Genotype-Phenotype Correlations of Late Infantile Neuronal Ceroid Lipofuscinosis

Study Description

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Brief Summary:

The primary aim of the study is to assess the genotype - phenotype correlations of the CNS manifestations of late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal, rare, recessive disorder of the CNS in children. This study will be accomplished by comparing the genotype to a neurologic assessment and Weill Cornell LINCL scale, the UBDRS scale, the standardized CHQ quality of life scale, and the Mullen scale; magnetic resonance imaging (MRI); and routine clinical evaluations. This study is designed to run parallel to a separate study which is being done by the Department of Genetic Medicine, which will use gene transfer to treat the central nervous system (CNS) manifestations of late infantile neuronal ceroid lipofuscinosis.

Condition or disease
Batten Disease; Late Infantile Neuronal Ceroid Lipofuscinosis

Detailed Description:

This protocol is designed to study the natural disease process of LINCL. We propose to assess the correlation between genotype (genetic constitution) and phenotype (observable characteristics) of late infantile neuronal ceroid lipofuscinosis (LINCL) in children diagnosed with LINCL in all stages. LINCL is a form of Batten disease that affects the brain of children and prevents it from functioning properly. These children are born with genetic changes called mutations that result in the inability of the brain to properly recycle proteins in the brain. The recycling failure leads to death of the nerve cells in the brain and progressive loss of brain function. Children with Batten disease are normal at birth but by age 2 to 4 have motor and vision problems which progress rapidly to death at age approximately 10 years old. There are no therapies available to treat the disease. This study is designed to run parallel to the gene transfer protocol, which will include 16 individuals in two groups: Group A will receive 9.0x10^11 genome copies (gc) of the vector and Group B will receive 2.85x10^11 gc; we anticipate that we will be able to capture a one-time genotype - phenotype snapshot for all n=32, and an 18 months genotype - phenotype progression assessment for n=16.

Study Design

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Study Type :	Observational
Estimated Enrollment :	75 participants
Observational Model:	Case-Only
Time Perspective:	Prospective
Official Title:	Genotype-Phenotype Correlations of Late Infantile Neuronal Ceroid Lipofuscinosis
Study Start Date :	March 2010
Estimated Primary Completion Date :	April 2020
Estimated Study Completion Date :	April 2025

Groups and Cohorts

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Outcome Measures

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Primary Outcome Measures :

1. Change in Weill-Cornell LINCL scale at 18 months [ Time Frame: Day 0, 18 months ]
   The Weill Cornell LINCL scale, a 12 point scale which combines assessment of feeding, gait, motor and language to give an overall assessment of various CNS functions
2. Change in MRI parameters at 18 months [ Time Frame: Day 0, 18 months ]
   MRI assessment at various intervals Day 0 and month 18. Based on previous analyses, we have determined that 3 imaging parameters (% grey matter volume, % ventricular volume and cortical apparent diffusion coefficient) correlate best with age and with the Weill Cornell LINCL scale. These 3 imaging parameters will be used to assess disease progression in this screening protocol and the effect of the gene transfer in the IRB approved gene transfer trials (IRB #0810010013 and #1005011054). For those children available to continue in the study, all parameters will be re-assessed by comparing baseline evaluations to month 18 evaluation.

Secondary Outcome Measures :

1. Change in CHQ or ITQoL [ Time Frame: Day 0, 18 months ]
   Quality of life questionnaires which will be completed by at least one parent/legal guardian at the time of the LINCL patients' visits to Weill Cornell16,17; we will administer either survey depending on the age of the subject independently to each parent to minimize observer bias if both parents are present.
2. Change in Mullen Scale [ Time Frame: Day 0, 18 months ]
   A pediatric developmental psychological rating scale

Biospecimen Retention:   Samples With DNA

whole blood, serum

Eligibility Criteria

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Ages Eligible for Study:	2 Years to 18 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No
Sampling Method:	Probability Sample

Study Population

The study will be carried out in children diagnosed with LINCL in all stages.

Criteria

Inclusion Criteria.

1. Definitive diagnosis of LINCL, based on clinical phenotype and genotype.
2. The subject must be between the age of 2 and 18 years.
3. The subject will not previously have participated in a gene transfer or stem cell study.
4. Parents of study participants must agree to comply in good faith with the conditions of the study, including attending all of the required baseline and follow-up assessments, and both parents or legal guardians must give consent for their child's participation.

Exclusion criteria.

1. Presence of other significant medical or neurological conditions may disqualify the subject from participation in this study e.g.,malignancy, congenital heart disease, liver or renal failure.
2. Subjects without adequate control of seizures.
3. Subjects with heart disease that would be a risk for anesthesia or a history of major risk factors for hemorrhage.
4. Subjects who cannot participate in MRI studies.
5. Concurrent participation in any other FDA approved Investigational New Drug.
6. Subjects with history of prolonged bleeding or abnormal platelet function or taking aspirin.

Contacts and Locations

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Locations

United States, New York
Weill Cornell Medical College- New York Presbyterian Hospital
New York, New York, United States, 10065

Sponsors and Collaborators

Weill Medical College of Cornell University

Rare Diseases Clinical Research Network

National Institute of Neurological Disorders and Stroke (NINDS)

National Institutes of Health (NIH)

Investigators

Study Director:	Ronald G. Crystal, MD	Weill Medical College of Cornell University
Principal Investigator:	Douglas Ballon, PhD	Weill Medical College of Cornell University

More Information

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Additional Information:

Rare Disease Clinical Research Network 

Responsible Party:	Weill Medical College of Cornell University
ClinicalTrials.gov Identifier:	NCT01035424 History of Changes
Other Study ID Numbers:	0901010186; U54NS065768 ( U.S. NIH Grant/Contract ); R01NS061848 ( U.S. NIH Grant/Contract ); 5R01NS061848-04 ( U.S. NIH Grant/Contract ); LDN 6716 ( Other Identifier: RDCRN )
First Posted:	December 18, 2009
Last Update Posted:	December 14, 2017
Last Verified:	December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Weill Medical College of Cornell University:

Batten Disease; Late Infantile Neuronal Lipofuscinosis; LINCL

Additional relevant MeSH terms:

Neuronal Ceroid-Lipofuscinoses; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Nervous System Diseases; Genetic Diseases, Inborn	Lipidoses; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Metabolic Diseases