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

Department of Neurology, Veterans Affairs Medical Center and University Hospitals, Case Western Reserve University, Cleveland, OH 44106-5040, USA.
Neurology (Impact Factor: 8.29). 12/2004; 63(10):1918-26. DOI: 10.1212/01.WNL.0000144275.76658.F4
Source: PubMed


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

Download full-text


Available from: Janet Rucker, Feb 27, 2014
  • Source
    • "Individuals who are heterozygotes or mild homozygotes for mutations in the a subunit gene have residual HexA catalytic function . This causes delayed onset and progression of disease symptoms such as unsteady gait and progressive deterioration of the nervous system, particularly the visual system (Rucker et al. 2004). Incidence of Tay Sachs disease is higher among certain populations including French Canadian, Eastern European, Askhenazi Jewish descent as compared to the general population. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The lysosomal storage diseases (LSDs) collectively account for death in 1 in 8,000 children. Although some forms are treatable, they are essentially incurable and usually are lethal in the first decade of life. The most intractable forms of LSD are those with neuronal involvement. In an effort to identify the pathological signaling driving pathology in the LSDs, invertebrate models have been developed. In this review, we outline our current understanding of LSDs and recent findings using invertebrate models. We outline strategies and pitfalls for the development of such models. Available models of LSD in Drosophila and Caenorhabditis elegans are uncovering roles for LSD-related proteins with previously unknown function using both gain-of-function and loss-of-function strategies. These models of LSD in Drosophila and C. elegans have identified potential pathogenic signaling cascades that are proving critical to our understanding of these lethal diseases.
    Full-text · Article · Dec 2011 · Invertebrate Neuroscience
  • Source
    • "We used eye movements recorded with coils in 14 patients diagnosed with LOTS and 10 healthy control subjects (for details, see Rucker et al., 2004). Horizontal saccades were simulated in Matlab (Mathworks, Natick, MA). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In late-onset Tay-Sachs disease (LOTS), saccades are interrupted by one or more transient decelerations. Some saccades reaccelerate and continue on before eye velocity reaches zero, even in darkness. Intervals between successive decelerations are not regularly spaced. Peak decelerations of horizontal and vertical components of oblique saccades in LOTS is more synchronous than those in control subjects. We hypothesize that these decelerations are caused by dysregulation of the fastigial nuclei (FN) of the cerebellum, which fire brain stem inhibitory burst neurons (IBNs).
    Preview · Article · Feb 2008 · Progress in brain research
  • Source
    • "Saccades in LOTS are interrupted by transient decelerations, during which velocity abruptly declines but generally remains greater than 501/s (Rucker et al., 2004). Normal initial velocity suggests integrity of excitatory burst neurons (EBNs) and motoneurons. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Saccades normally place the eye on target with one smooth movement. In late-onset Tay-Sachs (LOTS), intrasaccadic transient decelerations occur that may result from (1) premature omnipause neuron (OPN) re-activation due to malfunction of the latch circuit that inhibits OPNs for the duration of the saccade or (2) premature inhibitory burst neuron (IBN) activation due to fastigial nucleus (FN) dysregulation by the dorsal cerebellar vermis. Neuroanatomic analysis of a LOTS brain was performed. Purkinje cells were absent and gliosis of the granular cell layer was present in the dorsal cerebellar vermis. Deep cerebellar nuclei contained large inclusions. IBNs were present with small inclusions. The sample did not contain the complete OPN region; however, neurons in the OPN region contained massive inclusions. Pathologic findings suggest that premature OPN re-activation and/or inappropriate firing of IBNs may be responsible for interrupted saccades in LOTS. Cerebellar clinical dysfunction, lack of saccadic slowing, and significant loss of cerebellar cells suggest that the second cause is more likely.
    Preview · Article · Feb 2008 · Progress in brain research
Show more