Electrocardiographic and other cardiac anomalies in β-glucuronidase-null mice corrected by nonablative neonatal marrow transplantation

Schuldt, Adam J.T.; Hampton, Tracy; Chu, Victor; Vogler, CA; Galvin, Nancy; Lessard, Mark D.; Barker, Jane E.

doi:10.1073/pnas.0305284101

Cited by 14 publications

(12 citation statements)

References 49 publications

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“…While the cause of the reduced longevity of MPS VII mice is not clear, some have hypothesized that it may be related to the cardiac abnormalities observed in both patients and animal models of the disease (Schuldt et al 2004). Consistent with this hypothesis, our rAAV-treated MPS VII mice exhibited no improvement in lysosomal storage in the heart valves (Table 1) and no improvement in longevity.…”

Section: Discussionsupporting

confidence: 75%

Clinical response to persistent, low‐level β‐glucuronidase expression in the murine model of mucopolysaccharidosis type VII

Donsante¹,

Levy

Vogler

et al. 2007

J of Inher Metab Disea

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Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by beta-glucuronidase (GUSB) deficiency. This disease exhibits a broad spectrum of clinical signs including skeletal dysplasia, retinal degeneration, cognitive deficits and hearing impairment. Sustained, high-level expression of GUSB significantly improves the clinical course of the disease in the murine model of MPS VII. Low levels of enzyme expression (1-5% of normal) can significantly reduce the biochemical and histopathological manifestations of MPS VII. However, it has not been clear from previous studies whether persistent, low levels of circulating GUSB lead to significant improvements in the clinical presentation of this disease. We generated a rAAV2 vector that mediates persistent, low-level GUSB expression in the liver. Liver and serum levels of GUSB were maintained at approximately 5% and approximately 2.5% of normal, respectively, while other tissue ranged from background levels to 0.9%. This level of activity significantly reduced the secondary elevations of alpha-galactosidase and the levels of glycosaminoglycans in multiple tissues. Interestingly, this level of GUSB was also sufficient to reduce lysosomal storage in neurons in the brain. Although there were small but statistically significant improvements in retinal function, auditory function, skeletal dysplasia, and reproduction in rAAV-treated MPS VII mice, the clinical deficits were still profound and there was no improvement in lifespan. These data suggest that circulating levels of GUSB greater than 2.5% will be required to achieve substantial clinical improvements in MPS VII.

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Section: Discussionsupporting

confidence: 75%

Clinical response to persistent, low‐level β‐glucuronidase expression in the murine model of mucopolysaccharidosis type VII

Donsante¹,

Levy

Vogler

et al. 2007

J of Inher Metab Disea

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“…No patient with type VII showed aortic root dilation or aortic obstruction, contradicting the conclusions of Schuldt et al 28 and Honjo et al 29 Despite the short follow-up period, the progressive character of cardiac lesions and the strong association between the accumulation of dermatan sulphate and the severity of the cardiovascular damage were proven, and these facts were previously suggested by Dangel. 7 Prospective studies should be performed not only to monitor the evolution of the findings described here, but also to determine the impact of the new therapeutics on the natural history of the pathology.…”

Section: Discussionmentioning

confidence: 79%

Echocardiographic study of paediatric patients with mucopolysaccharidosis

et al. 2010

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Principle: Mucopolysaccharidosis is an inborn error of metabolism causing glucosaminoglycans tissue storage. Cardiovascular involvement is variable but contributes significantly towards the morbidity and mortality of the patients. Objective: To characterise the echocardiographic abnormalities in children and adolescents with different types of mucopolysaccharidosis. Method: Echocardiograms and medical records of 28 patients aged 2-14 years, seen from 2003 to 2005, were revised. At that time, the enzymatic replacement therapy was still not available in our institution. Results: Echocardiographic alterations were detected in 26 patients (93%), whereas 16 (57%) had abnormal auscultation, and only 6 (21%) presented with cardiovascular complaint. Mitral valve thickening with dysfunction (regurgitation, stenosis, or double lesion) was diagnosed in 60.8%, left ventricular hypertrophy in 43% and aortic valve thickening with regurgitation in 35.8% of the patients. There was no systolic dysfunction and mild left diastolic dysfunction was shown in 21.5% of the patients. Pulmonary hypertension was present in 36% of the patients, causing the only two deaths recorded. There was a strong association between the accumulation of dermatan sulphate and the presence of mitral valve dysfunction (p 5 0.0003), aortic valve dysfunction (p 5 0.006), and pulmonary hypertension (p 5 0.006). Among individuals with two or more examinations, 82% had a worsening evolution. Conclusions: Echocardiographic alterations in children with Mucopolysaccharidosis are frequent and have a progressive character. Left valve lesions, ventricular hypertrophy, and pulmonary hypertension were the most common findings and there was an association between the accumulation of dermatan sulphate and cardiovascular involvement. Unlike in adults, pulmonary hypertension was the main cause of death, not left ventricle systolic dysfunction.

