Clinicopathologic report of ocular involvement in ALS patients with C9orf72 mutation

Abstract

Our objective was to present clinicopathologic evidence of anterior visual pathway involvement in patients with amyotrophic lateral sclerosis (ALS) secondary to a C9orf72 mutation. Two related patients from an extended pedigree with ALS and GGGGCC hexanucleotide repeat expansion in the C9orf72 gene (C9-ALS) underwent neuro-ophthalmologic examination. Following death and tissue donation of the younger ALS patient, histopathologic examination of the retina, optic nerve and central nervous system (CNS) was performed. Ophthalmologic examination revealed contrast sensitivity impairment in the younger C9-ALS patient. Immunohistochemistry performed on this patient’s donor tissue demonstrated p62-positive, pTDP43-negative perinuclear inclusions in the inner nuclear layer of the retina and CNS. Further colocalization with GLT-1 and recoverin suggested that the majority of retinal p62-positive inclusions are found within cone bipolar cells as well as some amacrine and horizontal cells. In conclusion, this is the first report that identifies disease-specific pathologic inclusions in the anterior visual pathway of a patient with a C9orf72 mutation. Cone bipolar cell involvement within the inner nuclear layer of the retina may explain the observed subtle visual function deficiencies in this patient. Further clinical and histopathologic studies are needed to fully characterize a larger population of C9-ALS patients and explore these findings in other forms of ALS.

Key words::

• Pathology
• neuropathology
• ubiquitin
• amyotrophic lateral sclerosis
• c9orf72
• retina
• midget bipolar cells

Acknowledgements

We acknowledge NIH- EY-021470 (AAF), NIH-NS050641 (TS), NIH-K12 EY 021475 (HEM) NIH-P30 EY 001792 (HEM), NIH-NIA-AG13854 (EB), Illinois Eye Bank (AAF), Eleanor Wood-Prince Grants: A Project of The Woman's Board of NMH (AAF), Illinois Society for the Prevention of Blindness (JS, AAF) and unrestricted funds from Research to Prevent Blindness, NY (Department of Ophthalmology, Northwestern University; Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago).

Teepu Siddique acknowledges the following support: Les Turner ALS Foundation, Les Turner ALS Foundation/Herbert C. Wenske Foundation Professor, Ride for Life and the Foglia Family Foundation. The authors wish to thank Drs. Steven H. DeVries and Jun Shi, of Northwestern University, who provided the recoverin antibody and critically reviewed the bipolar cell immunohistochemistry.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.