Genotype-Phenotype Correlations of Late Infantile Neuronal Ceroid Lipofuscinosis

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.

Study Overview

• Status: Completed
• Conditions: 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 Type: Observational
• Enrollment (Actual): 48

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Weill-Cornell LINCL scale at 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	Day 0, 18 months
Change in MRI parameters at 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.	Day 0, 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in CHQ or ITQoL	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.	Day 0, 18 months
Change in Mullen Scale	A pediatric developmental psychological rating scale	Day 0, 18 months

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); National Institutes of Health (NIH); Rare Diseases Clinical Research Network

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2009
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: December 16, 2009
• First Submitted That Met QC Criteria: December 16, 2009
• First Posted (Estimate): December 18, 2009

Study Record Updates

• Last Update Posted (Actual): July 29, 2020
• Last Update Submitted That Met QC Criteria: July 28, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Batten Disease; LINCL; Late Infantile Neuronal Lipofuscinosis
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Neurodegenerative Diseases; Metabolism, Inborn Errors; Heredodegenerative Disorders, Nervous System; Lipid Metabolism Disorders; Lipidoses; Lipid Metabolism, Inborn Errors; Neuronal Ceroid-Lipofuscinoses
• 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)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No