Mucolipidosis III (Pseudo-Hurler Polydystrophy): Multiple Lysosomal Enzyme Abnormalities in Serum and Cultured Fibroblast Cells

Thomas, George H.; Taylor, Henry; Reynolds, Linda; Miller, Carol S.

doi:10.1203/00006450-197309000-00004

Cited by 62 publications

(17 citation statements)

References 7 publications

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“…The activity of selected lysosomal acid hydrolases was assayed in plasma and cultured fibroblasts according to the methods described by Thomas et al 5 Metabolic labeling and sorting of the lysosomal hydrolase cathepsin D in control and patient fibroblasts were performed as described previously. 6,7 Briefly, cell monolayers at about 60-80% confluency were washed twice with phosphate-buffered saline and methionine starved using cysteine/methioninefree Dulbecco's modified Eagle's medium for 30 min, followed by a pulse label for 1 h with 1 ml of 1 mCi/ml Tran 35 S-label (MP Biomedicals, Solon, OH, USA) in the same media.…”

Section: Methodsmentioning

confidence: 99%

A novel intermediate mucolipidosis II/IIIαβ caused by GNPTAB mutation in the cytosolic N-terminal domain

et al. 2013

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Mucolipidosis (ML) II and ML IIIa/b are allelic autosomal recessive metabolic disorders due to mutations in GNPTAB. The gene encodes the enzyme UDP-GlcNAc-1-phosphotransferase (GNPT), which is critical to proper trafficking of lysosomal acid hydrolases. The ML phenotypic spectrum is dichotomous. Criteria set for defining ML II and ML IIIa/b are inclusive for all but the few patients with phenotypes that span the archetypes. Clinical and biochemical findings of the 'intermediate' ML in eight patients with the c.10A4C missense mutation in GNPTAB are presented to define this intermediate ML and provide a broader insight into ML pathogenesis. Extensive clinical information, including radiographic examinations at various ages, was obtained from a detailed study of all patients. GNPTAB was sequenced in probands and parents. GNPT activity was measured and cathepsin D sorting assays were performed in fibroblasts. Intermediate ML patients who share the c.10A4C/p.K4Q mutation in GNPTAB demonstrate a distinct, consistent phenotype similar to ML II in physical and radiographic features and to ML IIIa/b in psychomotor development and life expectancy. GNPT activity is reduced to 7-12% but the majority of newly synthesized cathepsin D remains intracellular. The GNPTAB c.10A4C/p.K4Q missense allele results in an intermediate ML II/III with distinct clinical and biochemical characteristics. This delineation strengthens the utility of the discontinuous genotypephenotype correlation in ML II and ML IIIa/b and prompts additional studies on the tissue-specific pathogenesis in GNPT-deficient ML.

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Section: Methodsmentioning

confidence: 99%

A novel intermediate mucolipidosis II/IIIαβ caused by GNPTAB mutation in the cytosolic N-terminal domain

et al. 2013

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“…Patients with these conditions have a deficiency of N-acetylglucosaminyl-1-phosphotransferase, which prevents the import of most lysosomal hydrolases into the lysosome. This leads to the accumulation of various GAG species in different tissues (Leroy et al 1972;Thomas et al 1973;Reitman et al 1981), and likely explains the accumulation of urine keratan sulfate observed in these patients. However, the Tomatsu et al study only included 11 samples, and the type of ML, or clinical severity, was not indicated.…”

