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Genetic Studies of Lysosomal Storage Disorders

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ClinicalTrials.gov Identifier: NCT00001215
Recruitment Status : Enrolling by invitation
First Posted : November 4, 1999
Last Update Posted : July 23, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) )

Brief Summary:

The purpose of this study is to identify genetic, biochemical, and clinical factors that are associated with disease severity in people with Gaucher disease and other lysosomal storage disorders.

There is a vast spectrum of clinical manifestations in people with Gaucher disease as well as other lysosomal storage disorders. This study will evaluate patients with lysosomal disorders on an outpatient or inpatient basis in order to better characterize the clinical, genetic, and pathophysiological features of these disorders. Participants will be re-evaluated on an annual basis.


Condition or disease
Lysosomal Storage Disorders Gaucher Disease Parkinson Disease

Detailed Description:

There is a vast spectrum of clinical manifestations encountered in individuals with lysosomal storage diseases. Lysosomal storage disorders occur when an enzyme necessary for breaking down intracellular fats, proteins, recycled products and organelles in the cell is deficient. As a result, substrate accumulates within the lysosomes affecting different organ systems. The most common lysosomal storage disease, Gaucher disease (GD), results from the inherited deficiency of the enzyme glucocerebrosidase, which breaks down the lipid glucocerebroside. The disease is characterized by extremely variable manifestations, with some patients presenting in childhood with hepatosplenomegaly, anemia, thrombocytopenia and bony problems, some in infancy with a lethal neurodegeneriative course, while others remain asymptomatic into their eighth decade. GD has traditionally been divided into three clinical subtypes, type 1 (non-neuronopathic), type 2 (acute neuronopathic), and type 3 (chronic neuronopathic) delineated by the absence or presence of neurologic involvement and its rate of progression. Some patients, however, defy classification into these three categories, and it may be more accurate to regard GD as a continuum of phenotypes. In addition, patients and carriers of mutations in GBA1, the gene for GD, are at increased risk for developing Parkinson disease (PD) and related neurodegenerative disorders.

This is a longitudinal natural history study of patients with lysosomal storage disorders with emphasis on phenotypic heterogeneity of GD and those at risk for the development of parkinsonism. Our goal is to identify genetic, biochemical, and clinical parameters that are associated with disease severity in individuals with lysosomal storage disorders to identify individuals with milder or early phenotypic manifestations, and to explore the natural history and extent of associated clinical manifestations. We also study subjects with GBA1 mutations who are at higher risk for developing parkinsonism to identify early disease manifestations and potential biomarkers. Participants are evaluated at the NIH to better characterize the clinical, genetic and pathophysiological features of these disorders. In order to better understand the entire effect of the enzyme deficiencies and the function of the specific proteins involved, emphasis is placed on individuals with atypical presentations. In particular, we will focus on subjects with GD and PD, to better understand the association between the two disorders. Following an initial comprehensive workup, participants will be studied either in the inpatient wards or the outpatient clinic, and will be re-evaluated at periodic intervals longitudinally.

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Study Type : Observational
Estimated Enrollment : 1050 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Studies of Genetic Heterogeneity in Patients With Lysosomal Storage Disorders
Actual Study Start Date : May 16, 1986


Group/Cohort
Control
healthy volunteers
Family Member
a family member of a documented proband
Patient
the participant on initial screening must be found to have or be a carrier of a documented lysosomal storage disorder



Primary Outcome Measures :
  1. Clinical Phenotypes [ Time Frame: ongoing ]
    The purpose of this study is to clearly describe the clinical phenotypes of individuals with lysosomal storage diseases in order to better understand the pathophysiology of these disorders and to develop new therapies.


Secondary Outcome Measures :
  1. development o Parkinsonism [ Time Frame: ongoing ]
    We aim to identify factors that may be predictive of the development of Parkinsonism in an at-risk population



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Patient (or family members of patient) must be found to have or be a carrier of a documented lysosomal storage disorder.@@@
Criteria
  • INCLUSION/EXCLUSION CRITERIA:

For inclusion, the participant, of any age after birth, on initial screening must be found to have or be a carrier of a documented lysosomal storage disorder or be a family member of a documented proband. Healthy controls, > 18 years of age, will be recruited through the NIH healthy volunteer pool or we will invite unaffected spouses or relatives to participate. Healthy controls are necessary to determine the frequency of motor and non-motor symptoms in the general population. Parkinson disease patients, > 18 years of age, will be recruited from the Parkinson disease clinic at the NIH or by self-referral and will also be used for phenotypic comparison with GBA1-associated parkinsonism.

Individuals who, in the opinion of the Investigator, are unable to comply with the protocol or have medical or social conditions that would potentially increase the risk of participation will be excluded from enrolling in the study. There will be no exclusion based upon age, gender, ethnicity, socioeconomic status, or any other factor. Cognitively impaired individuals may be enrolled if the legal guardian or durable power of attorney (DPA) consents, and assent will be obtained, when appropriate because a significant portion of patients with neurodegenerative disorders may develop cognitive impairment and it is important to include this information in the clinical phenotype. Pregnant or nursing women will also be included because all evaluations and procedures in this protocol do not pose risk to the mother and the fetus as no radiation or imaging studies will be performed for research purpose. Pregancy in patients with GD and other lysosomal storage disorders presents specific challenges with regards to skeletal, hematological, and possibly visceral complications throughout gestation. It is important to capture the natural history of the disease during pregnancy to assess benefits of initiation/continuation/discontinuation of therapy depending on clinical signs and symptoms. Information obtained from participation of this population is of great value for counseling, prevention of complications, and prognostic implications. Participants are free to refuse any evaluation without affecting participation in this protocol.

These are generally pan-ethnic disorders. Efforts will be made to include any patient from an under-represented minority with these disorders.

Family members eligible/recruited include adult obligate carrier relatives, parents and siblings of Gaucher disease probands, and/or any relative with and without parkinsonism, where noncarriers volunteer for participation to serve as controls.

Eligibility criteria for healthy and PD control group participants include healthy participants recruited from the Healthy volunteers office or healthy non-mutation carriers family members who voluntarily agree to participate. Patients with Parkinson disease who do not carry GBA1 mutations are eligible to participate to serve as controls


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00001215


Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Human Genome Research Institute (NHGRI)
Investigators
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Principal Investigator: Ellen Sidransky, M.D. National Human Genome Research Institute (NHGRI)
Additional Information:
Publications:
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Responsible Party: National Human Genome Research Institute (NHGRI)
ClinicalTrials.gov Identifier: NCT00001215    
Other Study ID Numbers: 860096
86-HG-0096
First Posted: November 4, 1999    Key Record Dates
Last Update Posted: July 23, 2021
Last Verified: July 14, 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) ):
Variants
Chemical Phenotype
Enzyme
Phenotype
Glucocerebrosidase
Additional relevant MeSH terms:
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Parkinson Disease
Gaucher Disease
Lysosomal Storage Diseases
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipidoses
Lipid Metabolism, Inborn Errors
Metabolic Diseases
Lipid Metabolism Disorders