A Natural History Study of the Gangliosidoses

Sandhoff Disease Clinical Trial

Official title:

A Natural History Study of the Gangliosidoses

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00668187
• Other study ID #: 0801M24964
• Secondary ID: U54NS065768
• Status: Recruiting
• Start date: December 2010
• Est. completion date: March 1, 2027

Study information

• Verified date: March 2024
• Source: University of Minnesota
• Contact: Jeanine R. Jarnes, PharmD
• Phone: 612-626-5131
• Email: utzx0002[@]umn.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 52
• Est. completion date: March 1, 2027
• Est. primary completion date: March 1, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

1. Subjects must have a documented gangliosidosis disease.

2. Subjects must be able to complete appropriate neuropsychological and neurobehavioral assessments.

3. 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.

Related Conditions & MeSH terms

• Gangliosidoses
• Gangliosidoses, GM2
• Gangliosidosis, GM1
• GM1 Gangliosidosis
• GM2 Gangliosidosis
• Late Onset Tay-Sachs Disease
• Sandhoff Disease
• Tay-Sachs Disease

Locations

Country	Name	City	State
United States	University of Minnesota - Pediatric Genetics and Metabolism	Minneapolis	Minnesota

Sponsors (6)

Lead Sponsor	Collaborator
University of Minnesota	Lysosomal Disease Network, National Center for Advancing Translational Sciences (NCATS), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Neurological Disorders and Stroke (NINDS), Rare Diseases Clinical Research Network

Country where clinical trial is conducted

United States, 

References & Publications (10)

Frey LC, Ringel SP, Filley CM. The natural history of cognitive dysfunction in late-onset GM2 gangliosidosis. Arch Neurol. 2005 Jun;62(6):989-94. doi: 10.1001/archneur.62.6.989. — View Citation

Jarnes Utz JR, Kim S, King K, Ziegler R, Schema L, Redtree ES, Whitley CB. Infantile gangliosidoses: Mapping a timeline of clinical changes. Mol Genet Metab. 2017 Jun;121(2):170-179. doi: 10.1016/j.ymgme.2017.04.011. Epub 2017 Apr 29. — View Citation

Kaback M, Lim-Steele J, Dabholkar D, Brown D, Levy N, Zeiger K. Tay-Sachs disease--carrier screening, prenatal diagnosis, and the molecular era. An international perspective, 1970 to 1993. The International TSD Data Collection Network. JAMA. 1993 Nov 17;270(19):2307-15. — View Citation

MacQueen GM, Rosebush PI, Mazurek MF. Neuropsychiatric aspects of the adult variant of Tay-Sachs disease. J Neuropsychiatry Clin Neurosci. 1998 Winter;10(1):10-9. doi: 10.1176/jnp.10.1.10. — View Citation

Navon R, Argov Z, Frisch A. Hexosaminidase A deficiency in adults. Am J Med Genet. 1986 May;24(1):179-96. doi: 10.1002/ajmg.1320240123. — View Citation

Nestrasil I, Ahmed A, Utz JM, Rudser K, Whitley CB, Jarnes-Utz JR. Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses: Volumetric quantitative MRI study. Mol Genet Metab. 2018 Feb;123(2):97-104. doi: 10.1016/j.ymgme.20 — View Citation

Neudorfer O, Pastores GM, Zeng BJ, Gianutsos J, Zaroff CM, Kolodny EH. Late-onset Tay-Sachs disease: phenotypic characterization and genotypic correlations in 21 affected patients. Genet Med. 2005 Feb;7(2):119-23. doi: 10.1097/01.gim.0000154300.84107.75. — View Citation

Toro C, Shirvan L, Tifft C. HEXA Disorders. 1999 Mar 11 [updated 2020 Oct 1]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK1218/ — View Citation

Utz JR, Crutcher T, Schneider J, Sorgen P, Whitley CB. Biomarkers of central nervous system inflammation in infantile and juvenile gangliosidoses. Mol Genet Metab. 2015 Feb;114(2):274-80. doi: 10.1016/j.ymgme.2014.11.015. Epub 2014 Dec 6. — View Citation

Zaroff CM, Neudorfer O, Morrison C, Pastores GM, Rubin H, Kolodny EH. Neuropsychological assessment of patients with late onset GM2 gangliosidosis. Neurology. 2004 Jun 22;62(12):2283-6. doi: 10.1212/01.wnl.0000130498.19019.02. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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 ß-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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Homepage of the Rare Diseases Clinical Research Network
•   Talking Glossary of Genetic Terms from the National Human Genome Research Institute. (Uses Adobe Flash plugin.) This Talking Glossary is available as an app for mobile devices, from a link on this page.
•   The Lysosomal Disease Network's page on the Rare Diseases Clinical Research Network's web site
•   The Lysosomal Disease Network, a research consortium funded by the NIH's Rare Diseases Clinical Research Network