Genetic Studies of Lysosomal Storage Disorders

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



Type 2 -Acute neuronopathic form



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.

- 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.