Exome sequencing in paediatric patients with movement disorders.

BACKGROUND: Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. RESULTS: We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. CONCLUSIONS: A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

Long-term lutein administration attenuates retinal inflammation and functional deficits in early diabetic retinopathy using the Ins2Akita/+ mice.

INTRODUCTION: Lutein is a carotenoid whose protective effects in the retina have been reported in various studies. The effect of lutein has not been reported in the retina of the Ins2Akita/+ mouse, a well-characterized genetic model for diabetic retinopathy (DR) in which the etiology of diabetes is better defined than the chemically induced diabetes. The objective of the present study is to investigate the effect of long-term administration of lutein in early stages of DR using the Ins2Akita/+ mouse. RESEARCH DESIGN AND METHODS: Heterozygous male Ins2Akita/+ and age-matched wild-type mice were used. Lutein was administered to the mice in drinking water starting 6 weeks old daily until analysis at 4.5, 6.5 or 9 months of age. Plain water served as non-treatment control. Microglia were immunostained with ionized calcium-binding adapter molecule 1 (Iba-1) and cluster of differentiation 68 (CD68) in retinal flat-mounts. Vascular endothelial growth factor (VEGF) level in the retina was assessed by enzyme-linked immunosorbent assay (ELISA). Vascular permeability was analyzed in retinal flat-mounts after fluorescein isothiocyanate (FITC)-dextran perfusion. Retinal occludin expression was assessed via Western blots. Retinal function was examined by electroretinography (ERG). RESULTS: Increased microglial reactivity was detected in the Ins2Akita/+ mouse retina and was suppressed by lutein. Lutein administration also reduced the upregulation of VEGF in the Ins2Akita/+ mouse retina. Increased vascular leakage and decreased occludin expression were observed in the Ins2Akita/+ mouse retina, and these alterations were attenuated by lutein treatment. ERG recordings showed reduced a-wave and b-wave amplitudes in the Ins2Akita/+ mice. With lutein treatment, the ERG deficits were significantly alleviated. CONCLUSIONS: We showed beneficial effects of long-term lutein administration in the Ins2Akita/+ mouse retina, including suppression of retinal inflammation, protection of retinal vasculature and preservation of retinal function. These results point to lutein's potential as a long-term therapeutic intervention for prevention of inflammation and retinal degeneration in patients with early DR.