Natural history of infantile G(M2) gangliosidosis.

OBJECTIVE: G(M2) gangliosidoses are caused by an inherited deficiency of lysosomal ß-hexosaminidase and result in ganglioside accumulation in the brain. Onset during infancy leads to rapid neurodegeneration and death before 4 years of age. We set out to quantify the rate of functional decline in infantile G(M2) gangliosidosis on the basis of patient surveys and a comprehensive review of existing literature. METHODS: Patients with infantile G(M2) gangliosidosis (N = 237) were surveyed via questionnaire by the National Tay Sachs & Allied Diseases Association (NTSAD). These data were supplemented by survival data from the NTSAD database and a literature survey. Detailed retrospective surveys from 97 patients were available. Five patients who had received hematopoietic stem cell transplantation were evaluated separately. The mortality rate of the remaining 92 patients was comparable to that of the 103 patients from the NTSAD database and 121 patients reported in the literature. RESULTS: Common symptoms at onset were developmental arrest (83%), startling (65%), and hypotonia (60%). All 55 patients who had learned to sit without support lost that ability within 1 year. Individual functional measures correlated with each other but not with survival. Gastric tube placement was associated with prolonged survival. Tay Sachs and Sandhoff variants did not differ. Hematopoietic stem cell transplantation was not associated with prolonged survival. CONCLUSIONS: We studied the timing of regression in 97 cases of infantile G(M2) gangliosidosis and conclude that clinical disease progression does not correlate with survival, likely because of the impact of improved supportive care over time. However, functional measures are quantifiable and can inform power calculations and study design of future interventions.

Critical role of iron in the pathogenesis of the murine gangliosidoses.

Neurodegeneration is a prominent feature of the gangliosidoses, a group of lysosomal storage diseases. Here we show altered iron homeostasis in mouse models of both GM1 and GM2 gangliosidoses, which are characterized by progressive depletion of iron in brain tissue. This finding contrasts with the findings in many other neurological disorders, where excess iron deposition has been reported. We found that key regulators of iron homeostasis, hepcidin and IL-6, were increased in gangliosidoses mice. In the brain, the principal iron transport and delivery protein transferrin was reduced, accompanied by a progressive inability of the brain to acquire iron from the circulation. Expression of the transferrin receptor was up-regulated reciprocally. Despite the deregulation of iron homeostasis administration of iron prolonged survival in the diseased mice by up to 38%, with onset of disease delayed and motor function preserved.