Use of VIsual Psychophysical and Electrophysiological Tests for the evaluation of different dystrophins in patients with Duchenne Muscular Dystrophy

• Grant number: 23/08095-2
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2024
• End date: December 31, 2025
• Field of knowledge: Humanities - Psychology - Physiological Psychology
• Principal Investigator: Dora Selma Fix Ventura
• Grantee: Alódia Brasil Costa
• Host Institution: Instituto de Psicologia (IP). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 22/00191-0 - Mechanisms, genetics and performance of the visual system: clinical research in humans and animal experiments, AP.TEM

Abstract

Duchenne Muscular Dystrophy (DMD) is caused by the alteration of dystrophin proteins (Blake et al., 2002; Blake and Kröger, 2000). Of the five known dystrophin proteins, four are present in the retina: Dp427, Dp260, Dp140, and Dp71 (Bar et al., 1990; Byers, Lidov, and Kunkel, 1993; D'Souza et al., 1995; Pillers et al., 1993). The different dystrophins occupy retinal locations in the various cellular layers, such as the terminal of the photoreceptor cells, the outer plexiform layer, bipolar and horizontal cells that receive information from cone and rod photoreceptors, as well as in the retinal blood vessels, and Müller glial cells (Blank et al., 1999; Ueda et al., 1995, 1997). The role of the different dystrophin proteins in retinal physiology is still poorly understood. Dp71, the smallest product of the DMD gene, is expressed by Müller glial cells, astrocytes in the internal limiting membrane (ILM), and in the retinal blood vessels (Austin et al., 2000). Alterations in the expression of dystrophin proteins in the retina are reflected in the full-field electroretinogram (ERG) (Cibis et al., 1993; Pillers et al., 1993) and in visual functions whose processing is carried out by the central areas of the retina, such as color vision and sensitivity to temporal and spatial contrast (Barboni et al., 2016; Costa et al., 2007; Costa, Barboni, and Ventura, 2011). In the full-field ERG, there is a decrease in the b-wave in patients with alterations in multiple dystrophin proteins. Patients with genetic alterations affecting the expression of the Dp71 protein have been observed to have a more altered full-field ERG compared to other DMD patients (Ricotti et al., 2016). On the other hand, surprising results were obtained in five patients with genetic alterations affecting Dp71 expression, showing a normal course of dark adaptation and normal sensitivity of rod photoreceptors, while there is clear loss of sensitivity in patients with Dp260 alteration but preserved Dp71. Given the relevance of the ERG as a biomarker for DMD in the retina, the project will explore the available protocols of full-field ERG to assess the functional weight of different cellular types and processing pathways in the retina dependent on the integrity of Dp71, and compare them with those dependent on the integrity of Dp260, which are better known. If possible, the analysis will be extended to the other dystrophin proteins. The application of functional tests that subjectively evaluate (psychophysical tests) and objectively evaluate (multifocal ERG) the function of central regions of the retina (macula) associated with morphological evaluation of the macula through optical coherence tomography (OCT) will allow understanding whether retinopathy in DMD would be characterized by dysfunctions that asymmetrically compromise central and peripheral regions of the retina. The roles played by dystrophin proteins in the retina have not yet been elucidated, leading us to suppose that the use of more sensitive protocols to stimulate retinal mechanisms will identify losses caused by this rare alteration.