A Natural History Study of the Gangliosidoses

Study Overview
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Brief Summary
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Hypothesis: To characterize and describe disease progression and heterogeneity of the gangliosidosis diseases. This research study seeks to develop a quantitative method to delineate disease progression for the gangliosidosis diseases (Tay-Sachs disease, Sandhoff disease, and GM1 gangliosidosis) in order to better understand the natural history and heterogeneity of these diseases. Such a quantitative method will also be essential for evaluating any treatments that may become available in the future, such as gene therapy. The data from this study will be necessary to provide end-points for future therapies, guide medical decisions about treatment, provide objective measurement of treatment outcomes, and accurately inform parents regarding potential outcomes.

Detailed Description
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The infantile form of GM2 and GM1 gangliosidosis diseases (classic infantile) is the most common. Infants with Tay-Sachs disease, Sandhoff disease or GM1 gangliosidosis appear normal at birth, but at approximately 6-10 months of age begin to manifest progressive weakness and loss of muscle strength, such as loss of the ability to sit up or turn over. They may evidence deafness, and display decreased attentiveness. This is followed by rapid deterioration of motor skills and slowed mental development (neurodegeneration), often with seizures. Retinal involvement leads to visual impairment and eventual blindness. Death typically occurs by the age of five. Currently there is no treatment for Tay-Sachs disease, Sandhoff disease or GM1 gangliosidosis. Late Onset Tay-Sachs disease (LOTS) occurs in patients beginning in their twenties or thirties, and is characterized by poor motor coordination and psychotic behaviors. Patients with LOTS also have decreased life expectancy, although to a lesser degree than those with infantile or juvenile Tay-Sachs or Sandhoff diseases. Currently there is no treatment for LOTS. This study is comprised of two different 'arms.' The first arm, entitled Aim 1, will focus on the developmental course of infantile and juvenile Tay-Sachs disease, Sandhoff disease, and GM1 gangliosidosis. Longitudinal data from individuals with these diseases will be collected in order to delineate the natural history of these diseases. This data will help to objectify disease progression, and can be used to create a disease stage and severity index. The second arm, entitled Aim 2, will focus on LOTS and will seek to understand the progression of central nervous system disease, with special focus upon cerebellar and frontal systems. This will be accomplished by using quantitative methods including neuroimaging and neuropsychological measures that explore motor and executive functions, visual-spatial and emotional-behavioral dysfunction.

Official Title
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A Natural History Study of the Gangliosidoses

Conditions
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Tay-Sachs Disease, Sandhoff Disease, Late Onset Tay-Sachs Disease, GM1 Gangliosidosis, GM2 Gangliosidosis

