Genetic Studies of Lysosomal Storage Disorders

• ClinicalTrials.gov Identifier: NCT00001215
• Recruitment Status: Enrolling by invitation
• First Posted: November 4, 1999
• Last Update Posted: December 11, 2020
• Sponsor: National Human Genome Research Institute (NHGRI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) )

Study Description

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 Disease; Gaucher Disease; Parkinson Disease

Detailed Description:

There is a vast spectrum of clinical manifestations encountered in individuals with lysosomal storage diseases. Lysosomes are organelles that are involved in the degradation of intracellular proteins, recycled products and organelle in the cell. Lysosomal storage disorders occur when an enzyme necessary for breaking down these molecules is deficient, and, as a result, the substrate accumulates within the lysosomes of cells and may affect different organ systems. This is a longitudinal natural history study of patients with Gaucher disease and other storage disorders. Gaucher disease, the most common lysosomal storage disorder, results from the inherited deficiency of the enzyme glucocerebrosidase, which breaks down the lipid glucocerebroside. The disease is characterized by extremely variable phenotypes, with some patients presenting in childhood with virtually all the complications of Gaucher disease, while others remain asymptomatic into their eighth decade. Often patients with Gaucher disease develop hepatosplenomegaly, anemia, thrombocytopenia and bony problems. Gaucher disease has traditionally been divided into three clinical subtypes, delineated by the absence or presence of neurologic involvement and its progression:

Type 1 -Non-neuronopathic form

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Type 2 -Acute neuronopathic form

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Type 3 -Chronic neuronopathic form

Some patients, however, defy classification into these three categories, and it may be more

accurate to regard Gaucher disease as a continuum of phenotypes..In addition, patients and

carriers for Gaucher disease are at increased risk for developing Parkinson disease and related disorders.

Our goal in this study is to identify genetic, biochemical, and clinical parameters that are associated with disease severity in individuals with lysosomal storage disorders, identify mild phenotypic manifestations in their relatives, and explore the natural history and extent of associated clinical manifestations. We also want to investigate non-motor manifestations in subjects at higher risk for developing parkinsonism that could contribute to earlier diagnosis. Participants will be 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 will be placed on individuals with atypical presentations. In particular, we will focus on subjects with Gaucher disease and parkinsonism, 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.

Study Design

• Study Type: Observational
• Actual Enrollment: 550 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

Groups and Cohorts

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

Outcome Measures

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

Eligibility Criteria

• 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 CRITERIA:

Participants must be found to have or be a carrier of a documented lysosomal storage disorder or be a family member of a documented proband.

EXCLUSION CRITERIA:

There are no exclusion criteria.

Contacts and Locations

Locations

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

• Principal Investigator: Ellen Sidransky, M.D.; National Human Genome Research Institute (NHGRI)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Steward AM, Wiggs E, Lindstrom T, Ukwuani S, Ryan E, Tayebi N, Roshan Lal T, Lopez G, Schiffmann R, Sidransky E. Variation in cognitive function over time in Gaucher disease type 3. Neurology. 2019 Dec 10;93(24):e2272-e2283. doi: 10.1212/WNL.0000000000008618. Epub 2019 Nov 12.

Gary SE, Ryan E, Steward AM, Sidransky E. Recent advances in the diagnosis and management of Gaucher disease. Expert Rev Endocrinol Metab. 2018 Mar;13(2):107-118. doi: 10.1080/17446651.2018.1445524. Epub 2018 Mar 12.

Lopez G, Steward A, Ryan E, Groden C, Wiggs E, Segalà L, Monestime GM, Tayebi N, Sidransky E. Clinical evaluation of sibling pairs with gaucher disease discordant for parkinsonism. Mov Disord. 2020 Feb;35(2):359-365. doi: 10.1002/mds.27916. Epub 2019 Nov 30.

• 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
• Last Update Posted: December 11, 2020
• Last Verified: December 8, 2020

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) ):

Variants; Chemical Phenotype; Proteins; Phenotype; Glucocerebrosidase

Additional relevant MeSH terms:

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