Ubiquitin C-terminal hydrolase-L1 (UCHL1), a neuron-specific deubiquitinating enzyme, is one of the most abundant proteins in the brain. We describe three siblings from a consanguineous union with a previously unreported early-onset progressive neurodegenerative syndrome featuring childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfuction, and spasticity with upper motor neuron dysfunction. Through homozygosity mapping of the affected individuals followed by whole-exome sequencing of the index case, we identified a previously undescribed homozygous missense mutation within the ubiquitin binding domain of UCHL1 (UCHL1 GLU7ALA ), shared by all affected subjects. As demonstrated by isothermal titration calorimetry, purified UCHL1 GLU7ALA , compared with WT, exhibited at least sevenfold reduced affinity for ubiquitin. In vitro, the mutation led to a near complete loss of UCHL1 hydrolase activity. The GLU7ALA variant is predicted to interfere with the substrate binding by restricting the proper positioning of the substrate for tunneling underneath the cross-over loop spanning the catalytic cleft of UCHL1. This interference with substrate binding, combined with near complete loss of hydrolase activity, resulted in a >100-fold reduction in the efficiency of UCHL1 GLU7ALA relative to WT. These findings demonstrate a broad requirement of UCHL1 in the maintenance of the nervous system. protein quality control | recessive inherited neurodegeneration

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This is the largest case-control study of CSC to evaluate demographic morphological characteristics and risk factors. Multiple factors are associated with CSC.

ABSTRACT.Purpose: To evaluate the anatomic and visual outcomes of intravitreal triamcinolone acetonide injection in patients with cystoid macular oedema (CMO) secondary to retinitis pigmentosa (RP). Methods: Five eyes of five patients with CMO secondary to RP, aged 25-41 years (mean 33.2 years) made up the study population. All eyes had persistent CMO despite medical treatment with 250 mg of oral acetazolamide twice daily for 1 month. Intravitreal injection of 4 mg (0.1 ml) triamcinolone acetonide was offered to treat macular oedema. The visual and anatomic responses were observed, as well as complications related to the injection procedure and corticosteroid medication. Results: Follow-up periods varied between 6 and 8 months (mean 6.8 months); all patients completed 6 months of follow-up. After intravitreal triamcinolone acetonide injection all patients showed good anatomic response. The baseline median central macular thickness was 418 mm (range 376-626 mm). At 1 month, the median central macular thickness had decreased to 224 mm (range 214-326 mm). At 3 and 6 months, the median central macular thicknesses were 275 mm (range 215-584 mm) and 312 mm (range 239-521 mm), respectively. Recurrent CMO was found in one patient at the 3-month follow-up and in two patients at the 6-month follow-up. Retreatment was performed in these patients. At the 1-month follow-up, no patient was found to have lost vision and two patients showed improvement. At the 3-and 6-month follow-ups, no patient had lost vision from baseline but no patient had maintained their improved visual acuity (VA). Conclusions: In our small series, all patients showed an anatomic improvement in CMO after intravitreal injection of triamcinolone acetonide. However, in three out of five patients, despite good anatomic results, no improvement in VA was achieved. Because of the limitations of this pilot study, it is difficult to explain why no improvement in VA was achieved despite good anatomic results in some patients. Further study with longer follow-up periods and larger series is warranted to assess the efficacy of the treatment.

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