Extra-muscle involvement in dystrophinopathies: an electroretinography and evoked potential study

Girlanda, Paolo; Quartarone, Angelo; Buceti, R; Sinicropi, S.; Macaione, Vincenzo; Saad, Fawzy A.; Messina, Lorenzo; Danieli, Gian Antonio; Ferreri, Giuseppe; Vita, Giuseppe

doi:10.1016/s0022-510x(96)00292-4

Cited by 27 publications

(32 citation statements)

References 31 publications

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“…These changes have also been consistently seen in DMD patients 16,46 ( Table 2). The recent discovery of additional Dp427 mRNA closer to the inner nuclear layer in mice (likely in OFF-bipolar and amacrine cells 4 ) may indicate its involvement in amacrine-OFF-bipolar cell feedback interactions, touted to be the likely generators of the OPs.…”

Section: Rod-mediated Function In MDX 3cvsupporting

confidence: 66%

“…57 Otherwise, the STR would be halved, as seen in mice lacking the principal inward rectifying Kir4.1 channels that underlie K þ buffering. 58 Clinically normal pattern-reversal visual evoked potentials (an indirect indicator of intact optic nerve and RGC function 59 ) in DMD patients 46,60 are also consistent with the notion that RGC activity is not directly affected in the disease.…”

Section: Rod-mediated Function In MDX 3cvsupporting

confidence: 53%

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Asymmetrical Functional Deficits of ON and OFF Retinal Processing in the mdx^3Cv Mouse Model of Duchenne Muscular Dystrophy

Tsai

Barboni

Nagy

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Tsai TI, Barboni MTS, Nagy BV, et al. Asymmetrical functional deficits of ON and OFF retinal processing in the mdx 3Cv mouse model of Duchenne muscular dystrophy. Invest Ophthalmol Vis Sci. 2016;57:5788-5798. DOI:10.1167/ iovs.16-19432 PURPOSE. The dystrophin mouse mutant mdx 3Cv exhibits scotopic electroretinograpic (ERG) abnormalities, which resemble clinical changes observed in Duchenne muscular dystrophy (DMD) patients. In the present study, ERGs obtained from mdx 3Cv and their wild-type littermates under scotopic, mesopic, and photopic conditions were analyzed to provide further insight on the affected retinal pathways, and to compare them with human data. METHODS.Electroretinograms of mdx 3Cv (n ¼ 9) and age-matched C57BL/6J mice (n ¼ 10) included the scotopic full-field flash (for outer retinal deficits in rod pathway), scotopic threshold response (for inner retinal integrity), photopic flash, sinusoidal flicker (for outer retinal deficits in cone pathway), mesopic rapid-on/-off sawtooth flicker, and photopic longduration flash measurements (for separate ON-/OFF-responses under different conditions). RESULTS.The mdx 3Cv mice exhibited diminished and delayed scotopic and photopic ERGs, particularly in their b-wave and oscillatory potentials. Interestingly, homologues to the a-and b-wave of the mesopic ON-response were affected in their peak/trough times but not in their amplitude, whereas changes to both features were uncovered for photopic ON-response and sinusoidal flicker. Mesopic and photopic OFF-components were within the norm.CONCLUSIONS. Abnormal scotopic and photopic flash ERGs were observed in mdx 3Cv , which corroborate with deficits that are likely restricted to the level of photoreceptor-to-bipolar cell transmission. Further overlaps between mdx 3Cv mice and DMD patients exist, including asymmetrical ON versus OFF ERG alterations under mesopic versus photopic vision. In mice, ON-pathway function is compromised, whereas the OFF-pathway is spared.Keywords: Duchenne muscular dystrophy, dystrophin, electrophysiology, mouse model D ystrophin is a 427-kDa protein (Dp427), in which nonsense mutations in its gene (dmd) can cause Duchenne muscular dystrophy (DMD), a lethal, X-linked recessive muscle degenerative disease that primarily affects male children. 1 Shorter gene products of the protein, also transcribed by dmd, are present in different tissues.2 The retina, for example, is a tissue where extensive expressions of the dystrophin proteins occur. Besides Dp260, the predominant retinal gene products of dystrophin found in the outer plexiform layer (OPL), 3 the full protein Dp427, and shorter DMD gene products Dp140 and Dp71 are also found at various locations in the retina (reviewed in Ref. 4).Mouse strains lacking single or multiple dystrophin gene products have provided different models to study the mechanisms underlying electroretinographic (ERG) abnormalities in DMD patients. 5 Varying degrees of retinal dysfunction are associated with different dmd mutations. 6 Dp71, for example...

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Section: Rod-mediated Function In MDX 3cvsupporting

confidence: 66%

Section: Rod-mediated Function In MDX 3cvsupporting

confidence: 53%

Asymmetrical Functional Deficits of ON and OFF Retinal Processing in the mdx^3Cv Mouse Model of Duchenne Muscular Dystrophy

Tsai

Barboni

Nagy

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…Dystrophin is considered a developmental determinant of structural apposition of photoreceptors with bipolar cells. 43 We anticipated that patients with DMD might show altered patterns of retinal lamination; however, high-resolution spectral domain OCT axial images of the in vivo retina did not show any irregularity of the outer plexiform lamina nor abnormal lamina thicknesses in a comparison with normal.…”

Section: Ocular and Neurodevelopmental Features Of Dmd V Ricotti Et Almentioning

confidence: 93%

Ocular and neurodevelopmental features of Duchenne muscular dystrophy: a signature of dystrophin function in the central nervous system