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have a documented gangliosidosis disease. Subjects must be able to complete appropriate neuropsychological and neurobehavioral assessments. Late-onset gangliosidosis subjects must be able to tolerate a head MRI. Exclusion Criteria: 1. There are no exclusion criteria, beyond a desire not to participate.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Gangliosidosis Diseases Study Population<br>This study observes one cohort: 42 infantile or juvenile Tay-Sachs disease, Sandhoff disease, or GM1 gangliosidosis affected subjects; and 10 late-onset gangliosidosis disease affected subjects. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Child Developmental Status as Assessed by Neuropsychological Tests | Neuropsychological testing data will be collected at baseline and annually, that measure fine and gross motor skills, visual tracking and attention, verbal and non-verbal communication, and emotional and social behaviors. For infantile and juvenile Tay-Sachs disease, Sandhoff disease and GM1 gangliosidosis-affected subjects, age- and ability-appropriate neurobehavioral and neurodevelopmental testing will include instruments such as the Bayley Scales of Infant Development (Third Edition), and the Vineland Adaptive Behavior Scales. | Upon enrollment; then at 12, 24, 36, 48 and 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ascertainment of Enzyme Activity Levels | If either of the following diagnostic measures have been performed in the course of subjects' clinical care not connected with this study, the resulting data will be collected: for Tay-Sachs and Sandhoff disease-affected patients, levels of hexosaminidase enzyme activity; or for GM1 gangliosidosis-affected patients, levels of β-galactosidase enzyme activity. Determinations of these enzyme activity levels are a requisite part of the diagnostic process in all of the gangliosidosis diseases. | Upon enrollment | 
| Medication Regime | If any medications are given to subjects during the course of subjects' clinical care not connected with this study, the medications will be identified, quantified and recorded. | Upon enrollment; then at 12, 24, 36, 48 and 60 months | 
| Clinical Assessments | Clinical assessments will be performed that measure initial symptomology, along with the appearance and evolution of symptoms over time. For infants and juveniles, these may include: evaluation of motor control, gain and/or loss of developmental milestones, hyperacusis, seizures, macrocephaly, the appearance of retinal cherry-red spots ascertained by ocular exam, personal interaction, and reflexes. For adults, assessments may include: coordination, psychological disorder, verbal skills, muscle wasting with weakness, fasciculations, and posture abnormalities. | Upon enrollment; then at 12, 24, 36, 48 and 60 months | 
| Changes in Child Brain Structure Development and Status, as Assessed by Magnetic Resonance Imaging (MRI) Examination | For infantile and juvenile Tay-Sachs disease, Sandhoff disease and GM1 gangliosidosis-affected subjects, if any MRI brain imaging is performed during the course of subjects' clinical care not connected with this study, these MRI brain imaging data will be captured for this study. Any developmental abnormality, and the volumes of specific brain structures imaged, will be measured and the resulting data recorded. If data from multiple MRI examinations performed at different times in any given patient's life become available, the resulting brain structure measurements will be compared across time, and analyzed in order to reveal progressive changes in brain structure, if any have occurred. | Upon enrollment; then at 12, 24, 36, 48 and 60 months | 
| Identification of Genetic Mutation(s) | If any subject's genetic mutation(s) that are responsible for their gangliosidosis disease are identified during the course of subject's clinical care not connected with this study, that genetic mutation information will be collected for this study. | Upon Enrollment | 
| Changes in Chitotriosidase Enzyme Activity Levels | If the following biomarker measures are performed in the course of subjects' clinical care not connected with this study, the resulting data will be collected: plasma and/or cerebrospinal fluid chitotriosidase enzyme activity levels. If these measures are performed repeatedly at different times in the course of subjects' clinical care not connected with this study, the resulting data will be collected each time. | Upon enrollment; then at 12, 24, 36, 48 and 60 months | 
| Ascertainment of Ganglioside Levels | If either of the following diagnostic measures have been performed in the course of subjects' clinical care not connected with this study, the resulting data will be collected: for Tay-Sachs and Sandhoff disease-affected patients, levels of GM2 ganglioside; or for GM1 gangliosidosis-affected patients, levels of GM1 ganglioside. | Upon enrollment | 
| Change in Adult Neurocognitive Status as Assessed by Neuropsychological Tests | For adult-onset gangliosidosis-affected subjects, neuropsychological testing will be performed at baseline and annually as part of this study. Neuropsychological testing data will be collected using instruments including, but not limited to, the Wechsler Abbreviated Scale of Intelligence and the Test of Variables of Attention (TOVA). The resulting data will be recorded and compared across time, and analyzed in order to reveal progressive changes in subjects' neurocognitive status, if any have occurred. | Upon enrollment; then at 12, 24, 36, 48 and 60 months | 
| Changes in Adult Brain Structure Status, as Assessed by Magnetic Resonance Imaging (MRI) Examination | For adult-onset gangliosidosis-affected subjects, an MRI examination of the head will be performed at baseline and annually as part of this study. The volumes of specific brain structures imaged will be measured and recorded. These brain structure measurements will be compared across time, and analyzed in order to reveal progressive changes in brain structure, if any have occurred. | Upon enrollment; then at 12, 24, 36, 48 and 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tay-Sachs disease, Sandhoff disease, Late Onset Tay-Sachs disease, LOTS, hexosaminidase A deficiency, hexosaminidase A and B deficiency, infantile Tay-Sachs disease, adult-onset Tay-Sachs disease, prospective, natural history, GM1 gangliosidosis, gangliosidoses, β-galactosidase, β-galactosidase deficiency, hexosaminidase, hexosaminidase deficiency, Tay-Sachs, Sandhoff, juvenile Tay-Sachs, juvenile Tay-Sachs disease, late onset Tay-Sachs, juvenile Sandhoff, juvenile Sandhoff disease, GM2 gangliosidosis