Nervous System Degeneration in Glycosphingolipid Storage Disorders

The GM1 and GM2 gangliosidoses are lysosomal storage disorders that primarily affect the brain and are uniformly fatal. The glycoproteinoses sialidosis and galactosialidosis are ultra-rare disorders involving predominantly the skeletal and central nervous systems that are likewise fatal or severely debilitating. No effective therapy for patients with these diseases has yet been demonstrated. Historically, since these disorders are fatal very little natural history information or disease characterization using modern medical techniques has been collected. This information is vital in order to establish the pattern of disease progression and to identify clinical, biochemical and biophysical markers that can be used as endpoints in future therapeutic trials.

This protocol aims to study the natural history of the GM1 and GM2 gangliosidoses in affected individuals of all ages, races and genders using medical technologies including MRI/MRS, hearing evaluation and auditory evoked response testing, and EEG, as well as subspecialty evaluations in rehabilitative medicine, ophthalmology, speech language pathology, neurology, and psychology. Biomarkers of disease progression will be explored in CSF and blood samples for correlation with disease staging. Fibroblast cultures will be established for testing potential therapeutic agents. Some fibroblast lines will be used to create induced pluripotent stem cells (iPSC) for differentiation into neural tissues, more relevant for the study of these disorders that primarily affect the central nervous system (CNS).We hypothesize that relevant biomarkers will correlate with disease progression and will shed light on the pathophysiology of disease progression in these devastating disorders.

As a means of acquiring additional information, subjects or their parents may also be asked to complete a questionnaire regarding their medical and developmental history, initial clinical presentation of the disease and steps toward diagnosis. At their request, the same questionnaire may be sent to families who do not wish to undergo clinical evaluation at the NIH, who are medically fragile and unable to travel, or whose affected member(s) are already deceased.

We know that children with infantile GM2 gangliosidosis develop increasing macrocephaly as part of their disease. No normal curves for head circumference vs. age currently exist for this disorder. In an attempt to provide such curves to the clinical community parents may also be asked to provide head circumference data on their children whether they are being seen at NIH or whether a clinical questionnaire is being completed for children too medically fragile to travel or already deceased.

We know that for infantile onset disease the storage of ganglioside in neurons begins during the second trimester of pregnancy. In rare situations where carrier couples learn from prenatal diagnosis that they are carrying a fetus with infantile disease and have decided to terminate the pregnancy, we will accept samples of fetal tissue for analysis of biomarkers including gene expression analysis that may lend clues as to the underlying pathogenesis of disease. This may lead to increased understanding of the early events in disease pathogenesis and suggest possible therapies.

We anticipate that information obtained from the small population of patients with glycosphingolipid and glycoprotein disorders evaluated in this study will have a broader impact on patients with other neurodegenerative lysosomal storage disorders and perhaps more common disorders of neurodegeneration.