Synergistic Enteral Regimen for Treatment of the Gangliosidoses (Syner-G)

• Rate of Change in Neurocognitive Functioning [ Time Frame: Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment ] [ Designated as safety issue: No ]
  The Bayley Scales of Infant and Toddler Development will be administered upon enrollment and annually thereafter for five years. The assessed neurocognitive functional domains shall include expressive communication, receptive communication, fine motor skills, and gross motor skills. The rate of change in the resulting data (i.e. slope) will be calculated over the duration of follow-up, and will compared to available natural history data. This measurement and analysis will be performed separately for each of the two gangliosidoses sub-types: infantile onset and juvenile onset.
  
  

• Rate of Change in Adaptive Behavior [ Time Frame: Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment ] [ Designated as safety issue: No ]
  The Vineland Adaptive Behavior Scales will be administered upon enrollment and annually thereafter for five years. The assessed functional domain is the research subject's adaptive behavior. The rate of change in the resulting data (i.e. slope) will be calculated over the duration of follow-up, and will compared to available natural history data. This measurement and analysis will be performed separately for each of the two gangliosidoses sub-types: infantile onset and juvenile onset.
  
  
• Quality-of-Life Measure Specific to the Infantile-Onset Gangliosidoses [ Time Frame: Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment ] [ Designated as safety issue: No ]
  The Living Infantile Tay-Sachs Questionnaire will be administered to the caregivers of research subjects who have infantile-onset Tay-Sachs disease. The domain being assessed is the research subject's quality of life.
  
  
• Quality-of-Life Measure Specific to the Juvenile-Onset Gangliosidoses [ Time Frame: Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment ] [ Designated as safety issue: No ]
  The Living Juvenile Tay-Sachs Questionnaire will be administered to the caregivers of research subjects who have juvenile-onset Tay-Sachs disease; and if the subject has the ability to respond, to the research subject. The domain being assessed is the research subject's quality of life.
  
  
• Biomarker Analysis and Identification in Research Subjects' Cerebrospinal Fluid and Serum [ Time Frame: Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment ] [ Designated as safety issue: Yes ]
  Research subjects' cerebrospinal fluid and serum will be collected upon enrollment and annually for five years. These procedures will be performed by a qualified physician while the research subject is under general anesthesia. These samples will be extensively analyzed to identify potential molecular biomarkers that may be associated with disease severity and/or changes in disease status. Such biomarkers may be useful for sensitively indicating disease progression and as outcomes measures for any future treatments.
  
  
• Assessment of Change in Optic Nerve Atrophy and the Characteristic Retinal "Cherry Red Spot" [ Time Frame: Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment ] [ Designated as safety issue: Yes ]
  A qualified ophthalmologist will perform assessment of change in research subjects' optic nerve atrophy and their characteristic retinal "cherry red spot," upon enrollment and annually for five years. This assessment will be performed while the research subject is under general anesthesia.
  
  
• Assessment of Changes in Research Subjects' Cardiac Health [ Time Frame: Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment ] [ Designated as safety issue: No ]
  A qualified cardiologist will perform assessment of research subjects' cardiac health, including cardiac output, ejection fraction, and cardiomyopathies. This assessment will be performed upon enrollment and annually for five years.
  
  
• Assessment of Changes in Research Subjects' Seizure Frequency and Severity [ Time Frame: Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment ] [ Designated as safety issue: No ]
  Changes in research subjects' seizure frequency and severity will be assessed by a qualified neurologist, using interviews of the research subjects' caregivers. This assessment will be performed upon enrollment and annually for five years.
  
  
• Assessment of Changes in Anatomical and Structural Characteristics of Research Subjects' Brains [ Time Frame: Upon Enrollment, and thereafter at 12, 24, 36, 48 and 60 months post-enrollment ] [ Designated as safety issue: Yes ]
  Changes in research subjects' total brain volume, intracranial brain volumes of interest, and specific brain structures will be assessed upon enrollment and annually for five years. The change-assessment tool shall be semi-automated quantitative measurements made from research subjects' magnetic resonance imaging (MRI) brain data. The MRI brain data shall be gathered while the research subjects are under general anesthesia.
  
  
• The duration of survival of each research subject, measured in months [ Time Frame: From date of enrollment until 60 months thereafter, or the date of subject's death from any cause, whichever comes first, assessed up to 60 months ] [ Designated as safety issue: No ]
  The survival duration of patients with infantile and juvenile forms of gangliosidoses will be assessed, in order to judge the clinical impact of the Syner-G therapy regimen. This will be accomplished by recording the subject's age on the date of enrollment in this study, and the subject's age at the conclusion of this study, or on the date of their death, whichever comes first. The duration of each subject's survival, expressed in months and years, will be compared to available natural history data and the investigators' extensive clinical experience, in order to arrive at an expert assessment of the impact of the Syner-G therapy upon patient longevity.
  
  

The infantile and juvenile forms of GM1 and GM2 gangliosidoses are neurodegenerative conditions that are lethal during childhood. There are no known effective therapies available for treatment of infantile and juvenile gangliosidoses. Studies of monotherapy with miglustat for treatment of these conditions have demonstrated safety, but have not demonstrated notable clinical improvement. To date, combination therapy for the infantile and juvenile gangliosidoses has not been explored. This study will evaluate a multi-targeted combination therapy for treatment of the gangliosidoses, using FDA approved therapies that have demonstrated safety in children. It is the aim of this study to learn if combination therapy using the "Syner-G" regimen (that is, synergistic enteral regimen for treatment of the gangliosidoses) will show significant increase in overall survival and clinical benefits in neurodevelopmental abilities in children with gangliosidosis diseases.

This study is planned as a 5-year longitudinal treatment study. Subjects will be started on treatment regimen when they are enrolled in the study. Data will be collected during yearly evaluations and at completion of study. Investigators may choose to stop therapy at any time as clinically indicated for individual patients.

The Ketogenic Diet is a special diet that contains higher amounts of fat and lower amounts of carbohydrate compared an average diet. The purpose of this is to help the miglustat be more effective in the central nervous system and to help reduce seizures. The goal is to have 4 parts of fat for every 1 part of protein/carbohydrate. Each research subject's caregiver will work with a ketogenic dietitian to help their child to achieve this diet goal.

Miglustat will be used to reduce the amount of ganglioside accumulation in the child's cells. Miglustat is not FDA approved for treatment of the gangliosidoses. It is FDA approved for a different inherited metabolic disease called Gaucher disease type I. The dose of miglustat will increase every 2 days until the child reaches a goal dose of 300 mg per day. It will take approximately 13 weeks to reach the full dose of miglustat. This dose titration process may take longer if the child needs more time to adjust to each dose level.