Novel Lysosomal Glycoaminoacid Storage Disease With Angiokeratoma Corporis Diffusum

Kanzaki, Tamotsu; Mizuno, Nobuyuki; Yokota, Michiko; Matsumoto, Yukie; Hirabayashi, Yoshio

doi:10.1016/s0140-6736(89)92867-5

Cited by 61 publications

(37 citation statements)

References 18 publications

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“…Support for this concept was provided by the recent demonstration that the urinary sialoglycopeptides from the affected individuals were essentially identical (13). In this communication, we report that the specific enzymatic defect in the Japanese woman with angiokeratoma corporis diffusum and glycoaminoaciduria (8) is the deficient activity of lysosomal a-N-acetylgalactosaminidase. This finding not only identifies the enzymatic defect in an adult-onset form of angiokeratoma corporis diffusum, but also delineates the remarkably distinct adult and infantile phenotypes resulting from the deficient activity of a-N-acetylgalactosaminidase.…”

Section: Introductionmentioning

confidence: 57%

Lysosomal alpha-N-acetylgalactosaminidase deficiency, the enzymatic defect in angiokeratoma corporis diffusum with glycopeptiduria.

Kanzaki

Wang²,

Desnick³

1991

J. Clin. Invest.

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Recently a novel case of angiokeratoma corporis diffusum with glycoaminoaciduria was described in a 46-yr-old Japanese woman. Known causes of the cutaneous manifestation were eliminated by enzyme analyses, and further characterization of the accumulated urinary O-linked sialopeptides revealed identity to those excreted by patients with an infantile neuroaxonal dystrophy due to lysosomal a-N-acetylgalactosaminidase deficiency. Investigation of the a-N-acetylgalactosaminidase activity and protein in the proband revealed less than 2% of normal activity and the absence of detectable immunoreactive enzyme protein, findings comparable to those in the patients with infantile neuroaxonal dystrophy and a-N-acetylgalactosaminidase deficiency. In addition, the proband's unaffected offspring had half-normal levels of a-N-acetylgalactosaminidase activity, consistent with this enzymatic deficiency being the primary metabolic defect in this autosomal recessive trait. Ultrastructural examination of skin and blood cells from the adult proband revealed the presence of prominent lysosomal inclusions containing diffuse amorphous and filamentous material. In contrast, these morphologic findings were not observed in the nonneural tissues from patients with infantile neuroaxonal dystrophy and a-N-acetylgalactosaminidase deficiency. These studies document the occurrence of two forms of a-N-acetylgalactosaminidase deficiency and sialopeptiduria, a severe infantile-onset form of neuroaxonal dystrophy without angiokeratoma or visceral. lysosomal inclusions and an adult-onset form characterized by angiokeratoma, extensive lysosomal accumulation ofsialoglycopeptides and the absence ofdetectable neurologic involvement. (J. Clin. Invest. 1991. 87:707-711.)

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Section: Introductionmentioning

confidence: 57%

Lysosomal alpha-N-acetylgalactosaminidase deficiency, the enzymatic defect in angiokeratoma corporis diffusum with glycopeptiduria.

Kanzaki

Wang²,

Desnick³

1991

J. Clin. Invest.

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“…2 Two years later Kanzaki et al 3,4 reported the second independent case of a-NAGA deficiency with an entirely different clinical phenotype. This patient had a late onset disease with slight facial coarseness, disseminated angiokeratoma and mild intellectual impairment (IQ=70) but without neurological symptoms.…”

Section: Introductionmentioning

confidence: 99%

Human α-N-acetylgalactosaminidase (α-NAGA) deficiency: no association with neuroaxonal dystrophy?

