and eye discharge were mild even with some eyelashes misdirected toward cornea. CONCLUSIONS: Eyelash line resection is a simple and effective technique for cilial entropion and medial epiblepharon in patients with Down's syndrome. The surgery improves the SPK and frequency of spectacle wear. TRIAL REGISTRATION NUMBER: NCT01758718.

Increased choroidal thickness in patient with high-altitude retinopathy.

We report a case of high-altitude retinopathy with increased choroidal thickness detected by spectral-domain optical coherence tomography (SD-OCT). A 36-year-old Japanese man developed an acute vision decrease in his left eye after he had trekked at an altitude of 4600 m in Tibet for 1 week. His visual acuity was 20/20 OD and 20/200 OS with refractive errors of - 0.25 diopters (D) OD and - 0.50 D OS 3 weeks after the onset of the visual decrease. Funduscopic examinations revealed multiple intraretinal hemorrhages bilaterally and a macular hemorrhage in the left eye. SD-OCT showed that the thickness of choroidal layer at the fovea was 530 µm OD and 490 µm OS which is thicker than that in normal subjects of approximately 300 µm. We suggest that the increase in the retinal blood flow under hypoxic conditions may be associated with an increase in the choroidal blood flow resulting in an increase in choroidal thickness.

[Ocular findings in 304 children with Down syndrome].

PURPOSE: To identify the characteristics and frequency of ocular findings in Japanese children with Down syndrome. METHODS: A total of 304 Japanese children with Down syndrome at an average age of 7 years and 4 months were examined for ocular findings from June 2009 to January 2011. RESULTS: Most had hyperopia (69.1%) and astigmatism (58.5%). Both normal and oblique astigmatism were common. Spectacles were necessary in 91.3%. The average visual acuity at 8 years was 0.305 logMAR. Under 6 years, stripe and picture visual acuity charts were useful. Strabismus (36.5%, esotorpia 23.3%), nystagmus (25.7%), stereopsis (46.0%), entropion of eyelids (18.8%), cataract (10.5%), and corneal disease (3 cases) were found. Medullated nerve fibers (3 cases), pseudo disc edema (2 cases), and other retinal changes including Leber congenital amaurosis like chorioretinal degeneration (3 cases) were also found. CONCLUSION: The high incidence of refractive errors and strabisums in Down syndrome were confirmed. These must be treated during the sensitive period of visual development. For other ocular findings intensive ophthalmic care is important for children with Down syndrome from the time of infancy.

[Long-term observation over ten years of four cases of cone dystrophy with supernormal rod electroretinogram].

BACKGROUND: 'Cone dystrophy with a supernormal rod electroretinogram (ERG)' is rare form of cone dystrophy, and no longitudinal description of the disease course has been reported in a Japanese population. Here, we describe long-term courses of 10 to 15 years in four Japanese patients with mutations in the KCNV2 gene. CASES: Four patients from three families were recruited. Two were siblings (Case 1, 24 y/o women; Case 2, 17 y/o man), and two were sporadic cases (Case 3, 17 y/o women; Case 4, 21 y/o women). All the patients presented with characteristic ERG findings. There were minimal abnormalities in fundus appearance: slight mottling of retinal pigment epithelium in the macula in all four cases, and granular change in the macula in Case 4. The visual acuity in Cases 1 and 2 did not change during the follow-up period, but the acuity in Cases 3 and 4 gradually decreased. Photoreceptor abnormalities in optical coherence tomography were found in all the cases, but were more severe in Cases 3 and 4. CONCLUSION: The long-term courses in Japanese patients were variable. The OCT was helpful in evaluating the disease progression.

Molecular characteristics of four Japanese cases with KCNV2 retinopathy: report of novel disease-causing variants.

PURPOSE: To describe the molecular characteristics of four Japanese patients with cone dystrophy with supernormal rod responses (CDSRR). METHODS: Four individuals with a clinical and electrophysiological diagnosis of CDSRR were ascertained. The pathognomonic findings of the full-field electroretinograms (ERGs) included a decrease in the rod responses, a square-shaped a-wave, an excessive increase in the b-wave in the bright flash responses, and decreased cone-derived responses. Mutational screening of the coding regions and flanking intronic sequences of the potassium channel, subfamily V, member 2 (KCNV2) gene was performed with bidirectional sequencing. The segregation of each allele was confirmed by screening other family members. Subsequent in silico analyses of the mutational consequences for protein function were performed. RESULTS: There were two siblings from one family and one case in each of the two families. One family had a consanguineous marriage. Mutational screening revealed compound heterozygosity for the two alleles, p.C177R and p.G461R, in three patients, and homozygosity for complex alleles, p.R27H and p.R206P, in one patient from the consanguineous family. There were three putative novel variants, p.R27H, p.C177R, and p.R206P. The four variants in the families with KCNV2 were highly conserved in other species. In silico analyses predicted that all of the missense variants would alter protein function. CONCLUSIONS: Biallelic disease-causing variants were identified in four Japanese patients with CDSRR suggesting that the pathognomonic electrophysiological features are helpful in making a molecular diagnosis of KCNV2. Three novel variants were identified, and we conclude that there may be a distinct spectrum of KCNV2 alleles in the Japanese population.

Multiple patterns of spatiotemporal changes in layer-specific gene expression in the developing visual cortex of higher mammals.

The mammalian cerebral cortex, which is stratified into six layers, has functional domains that vertically span the six layers, thereby requiring tight interlaminar connectivity within a domain. The synaptic connections in individual layers are first broadly formed under predetermined programs and later reinforced between neurons which reside in the same functional domain via experience-dependent reorganization during the critical period. However, the molecular mechanisms that control these two processes within each layer are still unclear. Therefore, we performed a differential screen for candidates and found seven genes with layer-specific expression during postnatal development of cat visual cortex. APLP1, a transmembrane protein mediating synaptogenesis, started dual-layer expression in layers 2/3 and 5 before the critical period, suggesting that it might execute coarse synapse formation of these layers. STMN2 (SCG10), which promotes microtubule turnover, was unique, as it dramatically shifted its dual-layer distribution from layers 2/3 and 5 to the deeper layers 4 and 6 at the onset of the critical period; it lost this new expression pattern in the adult. Surprisingly, brief dark rearing disturbed the shift in its dual-layer distribution around the onset of the critical period. Thus, by accelerating structural remodeling, STMN2 (SCG10) might launch experience-dependent reorganization of particular layers.

English vowel spaces produced by Japanese speakers: the smaller point vowels' and the greater schwas'.

This study investigated how Japanese-speaking learners of English pronounce the three point vowels /i/, /u/, and /a/ appearing in the first and second monosyllabic words of English noun phrases, and the schwa /ə/ appearing in English disyllabic words. First and second formant (F1 and F2) values were measured for four Japanese speakers and two American English speakers. The hypothesis that the area encompassed by the point vowels in the F1-F2 vowel space tends to be smaller for the Japanese speakers than for the English speakers was verified. The hypothesis that the area formed by the three schwas in chicke_n, spoonfu_l, and Tarza_n is greater for the Japanese speakers than for the English speakers and its related hypothesis were largely upheld. Implications for further research are briefly discussed.