Ophthalmic features of spinocerebellar ataxia type 7

Campos‐Romo, Aurelio; Graue-Hernandez, E O; Pedro-Aguilar, Lucero; Hernández-Camarena, Julio C.; Parra, David Rivera-De la; Gálvez, Víctor; Dı́az, Rosalinda; Jiménez-Corona, Aída; Fernández-Ruíz, Juan

doi:10.1038/eye.2017.135

Cited by 17 publications

(17 citation statements)

References 32 publications

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“…In spinocerebellar ataxia, it has been shown that patients have a decreased corneal endothelial cell density. 30 Recently, Campos-Romo and colleagues 31 demonstrated an inverse relationship between the number of CAG TNRs and endothelial cell density, as well as an association between disease severity and decreased endothelial cell density. Our RNASeq analysis revealed that the spinocerebellar ataxia–associated gene ataxin 7 ( ATXN7 ) is expressed in the corneal endothelium, which suggests the possibility of a mechanism of disease similar to that found in FECD and DM1.…”

Section: Discussionmentioning

confidence: 98%

Fuchs' Endothelial Corneal Dystrophy in Patients With Myotonic Dystrophy, Type 1

Winkler

Milone

Martinez‐Thompson

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeRNA toxicity from CTG trinucleotide repeat (TNR) expansion within noncoding DNA of the transcription factor 4 (TCF4) and DM1 protein kinase (DMPK) genes has been described in Fuchs' endothelial corneal dystrophy (FECD) and myotonic dystrophy, type 1 (DM1), respectively. We prospectively evaluated DM1 patients and their families for phenotypic FECD and report the analysis of CTG expansion in the TCF4 gene and DMPK expression in corneal endothelium.MethodsFECD grade was evaluated by slit lamp biomicroscopy in 26 participants from 14 families with DM1. CTG TNR length in TCF4 and DMPK was determined by a combination of Gene Scan and Southern blotting of peripheral blood leukocyte DNA.ResultsFECD grade was 2 or higher in 5 (36%) of 14 probands, significantly greater than the general population (5%) (P < 0.001). FECD segregated with DM1; six of eight members of the largest family had both FECD and DM1, while the other two family members had neither disease. All DNA samples from 24 subjects, including four FECD-affected probands, were bi-allelic for nonexpanded TNR length in TCF4 (<40 repeats). Considering a 75% prevalence of TCF4 TNR expansion in FECD, the probability of four FECD probands lacking TNR expansion was 0.4%. Neither severity of DM1 nor DMPK TNR length predicted the presence of FECD in DM1 patients.ConclusionsFECD was common in DM1 families, and the diseases cosegregated. TCF4 TNR expansion was lacking in DM1 families. These findings support a hypothesis that DMPK TNR expansion contributes to clinical FECD.

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Section: Discussionmentioning

confidence: 98%

Fuchs' Endothelial Corneal Dystrophy in Patients With Myotonic Dystrophy, Type 1

Winkler

Milone

Martinez‐Thompson

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…Postmortem retinal sections reveal the almost complete loss of photoreceptors and the substantial loss of bipolar and ganglion cells resulting in severe thinning of the nuclear and plexiform layers especially in the foveal and parafoveal regions [32,48,57]. In addition, damages in the Bruch's membrane, hypertrophy or degeneration of the retinal pigmentary epithelium, hypomyelination of the optic nerve, decreased corneal endothelial cell density, and increased corneal thickness were also reported [11,33,34,48,49,62,64].…”

Section: Clinical and Neuropathological Featuresmentioning

confidence: 96%

Molecular Targets and Therapeutic Strategies in Spinocerebellar Ataxia Type 7

Niewiadomska-Cimicka

Trottier

2019

Neurotherapeutics

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Spinocerebellar ataxia type 7 (SCA7) is a rare autosomal dominant neurodegenerative disorder characterized by progressive neuronal loss in the cerebellum, brainstem, and retina, leading to cerebellar ataxia and blindness as major symptoms. SCA7 is due to the expansion of a CAG triplet repeat that is translated into a polyglutamine tract in ATXN7. Larger SCA7 expansions are associated with earlier onset of symptoms and more severe and rapid disease progression. Here, we summarize the pathological and genetic aspects of SCA7, compile the current knowledge about ATXN7 functions, and then focus on recent advances in understanding the pathogenesis and in developing biomarkers and therapeutic strategies. ATXN7 is a bona fide subunit of the multiprotein SAGA complex, a transcriptional coactivator harboring chromatin remodeling activities, and plays a role in the differentiation of photoreceptors and Purkinje neurons, two highly vulnerable neuronal cell types in SCA7. Polyglutamine expansion in ATXN7 causes its misfolding and intranuclear accumulation, leading to changes in interactions with native partners and/or partners sequestration in insoluble nuclear inclusions. Studies of cellular and animal models of SCA7 have been crucial to unveil pathomechanistic aspects of the disease, including gene deregulation, mitochondrial and metabolic dysfunctions, cell and non-cell autonomous protein toxicity, loss of neuronal identity, and cell death mechanisms. However, a better understanding of the principal molecular mechanisms by which mutant ATXN7 elicits neurotoxicity, and how interconnected pathogenic cascades lead to neurodegeneration is needed for the development of effective therapies. At present, therapeutic strategies using nucleic acid-based molecules to silence mutant ATXN7 gene expression are under development for SCA7.

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“…4,5 Common funduscopic changes include loss of foveal reflex, granular appearance of the retinal pigment epithelium, pigmentary macular changes, and diffuse retinal atrophy. 6 Molecular diagnosis, via polymerase chain reaction or Southern blot, is based on detection of the number of abnormal CAG expansions. Thirty-six or greater CAG expansions result in symptomatic individuals, although individuals with fewer than 36 expansions may have mild or subclinical symptoms.…”

Section: Discussionmentioning

confidence: 99%