Section: Discussionmentioning

confidence: 99%

Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs

et al. 2016

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Keratan sulfate (KS) is commonly elevated in urine samples from patients with mucopolysaccharidosis type IVA (MPS IVA) and is considered pathognomonic for the condition. Recently, a new method has been described by Martell et al. to detect and measure urinary KS utilizing LC-MS/MS. As a part of the validation of this method in our laboratory, we studied the sensitivity and specificity of elevated urine KS levels using 25 samples from 15 MPS IVA patients, and 138 samples from 102 patients with other lysosomal storage disorders, including MPS I (n ¼ 9), MPS II (n ¼ 13), MPS III (n ¼ 23), MPS VI (n ¼ 7), betagalactosidase deficiency (n ¼ 7), mucolipidosis (ML) type II, II/III and III (n ¼ 51), alpha-mannosidosis (n ¼ 11), fucosidosis (n ¼ 4), sialidosis (n ¼ 5), Pompe disease (n ¼ 3), aspartylglucosaminuria (n ¼ 4), and galactosialidosis (n ¼ 1). As expected, urine KS values were significantly higher (fivefold average increase) than age-matched controls in all MPS IVA patients. Urine KS levels were also significantly elevated (threefold to fourfold increase) in patients with GM-1 gangliosidosis, MPS IVB, ML II and ML II/III, and fucosidosis. Urine KS was also elevated to a smaller degree (1.1-fold to 1.7-fold average increase) in patients with MPS I, MPS II, and ML III. These findings suggest that while the UPLC-MS/MS urine KS method is 100% sensitive for the detection of patients with MPS IVA, elevated urine KS is not specific for this condition. Therefore, caution is advised when interpreting urinary keratan sulfate results.

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“…In general, a ten-to twenty-fold increase in serum lysosomal enzymes is diagnostic of these disorders (2,3). If cultured fibroblasts are available, the characteristic pattern of lysosomal enzyme deficiencies may be used, as well as the ratio of extracellular to intracellular enzyme activities for diagnosis (5,6).…”

Section: Discussionmentioning

confidence: 99%

“…ML-II and III are biochemically related genetic diseases that are rare and recessively inherited in autosomes. One of the most striking biochemical features of these disorders is the finding of markedly elevated levels of many lysosomal enzymes in serum (2,3). Cultured fibroblasts from these patients show lower intracellular activities of the same lysosomal enzymes (2,(4)(5)(6) and contain the characteristic inclusion bodies.…”

Section: Introductionmentioning

confidence: 99%

Biochemical Characteristics of a Korean Patient with Mucolipidosis III (Pseudo-Hurler Polydystrophy)

et al. 2003

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We performed a biochemical study on the patient with mucolipidosis III (ML-III, pseudo-Hurler polydystrophy) in Korea. Confluent fibroblasts from the patient and from normal controls were cultured for 4, 12, 24, 48, and 72 hr, respectively. Lysosomal enzyme activities in culture media after different incubation times and in plasma, leukocytes, and fibroblasts were determined. Most of the leukocyte lysosomal enzymes were within normal limits or slightly lowered; however, plasma lysosomal enzyme activities such as those of hexosaminidase and arylsulfatase A were markedly increased. Numerous phase-dense inclusions were present in the cytoplasm of cultured fibroblasts. Lysosomal enzyme activities of fibroblasts were markedly decreased except for -glucosidase. The rates of increase of the lysosomal enzyme activities with incubation time were greater in the culture medium of the patient than in normal control, whereas no difference in the -glucosidase activity of the culture media of the patient and the control was found. This study describes the first case of ML-III in Korea, with its typical biochemical characteristics, i.e., a problem with targeting and transporting of lysosomal enzymes which results in a marked increase in plasma lysosomal enzyme activities and a high ratio of extracellular to intracellular lysosomal enzyme activities in cultured fibroblasts.

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Mucolipidosis III (Pseudo-Hurler Polydystrophy): Multiple Lysosomal Enzyme Abnormalities in Serum and Cultured Fibroblast Cells

Cited by 62 publications

References 7 publications

A novel intermediate mucolipidosis II/IIIαβ caused by GNPTAB mutation in the cytosolic N-terminal domain

A novel intermediate mucolipidosis II/IIIαβ caused by GNPTAB mutation in the cytosolic N-terminal domain

Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs

Biochemical Characteristics of a Korean Patient with Mucolipidosis III (Pseudo-Hurler Polydystrophy)

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