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Following allogenic bone marrow transplantation with predominance of donor engraftment, patients with Maroteaux-Lamy syndrome (MPS VI) demonstrate several indications of metabolic correction, such as reduction in liver size, and achieve near-normal levels of urine glycosaminoglycan (GAG). Thus it was somewhat surprising that, a single infusion of galsulfase after 20 years of full donor engraftment resulted in a further decline of GAG into the normal range (Whitley and Jarnes-Utz, Mol Genet Metab 101(4): 346-348, 2010). Urine GAG declined from slightly high pre-treatment levels (7.63 mg GAG/mmol creatinine range 7.0-8.5, N=3) progressively declining below the age-specific normal range (

GM1-gangliosidosis and GM2-gangliosidosis (Tay-Sachs disease and Sandhoff disease) are unrelenting heritable neurodegenerative conditions of lysosomal ganglioside accumulation. Although progressive brain atrophy is characteristic, longitudinal quantification of specific brain structures has not been systematically studied.The goal of this longitudinal study has been to quantify and track brain MRI volume changes, including specific structure volume changes, at different times in disease progression of childhood gangliosidoses, and to explore quantitative brain MRI volumetry (qMRI) as a non-invasive marker of disease progression for future treatment trials.Brain qMRI studies were performed in 14 patients with gangliosidoses (9 infantile, 5 juvenile) yearly. Cerebellar cortex and white matter, caudate, putamen, corpus callosum, ventricles, total brain, and intracranial volumes were measured, as well as total brain volume. Age-matched controls were available for the patients with the juvenile phenotype.The infantile phenotype of all gangliosidoses showed a consistent pattern of macrocephaly and rapidly increasing intracranial MRI volume with both (a) brain tissue volume (cerebral cortex and other smaller structures) and (b) ventricular volume (P0.01 for all). In contrast to apparent enlargement of the total brain volume, and chiefly the enlarged cerebral cortex, a subset of smaller brain substructures generally decreased in size: the corpus callosum, caudate and putamen became smaller with time. The volume of cerebellar cortex also decreased in patients with infantile GM1-gangliosidosis and juvenile GM1- and GM2-gangliosidosis; however, infantile GM2-gangliosidosis cerebellar cortex was the exception, increasing in size. Elevated intracranial pressure (estimated by lumbar spinal pressure) was a common finding in infantile disease and showed continued increases as the disease progressed, yet lacked MRI signs of hydrocephalus except for increasing ventricular size. Notably, in patients with juvenile gangliosidosis, macrocephaly and elevated intracranial pressure were absent and total brain volume decreased with time compared to controls (P=0.004).The disease course of infantile versus juvenile gangliosidoses is clearly distinguished by the rate of brain disease progression as characterized by qMRI. Assessments by qMRI represent a robust non-invasive method for monitoring CNS changes in the clinical course of gangliosidoses and is ideally suited to monitor effects of novel CNS-directed therapies in future clinical trials.

Enzyme replacement and substrate reduction therapies have significantly improved outcomes in patients with Type 1 Gaucher disease (GD1), but do not completely return glucocerebroside levels to the normal range nor prevent continuing tissue injury. Preliminary biomarker analyses indicate a role for oxidative stress and inflammation in GD1 pathophysiology. Thus, additional treatment strategies that target oxidative stress and inflammation have the potential to ameliorate both systemic and brain symptoms and may alter disease progression. N-acetylcysteine (NAC), a FDA-approved medication with antioxidant/anti-inflammatory activity, is also available as an inexpensive dietary supplement with a good safety profile. Our objective is to determine whether oxidative stress and inflammation in the blood and brains of individuals with GD1 can be altered with orally administered NAC. In this open-label study, we have currently enrolled 13 patients who received NAC at 3600mg/day dose. Blood sample collection for biomarker analysis and brain imaging using magnetic resonance spectroscopy (MRS) was done before and following 3 months of NAC. Total glutathione in red blood cells, which is a measure of oxidative stress, and plasma NAC concentrations were measured using a validated liquid chromatography/mass spectrometry method. Intracellular antioxidant enzyme activity and plasma markers for inflammation and lipid and protein modifications were measured using colorimetric and immunoassays. Interim analysis of data from 10 patients revealed that NAC at this dose did not significantly alter any of the neurochemical markers. However, validated MRS markers related to neuronal health such as N-acetyl aspartate (NAA) and glutamate showed trends toward improvement. Similar trends were also observed in blood antioxidant and inflammatory biomarkers. Pharmacokinetic analysis using serial samples collected 90-days after NAC regimen is underway to determine if a dose increase is warranted. If these favorable trends subsequently are shown to be significant, NAC could be a new adjunctive therapeutic option.