Evaluation of Biochemical Markers and Clinical Investigation of Niemann-Pick Disease, Type C

This study will evaluate clinical and laboratory tests that might be useful in determining if an investigational drug can slow the progression of Niemann-Pick Disease, Type C (NPC), a genetic disorder that results in progressive loss of nervous system function. The study will: 1) look for a clinical or biochemical marker that can be used as a measure of response to treatment, and 2) define the rate of progression of biochemical marker abnormalities in a group of NPC patients who will later be invited to enroll in a treatment trial.

Patients of any age with NPC may be eligible for this study. Participants undergo the following procedures every 6 months during 4- to 5-day admissions at the NIH Clinical Center.

• Medical evaluation, including medical history, physical exam, neurological exam, neuropsychometric evaluation, and blood and urine tests.
• Lumbar puncture (spinal tap): A sample of cerebrospinal fluid (CSF), the fluid that bathes the brain and spinal cord, is obtained for study. After administration of a local anesthetic, a small needle is inserted in the space between the bones in the lower back where the CSF circulates below the spinal cord. A small amount of fluid is collected through the needle.
• Eye exam and eye movement study: The pupils of the eye are dilated to examine the structures of the eyes. For the eye movement study a special contact lens is placed on the eye and the patient looks at a series of target light spots moving on a screen.
• Hearing tests.
• Electroretinography (in patients who can cooperate with the test) to measure the function of the retina. Before the test, the patient's pupils are dilated and an electrode (small silver disk) is taped to the forehead. The patient sits in a dark room for 30 minutes and then a special contact lens is placed on one eye after it has been numbed with drops. The contact lens senses small electrical signals generated by the retina when lights flash. During the ERG recording, the eye is stimulated with flashes of light projected inside a hollow sphere. After the test, a full eye exam is done and photographs of the retina are taken.
• Magnetic resonance imaging (MRI): This test uses a magnetic field and radio waves to produce images of the brain and obtain information about brain chemicals. The patient lies on a table that can slide in and out of the scanner (a narrow cylinder), wearing earplugs to muffle loud knocking and thumping sounds that occur during the scanning process. Patients who cannot remain still in the scanner may be sedated for the test.
• Psychometric testing: Patients complete questionnaires.
• Photographs of the patient may be taken for use in teaching sessions or scientific presentations or publications, with the patient's consent. Patients may be recognizable, but are not identified by name.
• Pregnancy test in all female patients over 10 years of age at the beginning of each admission to the Clinical Center.

Study Overview

• Status: Recruiting
• Conditions: Niemann-Pick Disease, Type C

Detailed Description

Niemann-Pick type C disease (NPC) is an autosomal recessive, lysosomal storage disorder characterized by accumulation of cholesterol and gangliosides. NPC is a rare (estimated prevalence of 1:120,000-150,000) neurodegenerative disorder with a wide clinical spectrum and a variable age of onset. Classically, children with NPC demonstrate neurological dysfunction with cerebellar ataxia, dysarthria, seizures, vertical gaze palsy, motor impairment, dysphagia, psychotic episodes, and progressive dementia. In general, adolescent and adult onset forms have a more insidious onset and slower progression.

There is no effective treatment for NPC and it is a lethal disorder. A major impediment to the testing of therapeutic interventions is the lack of well-defined outcome measures. The purpose of this protocol is to obtain both baseline and rate of progression data on clinical and biochemical markers that may later be used as an outcome measure in a clinical trial.

