Natural History of Glycosphingolipid Storage Disorders and Glycoprotein Disorders

Overview

Study description: This is a natural history study that will evaluate any patient with enzyme or DNA confirmed GM1 or GM2 gangliosidosis, sialidosis or galactosialidosis. Patients may be evaluated every 6 months for infantile onset disease, yearly for juvenile onset and approximately every two years for adult-onset disease as long as they are clinically stable to travel. Data will be evaluated serially for each patient, and cross-sectionally for patients of similar ages and genotypes. Genotype-phenotype correlations will be made where possible although these are rare disorders and the majority of the patients are compound heterozygotes. Objectives: To study the natural history and progression of neurodegeneration in individuals with glycosphingolipid storage disorders (GSL), GM1 and GM2 gangliosidosis, and glycoprotein (GP) disorders including sialidosis and galactosialidosis using clinical evaluation of patients and patient/parent surveys. To develop sensitive tools for monitoring disease progression. To identify biological markers in blood, cerebrospinal fluid, and urine that correlate with disease severity and progression and can be used as outcome measures for future clinical trials. To further understand and characterize the mechanisms of neurodegeneration in GSL and GP storage disorders across the spectrum of disease beginning with ganglioside storage in fetal life. Endpoints: Exploring the natural history of Lysosomal Storage Diseases and Glycoprotein Disorders Study Population: Patients with enzyme or DNA confirmed GM1 or GM2 gangliosidosis, sialidosis or galactosialidosis. Accrual ceiling is 200 participants. No exclusions based on age, gender, demographic group, or demographic location. Patients included in our study are those that are seen at the NIH Clinical Center, subjects that have only sent in blood samples, as well as those who complete the questionnaire or provided head circumference measures.

The GM1 and GM2 gangliosidoses are rare 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 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, sialidosis and galactosialidosis in affected individuals of all ages, races and genders using medical technologies including MRI/MRS, hearing evaluation and auditory evoked response testing, EEG, sleep study, EMG/NCV, echocardiogram and abdominal ultrasound as well as subspecialty evaluations in rehabilitative medicine (including gait analysis), ophthalmology, speech language pathology, neurology, and psychology. Biomarkers of disease progression may be explored in CSF, blood, and urine 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 learned from prenatal diagnosis that they were carrying a fetus with infantile disease and had decided to terminate the pregnancy, we accepted samples of fetal tissue prior to June 5, 2019, 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.