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Neuro-ophthalmology of late-onset Tay–Sachs disease (LOTS)

From the Departments of Neurology (Drs. Rucker, Shapiro, and Leigh), Ophthalmology (Dr. Rucker), Biomedical Engineering (Dr. Leigh, Y.H. Han and A. N. Kumar), and Neuroscience (Dr. Leigh), Veterans Affairs Medical Center and University Hospitals, Case Western Reserve University, Cleveland, OH, and Department of Physiology and W.M. Keck Foundation Center for Integrative Neuroscience (Dr. Garbutt), University of California, and Smith–Kettlewell Eye Research Institute (Dr. Keller), San Francisco, CA.

Address correspondence and reprint requests to Dr. R.J. Leigh, Department of Neurology, University Hospitals, 11100 Euclid Ave., Cleveland, OH, 44106-5040; e-mail: rjl4{at}case.edu

Background: Late-onset Tay–Sachs disease (LOTS) is an adult-onset, autosomal recessive, progressive variant of GM2 gangliosidosis, characterized by involvement of the cerebellum and anterior horn cells.

Objective: To determine the range of visual and ocular motor abnormalities in LOTS, as a prelude to evaluating the effectiveness of novel therapies.

Methods: Fourteen patients with biochemically confirmed LOTS (8 men; age range 24 to 53 years; disease duration 5 to 30 years) and 10 age-matched control subjects were studied. Snellen visual acuity, contrast sensitivity, color vision, stereopsis, and visual fields were measured, and optic fundi were photographed. Horizontal and vertical eye movements (search coil) were recorded, and saccades, pursuit, vestibulo-ocular reflex (VOR), vergence, and optokinetic (OK) responses were measured.

Results: All patients showed normal visual functions and optic fundi. The main eye movement abnormality concerned saccades, which were "multistep," consisting of a series of small saccades and larger movements that showed transient decelerations. Larger saccades ended earlier and more abruptly (greater peak deceleration) in LOTS patients than in control subjects; these changes can be attributed to premature termination of the saccadic pulse. Smooth-pursuit and slow-phase OK gains were reduced, but VOR, vergence, and gaze holding were normal.

Conclusions: Patients with late-onset Tay–Sachs disease (LOTS) show characteristic abnormalities of saccades but normal afferent visual systems. Hypometria, transient decelerations, and premature termination of saccades suggest disruption of a "latch circuit" that normally inhibits pontine omnipause neurons, permitting burst neurons to discharge until the eye movement is completed. These measurable abnormalities of saccades provide a means to evaluate the effects of novel treatments for LOTS.

Received March 18, 2004. Accepted in final form July 19, 2004.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the November 23 issue to find the title link for this article.

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