• Study Type: Observational
• Enrollment (Estimated): 900

Contacts and Locations

• Study Contact: Name: Derek Alexander; Phone Number: (301) 827-0387; Email: derek.alexander@nih.gov
• Study Contact Backup: Name: Forbes D Porter, M.D.; Phone Number: (301) 435-4432; Email: fdporter@mail.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients of any age with Niemann-Pick type C

Description

• INCLUSION CRITERIA:

Affected Subjects

The following individuals may be enrolled as in this study:

• All patients with an established diagnosis of NPC (biochemical or molecular).
• Both NPC1 and NPC2 patients.
• Patients of any age
• Males or females
• Any ethnic background

EXCLUSION CRITERIA:

Individuals will not be enrolled in this study if:

• they cannot travel to the NIH because of their medical condition or are too ill to be cared for at home.
• they have rapidly progressive neonatal cholestasis.
• they are pregnant (a negative urine pregnancy test will be required for any menstruating female before participation in this study and at each NIH Clinical Center admission).

Unaffected Subjects

Individuals may be enrolled for biospecimen collection if:

• They are a known NPC1 or NPC2 heterozygote and consent to specimen collection (as specified in the protocol) from the carrier population
• There is no diagnosis or suspicion of NPC disease and they consent to specimen collection (as specified in the protocol) from a control population

Individuals will not be enrolled for biospecimen collection if:

• Consent is not provided
• They have a contraindication to the method of specimen collection

Patients will be excluded from the MRI section of the study if they have a contraindication to MRI or if they do not meet the safety criteria established by the NIH Clinical Center radiology department for MRI scanning.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Patients with a diagnosis of Niemann-Pick type C (NPC) of either sex and any age; Participants may range from neurologically asymptomatic to severe and may have liver disease or unrelated comorbidities, but must be stable enough to safely travel and tolerate medical evaluations.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Oxysterols	Oxysterols such as 24S-hydroxycholesterol, 25-hydroxycholesterol, and 27-hydroxycholesterol are derived from cholesterol and play a role in cholesterol homeostasis. No data is available on endogenous oxysterol levels in NPC patients. We plan to measure oxysterol levels in both serum and CSF and correlate these levels with disease status and progression.	ad hoc

Collaborators and Investigators

• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Forbes D Porter, M.D., Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Publications and helpful links

General Publications

• Solomon BI, Smith AC, Sinaii N, Farhat N, King MC, Machielse L, Porter FD. Association of Miglustat With Swallowing Outcomes in Niemann-Pick Disease, Type C1. JAMA Neurol. 2020 Dec 1;77(12):1564-1568. doi: 10.1001/jamaneurol.2020.3241.
• Solomon BI, Munoz AM, Sinaii N, Farhat NM, Smith AC, Bianconi S, Dang Do A, Backman MC, Machielse L, Porter FD. Phenotypic expression of swallowing function in Niemann-Pick disease type C1. Orphanet J Rare Dis. 2022 Sep 5;17(1):342. doi: 10.1186/s13023-022-02472-w.
• Thurm A, Chlebowski C, Joseph L, Farmer C, Adedipe D, Weiss M, Wiggs E, Farhat N, Bianconi S, Berry-Kravis E, Porter FD. Neurodevelopmental Characterization of Young Children Diagnosed with Niemann-Pick Disease, Type C1. J Dev Behav Pediatr. 2020 Jun/Jul;41(5):388-396. doi: 10.1097/DBP.0000000000000785.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): August 14, 2006

Study Registration Dates

• First Submitted: June 23, 2006
• First Submitted That Met QC Criteria: June 23, 2006
• First Posted (Estimated): June 26, 2006

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: February 26, 2024

More Information

Terms related to this study

• Keywords: Natural History; Biomarkers; Longitudinal; NPC; Lysosomal Storage Disorder; Lysosomal Storage; Niemann Pick Type C
• Additional Relevant MeSH Terms: Mental Disorders; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Lymphatic Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Genetic Diseases, Inborn; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Dementia; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Language Disorders; Communication Disorders; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Speech Disorders; Frontotemporal Lobar Degeneration; Aphasia; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain; Niemann-Pick Diseases; Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type C
• Other Study ID Numbers: 060186; 06-CH-0186

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: .Data from this study will be coded and shared in aggregate.

Drug and device information, study documents

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