Vreken

et al. 2001

Eur J Hum Genet

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Two new individuals with a-NAGA deficiency are presented. The index patient, 3 years old, has congenital cataract, slight motor retardation and secondary demyelinisation. Screening of his sibs revealed an a-NAGA deficiency in his 7-year-old healthy brother who had no clinical or neurological symptoms. Both sibs are homozygous for the E325K mutation, the same genotype that was found in the most severe form of a-NAGA deficiency presenting as infantile neuroaxonal dystrophy. Thus, at the age of 7 years the same genotype of a-NAGA may present as a`non-disease' (present healthy case) and can be associated with the vegetative state (the first two patients described with a-NAGA deficiency). The clinical heterogeneity among the 11 known individuals with a-NAGA deficiency is extreme, with a`non-disease' (two cases) and infantile neuroaxonal dystrophy (two cases) at the opposite sides of the clinical spectrum. The broad spectrum is completed by a very heterogeneous group of patients with various degrees of epilepsy/behavioural difficulties/psychomotor retardation (four patients) and a mild phenotype in adults without overt neurological manifestations who have angiokeratoma and clear vacuolisation in various cell types (three cases). These observations are difficult to reconcile with a straightforward genotype-phenotype correlation and suggest that factors or genes other than a-NAGA contribute to the clinical heterogeneity of the 11 patients with a-NAGA deficiency.

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“…The cells were fixed in PBS containing 2.5% glutaraldehyde and 2% paraformaldehyde, postfixed in 2% osmium tetroxide, dehydrated through a graded ethanol series, and embedded in Epon 812. Ultrathin sections were mounted on copper grids, contrasted with uranyl acetate and lead citrate, and finally examined under an electron microscope (Hitachi H-7100; Hitachi, Tokyo, Japan) (Kanzaki et al 1989). …”

Section: Immunocytochemical Analysis Of Schwann-cellassociated Markersmentioning

confidence: 99%

Establishment of immortalized Schwann cells from Fabry mice and their low uptake of recombinant α-galactosidase

et al. 2007

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Peripheral neuropathy is one of the important manifestations of Fabry disease. Enzyme replacement therapy with presently available recombinant a-galactosidases does not always improve the Fabry neuropathy. But the reason has not been determined yet. We established a Schwann cell line from Fabry mice, characterized it, and then examined the uptake of a-galactosidase by cells and its effect on the degradation of accumulated substrate. The cells exhibited a distinct Schwann cell morphology and biochemical phenotype (a-Galactosidase activity was deficient, and numerous cytoplasmic inclusion bodies were present in the cells). A recombinant a-galactosidase added to the culture medium was incorporated into the cultured Fabry Schwann cells dose dependently. But the increase in cell-associated enzyme activity was less than that in the cases of human and mouse Fabry fibroblasts. The administration of a high dose of the enzyme improved the pathological changes in cells, although a low dose of it did not. Cellular uptake of the enzyme was strongly inhibited in the presence of mannose 6-phosphate. This suggests that the enzyme is incorporated via cation-independent mannose 6-phosphate receptors in Schwann cells. The low expression of cation-independent mannose 6-phosphate receptors in Schwann cells must be one of the reasons their uptake of the present enzymes was low. The administration of a high dose of the enzyme or the development of an enzyme containing many mannose 6-phosphate residues is required to improve Fabry neuropathy.Keywords Fabry disease Á Schwann cell Á a-Galactosidase Á Globotriaosylceramide Á Enzyme replacement therapy Á Cation-independent mannose 6-phosphate receptor

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Novel Lysosomal Glycoaminoacid Storage Disease With Angiokeratoma Corporis Diffusum

Cited by 61 publications

References 18 publications

Lysosomal alpha-N-acetylgalactosaminidase deficiency, the enzymatic defect in angiokeratoma corporis diffusum with glycopeptiduria.

Lysosomal alpha-N-acetylgalactosaminidase deficiency, the enzymatic defect in angiokeratoma corporis diffusum with glycopeptiduria.

Human α-N-acetylgalactosaminidase (α-NAGA) deficiency: no association with neuroaxonal dystrophy?

Establishment of immortalized Schwann cells from Fabry mice and their low uptake of recombinant α-galactosidase

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