Is the retina affected in Huntington disease?

Abstract

Huntington disease (HD) is an inherited neurodegenerative disorder characterized by progressive motor dysfunctions, cognitive impairments and personality changes. HD is caused by an expanded polyglutamine repeat encoded by a (CAG)n block in exon 1 within the IT15 gene encoding the protein huntingtin (htt). HDaffected brains show progressive striatal and cortical atrophy. Intranuclear inclusions and cytoplasmic aggregates are histopathological hallmarks of HD. Among polyglutamine diseases spinocerebellar ataxia 7 (SCA7) is known to present retinal degenerations in affected humans and SCA7 mouse models [2]. Retinal degenerations were also obvious in a Drosophila model of HD [3] and R6/2 HD transgenic mice [1, 5] in a similar degeneration pattern as documented in SCA7 mouse models. R6/2 mice express exon 1 of the human IT15 gene with an expanded trinucleotide repeat and present with a severe neurological phenotype. Does the retinal pathology in this mouse model reflect human HD retinal pathology? Visual system impairment in HD patients had been documented on the basis of visual tests [4]. Postmortem morphological studies of human HD retinae have not yet been reported. We investigated here the retina from a 69-year-old male patient with a 28-year history of clinically established HD as confirmed by CAG blocks of 17/47. The last ophthalmological investigation of the patient took place 3 months before death; fundoscopy and visual impairments were never documented. Control eyes for this study were taken from two age-matched individuals with no known neurological or ophthalmological disorders. CAG expansions were excluded in the control individuals. First, we investigated the brain of the HD patient to evaluate the degree of HD-specific neuropathology. Coronal brain slices showed marked atrophy of the caudate nucleus, the putamen and cortical areas, as documented in a slice at the level of the anterior commissure (Fig. 1A). Peroxidase immunohistochemistry of N-terminal htt (Fig. 1B) and ubiquitin (Fig. 1C) presented abundant inclusions or aggregates in the cingulate gyrus of the HD patient. Macroscopical observations of the eye exhibited a normal fundus with neither pigmentary signs nor pale deposits (Fig. 1D, E). In contrast to the brain, N-terminal htt (Fig. 1F) and ubiquitin inclusions or aggregates (Fig. 1G) were absent in the HD retina. Supposedly unspecific ubiquitin staining in the nerve fiber layer (Fig. 1G) was also observed in control retinae. Microscopically, the entire HD retina showed no obvious histopathological changes. All retinal nuclear layers presented regular structures (Fig. 1H) as compared to the retina of an age-matched control individual (Fig. 1I) with normal CAG repeat lengths of 16/18 trinucleotides. Evaluation of the photoreceptor layer could be hampered by its detachment of the pigment epithelium (Fig. 1H). In flat sections regular rods and cones could be identified. The pigment epithelium appeared to be unchanged. Migration of cells with melanin pigment towards the outer retinal layers was not observed, a phenomenon identified in the retinae of SCA7 patients [2]. At the electron microscopical level, all retinal neurons exhibited nuclei without any HD characteristics of intranuclear inclusions, cytoplasE. Petrasch-Parwez (&) AE A. Schlichting AE R. Dermietzel Department of Neuroanatomy and Molecular Brain Research, Institute of Anatomy, Ruhr-University, Universitatsstrasse 150 MA 6/45, 44801 Bochum, Germany E-mail: Elisabeth.Petrasch-Parwez@rub.de Tel.: +49-234-3225008 Fax: +49-234-3214655