Sanfilippo Disease Type B: Enzyme Replacement and Metabolic Correction in Cultured Fibroblasts

O’Brien, John S.; Miller, A. T.; Loverde, A. W.; Veath, M. Lois

doi:10.1126/science.181.4101.753

Cited by 75 publications

(32 citation statements)

References 10 publications

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“…For the only therapeutic attempt reported for Sanfilippo B disease (16) no improvement was observed. Studies on the pinocytotic uptake and intracellular action of a-Nacetylglucosaminidase in cultured Sanfilippo B fibroblasts have been reported so far only for the enzyme from human urine (19) and placenta (20). Under the assumption that the serum enzyme has the same properties as the urinary enzyme with regard to pinocytosis and intracellular action it was calculated that per g cell protein, 80 ml of serum would be needed for half-maximal reduction of the accumulated mucopolysaccharides.…”

Section: Discussionmentioning

confidence: 99%

Serum α-N-acetylglucosaminidase: Determination, Characterization, and Corrective Activity in Sanfilippo B Fibroblasts

Figura¹,

Lögering²,

Kresse³

1975

Clinical Chemistry and Laboratory Medicine

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Summary: Assays for the determination of serum -N-acetylglucosaminidase (EC 3.2.1.50) activity are described employing p-nitrophenyl-N-acetyl-a-D-glucosaminide, phenyl-N-acetyl-a-.D-glucosaminide, and UDP-N-acetylglucosamine as substrates. A log normal distribution of the serum enzyme activity was found. The determination of serum -N-acetylglucosaminidase activity proved to be a valuable tool for the recognition of homozygous and heterozygous carriers of the Sanfilippo B gene.The enzyme was characterized with regard to its pH optimum, K m , isoelectric point, and the influence of several bivalent cations was studied.Serum -N-acetylglucosaminidase was added to Sanfilippo B fibroblast cultures, which are deficient in this enzyme. This resulted in an intracellular enzyme level, which was one twelvth of that found after addition of an equal amount of enzyme derived from human urine. The pinocytosed serum enzyme, however, exhibited the same corrective activity towards the accumulated heparan sulfate as the urinary enzyme.

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Section: Discussionmentioning

confidence: 99%

Serum α-N-acetylglucosaminidase: Determination, Characterization, and Corrective Activity in Sanfilippo B Fibroblasts

Figura¹,

Lögering²,

Kresse³

1975

Clinical Chemistry and Laboratory Medicine

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show abstract

“…The changes in urinary glycosaminoglycans noted in these patients were transient, presumably because most lysosomal enzymes have relatively short halflives intracellularly (10)(11)(12). Studies on enzymes present in aimniotic fluid (13), leukocyte homogenates (14), anid serum (15), however, generally indicate a higher degree of stability.…”

Section: Introductionmentioning

confidence: 94%

“…Furthermore, in in vitro studies with cells from patients with mucopolysaccharidosis IIIB (Sanfilippo B disease) it has been shown that 2-5% of normal intracellular levels of enzyme would induce 42-70% correction of their abnormal glycosaminoglycan metabolism (10 …”

Section: +19mentioning

confidence: 99%

Enzyme replacement therapy by fibroblast transplantation: long-term biochemical study in three cases of Hunter's syndrome.

Dean¹,

Stevens²,

Muir³

et al. 1979

J. Clin. Invest.

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A B S T R A C T We have assessed the effectiveness of transplanted histocompatible fibroblasts as a long-lived source of lysosomal enzymes for replacement therapy in three patients with Hunter's syndrome, over periods ranging from 2.5 to 3.75 yr. The level of Hunter corrective factor excreted by all three patients increased after transplantation, as did the activity of a-L-idurono-2-sulfate sulfatase in serum, when measured directly with a radioactive disulfated disaccharide substrate. Sulfatase activity was also raised in leukocyte homogenates from the two patients that we were able to assess. These increases in enzyme activity were accompanied by corresponding increases in catabolism of heparan and dermatan sulfates, as shown by (a) a decrease in sulfate:uronic ratios of urinary oligosaccharides, (b) an increase in iduronic acid monosaccharide, and (c) a normalization of Bio-Gel P-2 gel filtration profiles. Both the increase in enzyme activity and increased catabolism were maintained during the period of study and were not affected by either a gradual decrease or total withdrawal of immunosuppressive therapy.

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“…73 Early tissue culture experiments showed that exogenous enzymes could gain access to and degrade the accumulated intracellular substrates. 74,75 Even with achievement of 1-5% of normal cellular activity after supplying exogenous enzymes, these in vitro studies showed that storage substances dwindled. After these early exciting discoveries in 1970s, the progress in the 1980s was relatively slow.…”

Section: Screening and Testing For Imdsmentioning

confidence: 99%

Inherited metabolic disorders involving the eye: a clinico-biochemical perspective

Rajappa

Goyal

Kaur

2009

Eye

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The diagnosis of inborn errors of metabolism is challenging for most physicians. Improvements in medical technology and greater knowledge of the human genome are resulting in significant changes in the diagnosis, classification, and treatment of inherited metabolic disorders (IMDs). Many known inborn errors of metabolism will be recognised earlier or treated differently because of these changes. It is important that physicians recognise the clinical signs of IMDs and know when to propose advanced laboratory testing or referral to a higher centre for better patient management. Ocular manifestations occur in various metabolic disorders. Although there is an extensive understanding of many inborn errors of metabolism at the biochemical, molecular, and metabolic levels, little is known about their pathogenesis. In particular, how systemic metabolic disease contributes to ocular defects remains to be elucidated in IMDs. The occurrence of eye abnormalities could be due to direct toxic mechanisms of abnormal metabolic products or accumulation of normal metabolites by errors of synthetic pathways or by deficient energy metabolism. A detailed ophthalmological assessment is essential. Definitive diagnosis and management of patients with IMDs is ideally carried out by a combination of specialists, including an ophthalmologist, paediatrician, biochemist, and medical geneticist. Recent advances in the diagnosis and treatment of IMDs have substantially improved the prognosis for many of these conditions.

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Sanfilippo Disease Type B: Enzyme Replacement and Metabolic Correction in Cultured Fibroblasts

Cited by 75 publications

References 10 publications

Serum α-N-acetylglucosaminidase: Determination, Characterization, and Corrective Activity in Sanfilippo B Fibroblasts

Serum α-N-acetylglucosaminidase: Determination, Characterization, and Corrective Activity in Sanfilippo B Fibroblasts

Enzyme replacement therapy by fibroblast transplantation: long-term biochemical study in three cases of Hunter's syndrome.

Inherited metabolic disorders involving the eye: a clinico-biochemical perspective

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