Ricotti

Jägle²,

Theodorou

et al. 2015

Eur J Hum Genet

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Multiple isoforms of dystrophin (Dp427, Dp260, Dp140, Dp71) are expressed differentially in the central nervous system (CNS) including the retinal layers. Disruption of these protein products is responsible for cognitive dysfunction, electroretinogram (ERG) abnormalities and behavioural disorders in Duchenne muscular dystrophy (DMD). We studied the ocular characteristics and neuropsychiatric profile of 16 DMD boys. The ISCEV standard, full-field flash ERGs were assessed. Intellectual ability and behavioural disturbances were measured. All genotypes were associated with mildly abnormal photopic ERG a:b-wave amplitude ratios. In addition, we identified the following genotype/phenotype correlations: boys with mutations upstream of exon 30 (ie, isolated Dp427 altered expression) showed normal scotopic a:b ratios, abnormal photopic oscillatory potential OP2 and normal scotopic OP2. Conversely, all boys with DMD mutations downstream of exon 30 showed profoundly 'negative' scotopic ERGs (a:b ratios 41). In these patients, the involvement of Dp260 isoform resulted in the absence of slow rod pathway signalling in15 Hz scotopic flicker ERGs. These boys had abnormal scotopic OP2 and normal photopic OP2. Finally, children with mutations also affecting Dp71 were associated with more pronounced electronegative ERGs. When correlating ERGs to neurodevelopmental outcome, we found a positive correlation between negative scotopic ERGs and neurodevelopmental disturbances, and the most severe findings were in boys with Dp71 disruption. These findings suggest a strong association between DMD mutations affecting different DMD isoforms with characteristically abnormal scotopic ERGs and severe neurodevelopmental problems. The role of the ERG as a potential biomarker for dystrophin function in the CNS and response to novel genetic therapies warrants further exploration.

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“…These alterations have been found in different studies and vary from 50% to 88% of cases (Blake & Kroger, 2000;Girlanda et al, 1997;Mehler, 2000). The scotopic ERG obtained in the patients with DMD is characterized by a large amplitude reduction that produces a complete suppression of the b-wave, resulting in a negative ERG (i.e., a reduction of the b/a-wave ratio to values below 1; Ino-ue et al, 1997; Pillers, 1999).…”

Section: Introductionmentioning

confidence: 99%

Psychophysical measurements of luminance and chromatic spatial and temporal contrast sensitivity in Duchenne muscular dystrophy.

Costa¹,

Barboni²,

Ventura³

2011

Psychology & Neuroscience

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In children with Duchenne muscular dystrophy, color vision losses have been related to dystrophin deletions downstream of exon 30, which affect a dystrophin isoform, Dp260, present in the retina. To further evaluate visual function in DMD children, we measured spatial, temporal, and chromatic red-green and blue-yellow contrast sensitivity in two groups of DMD children with gene deletion downstream and upstream of exon 30. Psychophysical spatial contrast sensitivity was measured for low, middle, and high spatial frequencies with achromatic gratings and for low and middle frequencies with red-green and blue-yellow chromatic gratings. Temporal contrast sensitivity was also measured with achromatic stimuli. A reduction in sensitivity at all spatial luminance contrasts was found for the DMD patients with deletion downstream of exon 30. Similar results were found for temporal luminance contrast sensitivity. Red-green chromatic contrast sensitivity was reduced in DMD children with deletion downstream of exon 30, whereas blue-yellow chromatic contrast sensitivity showed no significant differences. We conclude that visual function is impaired in DMD children. Furthermore, we report a genotype-phenotype relationship because the visual impairment occurred in children with deletion downstream but not upstream of exon 30, affecting the retinal isoform of dystrophin Dp260.

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Extra-muscle involvement in dystrophinopathies: an electroretinography and evoked potential study

Cited by 27 publications

References 31 publications

Asymmetrical Functional Deficits of ON and OFF Retinal Processing in the mdx^3Cv Mouse Model of Duchenne Muscular Dystrophy

Asymmetrical Functional Deficits of ON and OFF Retinal Processing in the mdx^3Cv Mouse Model of Duchenne Muscular Dystrophy

Ocular and neurodevelopmental features of Duchenne muscular dystrophy: a signature of dystrophin function in the central nervous system

Psychophysical measurements of luminance and chromatic spatial and temporal contrast sensitivity in Duchenne muscular dystrophy.

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Extra-muscle involvement in dystrophinopathies: an electroretinography and evoked potential study

Cited by 27 publications

References 31 publications

Asymmetrical Functional Deficits of ON and OFF Retinal Processing in the mdx3Cv Mouse Model of Duchenne Muscular Dystrophy

Asymmetrical Functional Deficits of ON and OFF Retinal Processing in the mdx3Cv Mouse Model of Duchenne Muscular Dystrophy

Ocular and neurodevelopmental features of Duchenne muscular dystrophy: a signature of dystrophin function in the central nervous system

Psychophysical measurements of luminance and chromatic spatial and temporal contrast sensitivity in Duchenne muscular dystrophy.

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Asymmetrical Functional Deficits of ON and OFF Retinal Processing in the mdx^3Cv Mouse Model of Duchenne Muscular Dystrophy

Asymmetrical Functional Deficits of ON and OFF Retinal Processing in the mdx^3Cv Mouse Model of Duchenne Muscular Dystrophy