Globoid cell leukodystrophy (GLD) or Krabbe disease is a neurodegenerative disorder caused by a deficiency of galactocerebrosidase (GALC) activity. GALC is required for the lysosomal degradation of galactosylceramide, psychosine, and possibly other galactolipids. This process is extremely important during active myelination. In the absence of functional GALC, psychosine accumulates, resulting in the apoptotic death of myelin-producing cells. While most patients are infants who do not survive beyond 2 years of age, some older patients are also diagnosed. Hematopoietic stem cell transplantation has proven to have a positive effect on the course of some patients with late-onset Krabbe disease. Murine models of this disease provide an excellent opportunity to evaluate therapeutic alternatives including gene therapy. In this study we used serotype 1 AAV to express mouse GALC under the control of the human cytomegalovirus promoter. Direct administration of these viral particles into the brains of neonatal mice with GLD resulted in sustained expression of GALC activity, improved myelination, attenuated symptoms, and prolonged life span. While this treatment also resulted in significant pathological improvements, the treated mice died with symptoms similar to those of the untreated mice. Additional initiatives may be required to prevent the onset of disease and reverse the course of the disease in animal models and human patients.
Abstract Particulate fractions of rat brain catalyze the hydrolysis of radiochemically pure monogalactosyl and digalactosyl diglycerides, which had been synthesized in vitro by enzymes derived from rat brain or spinach chloroplasts. Monogalactosyl-U-14C diglyceride (the galactose being uniformly labeled) yields 14C-galactose when incubated with the mitochondrial fraction of brain at the optimum pH of 4.4 (galactosidase conditions) and monogalactosyl-U-14C glycerol when incubated with the microsomal fraction of brain at the optimum pH of 7.2 (galactolipase conditions). Biosynthesized digalactosyl-U-14C diglyceride is degraded in a similar way. There is no cross-contamination of the two degradative enzyme systems. Studies of activity plotted against age reveal that the galactolipase activity with either monogalactosyl or digalactosyl diglyceride as substrate increases with age (up to at least 40 days) except during the period of most active myelination (approximately 10 to 20 days of age), at which time the galactolipase activity is notably depressed.
Sialic acid storage disease (Salla disease) is an autosomal recessive disorder caused by mutations in a lysosomal sialic acid export protein, SLC17A5 (OMIM #604369). This disorder was initially described in Northern Finland but more recently has been reported in patients of other ethnicities. We describe the clinical presentation and the neuroimaging findings of two non-Finnish children where a diagnosis of Salla disease was suspected on the basis of brain magnetic resonance imaging. The biochemical confirmation of this diagnosis posed a challenge as both patients had elevated percent free urine sialic acid but biochemical analyses in fibroblasts were not conclusive; therefore, molecular testing was necessary for confirmation of the diagnosis. The described encounters demonstrate the importance of pursuing confirmatory molecular diagnostic testing when a sialic acid storage disorder is suspected.
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