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“…Furthermore, carnitine deficiency, a lipid metabolism deficiency, results in cardiac hypertrophy (24). Significant cardiac hypertrophy is seen in MPSVII mice (25). As determined by echocardiography, MPS-VII mice have left ventricular hypertrophy as indicated by the increase in left ventricular mass, increased wall thickness, and increased left ventricular lumen.…”

Section: Resultsmentioning

confidence: 99%

Metabolic Adaptations to Interrupted Glycosaminoglycan Recycling

Woloszynek

Kovács

Ohlemiller

et al. 2009

Journal of Biological Chemistry

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Lysosomal storage diseases (LSD) are metabolic disorders characterized by accumulation of undegraded material. The mucopolysaccharidoses (MPS) are LSDs defined by the storage of glycosaminoglycans. Previously, we hypothesized that cells affected with LSD have increased energy expenditure for biosynthesis because of deficiencies of raw materials sequestered within the lysosome. Thus, LSDs can be characterized as diseases of deficiency as well as overabundance (lysosomal storage). In this study, metabolite analysis identified deficiencies in simple sugars, nucleotides, and lipids in the livers of MPSI mice. In contrast, most amino acids, amino acid derivatives, dipeptides, and urea were elevated. These data suggest that protein catabolism, perhaps because of increased autophagy, is at least partially fulfilling intermediary metabolism. Thus, maintaining glycosaminoglycan synthesis in the absence of recycled precursors results in major shifts in the energy utilization of the cells. A high fat diet increased simple sugars and some fats and lowered the apparent protein catabolism. Interestingly, autophagy, which is increased in several LSDs, is responsive to dietary intervention and is reduced in MPSVII and MPSI mice fed a high fat diet. Although long term dietary treatment improved body weight in MPSVII mice, it failed to improve life span or retinal function. In addition, the ventricular hypertrophy and proximal aorta dilation observed in MPSVII mice were unchanged by a high fat, simple sugar diet. As the mechanism of this energy imbalance is better understood, a more targeted nutrient approach may yet prove beneficial as an adjunct therapy to traditional approaches. Lysosomal storage disease (LSD)2 typically results from a genetic deficiency of an acid hydrolase (1). The material usually degraded by the enzyme now accumulates in the lysosomes of cells throughout the body. In normal cells, some proportion of the degraded material is exported to the cytosol for reuse, thereby reducing the energy burden on the cell (2, 3). In the case of LSDs, more energy must be diverted to the synthesis of raw material because of the impaired recycling. Thus, this class of disorders presents with an energy imbalance caused by a simultaneous excess of stored material and a deficiency of raw material (4).Deficiencies in lysosomal enzymes involved in glycosaminoglycan (GAG) catabolism result in the mucopolysaccharidoses (MPS) (5). The biochemical, histological, and clinical phenotypes of MPS are likely due to a combination of the adaptations to both lysosomal storage and a deficiency of recycled monosaccharides. Maintaining a normal rate of GAG biosynthesis would require newly imported or synthesized monosaccharides, irrespective of the adaptations to stored material. The increased demand for GAG precursors is likely to be considerable. It has been shown previously in cultured cells that reutilization of catabolites from lysosomal GAG degradation is substantial (2). Therefore, the increased energy burden required for de novo synthesis...

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Electrocardiographic and other cardiac anomalies in β-glucuronidase-null mice corrected by nonablative neonatal marrow transplantation

Cited by 14 publications

References 49 publications

Clinical response to persistent, low‐level β‐glucuronidase expression in the murine model of mucopolysaccharidosis type VII

Clinical response to persistent, low‐level β‐glucuronidase expression in the murine model of mucopolysaccharidosis type VII

Echocardiographic study of paediatric patients with mucopolysaccharidosis

Metabolic Adaptations to Interrupted Glycosaminoglycan Recycling

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