Congenital enterocyte heparan sulphate deficiency with massive albumin loss, secretory diarrhoea, and malnutrition

Murch, Simon; Winyard, Paul J D; Koletzko, S.; Wehner, B.; Cheema, Huma Arshad; Risdon, R. A.; Phillips, Alan D.; Meadows, Nigel; Klein, Nigel; Walker-Smith, J A

doi:10.1016/s0140-6736(96)90941-1

Cited by 141 publications

(71 citation statements)

References 9 publications

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“…30 The involvement of HS in PLE was also seen in a study of three infants with normal small bowel biopsies, who had massive PLE from birth and loss of HS from the basolateral enterocyte membrane. 31 HS loss from the glomerular basement membrane leads to albumin leakage across the vascular endothelium in kidney [45][46][47][48] and thus enterocyte HS deficiency may be analogous to congenital nephrotic syndrome. 47 The findings here suggest that CDG-1c causes a similar loss of HS from the enterocyte basolateral membrane.…”

Section: Discussionmentioning

confidence: 99%

“…29 -31 Specific enzymatic digestions confirm that this technique detects HS in epithelial and endothelial cells, and chondroitin and dermatan sulfates within the mucosal tissues. 29,31 Immunostaining of syndecan-1, the major HS core protein, was done as previously described, 17 using mAb MCA681H (Serotec, Kidlington, UK) specific for human syndecan-1.…”

Section: Immunohistochemical and Histochemical Analysismentioning

confidence: 99%

“…The basolateral epithelial membrane usually has abundant heparanase-sensitive, chondroitinase-insensitive sulfated GAGs, 31 but these were completely absent during PLE (Figure 2, B and C). A small amount of punctate, intraepithelial staining was found, mostly above the nucleus (arrow in Figure 2B).…”

Section: Histological Histochemical and Immunohistochemical Analysimentioning

confidence: 99%

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Reduced Heparan Sulfate Accumulation in Enterocytes Contributes to Protein-Losing Enteropathy in a Congenital Disorder of Glycosylation

Westphal

Murch

Kim

et al. 2000

The American Journal of Pathology

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Intestinal biopsy in a boy with gastroenteritis-induced protein-losing enteropathy (PLE) showed loss of heparan sulfate (HS) and syndecan-1 core protein from the basolateral surface of the enterocytes, which improved after PLE subsided. Isoelectric focusing analysis of serum transferrin indicated a congenital disorder of glycosylation (CDG) and subsequent analysis showed three point mutations in the ALG6 gene encoding an ␣1,3-glucosyltransferase needed for the addition of the first glucose to the dolichol-linked oligosaccharide. The maternal mutation, C998T, causing an A333V substitution, has been shown to cause CDG-Ic, whereas the two paternal mutations, T391C (Y131H) and C924A (S308R) have not previously been reported. The mutations were tested for their ability to rescue faulty N-linked glycosylation of carboxypeptidase Y in an ALG6-deficient Saccharomyces cerevisiae strain. Normal human ALG6 rescues glycosylation and A333V partially rescues, whereas the combined paternal mutations (Y131H and S308R) are ineffective. Underglycosylation resulting from each of these mutations is much more severe in rapidly dividing yeast. Similarly, incomplete protein glycosylation in the patient is most severe in rapidly dividing enterocytes during gastroenteritis-induced stress. 1-4 These defects reduce the amount or change the structure of the lipid-linked oligosaccharide (LLO) precursor for N-linked glycosylation, leading to underglycosylation of many proteins, 3 including antithrombin-III, factor XI, or protein C. This reduces their levels, leaving patients at risk for coagulopathy. Mutations in phosphomannose isomerase (MPI, causing CDG-Ib) and phosphomannomutase (PMM2, causing CDG-Ia) reduce the amount of GDP-Man, the immediate precursor of LLO,5 thus reducing the amount of N-linked glycosylation. Mutations in ALG6, which encodes an ␣1,3-glucosyltransferase, cause CDG-Ic. 6 -8 This enzyme is required for the addition of the first of three glucose residues to LLO, and without the first glucose, further glucosylation is prevented. The nonglucosylated precursor oligosaccharide is a poor substrate for the oligosaccharyltransferase complex and is inefficiently transferred to proteins. 9,10

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Section: Discussionmentioning

confidence: 99%

Section: Immunohistochemical and Histochemical Analysismentioning

confidence: 99%

Section: Histological Histochemical and Immunohistochemical Analysimentioning

confidence: 99%

See 1 more Smart Citation

Reduced Heparan Sulfate Accumulation in Enterocytes Contributes to Protein-Losing Enteropathy in a Congenital Disorder of Glycosylation

Westphal

Murch

Kim

et al. 2000

The American Journal of Pathology

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“…Decrease in HSPG or lack of HSPG in the basal membrane results in protein loss from the intestines into the lumen (20,21). Murch et al (22) found congenital intestinal heparan sulphate deficinecy in a patient who presented with diarrhea, nutritional disorder and excessive albumin loss from the intestines. In tissue culture and mouse models, it has been shown that increased venous pressure, increase in inflammatory cytokines including INF α and TNF α and loss of HSPG in the basal membrane cause protein loss from the intestines separately.…”

Section: Pathophysiologymentioning

confidence: 99%

Protein losing enteropathy in children

Çaltepe¹,

Comba²

2013

Turk Pediatri Ars

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Review Sum maryProtein-losing enteropathy is a medical condition which is characterized by loss of protein, vitamin and trace elements into the intestines which can be complicated by various diseases. The main causes of protein-losing enteropathy in children are primary or secondary intestinal lymphangiectesia, Menetrier disease, inflammatory and immunological disorders. Hypoalbuminemia, developed due to intestinal protein loss, provides the basis of clinical findings. Treatment and prognosis of the disease is closely related to the underlying disease. In this paper, the causes of protein-losing enteropapathy, clinical findings and treatment approaches were reviewed in the light of current information. (Turk Arch Ped 2013; 48: 7-12)

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“…33 A new syndrome of congenital heparan sulphate deficiency was also described. 34 The advent of parenteral nutrition was a vital preliminary for survival among these children with intractable diarrhoea after which small intestinal biopsy could be undertaken. 35 It was in…”

Section: Technological Advances In Diagnosismentioning

confidence: 99%

Paediatric gastroenterology 1966–2000

Walker-Smith

2008

Clinical Medicine

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Congenital enterocyte heparan sulphate deficiency with massive albumin loss, secretory diarrhoea, and malnutrition

Cited by 141 publications

References 9 publications

Reduced Heparan Sulfate Accumulation in Enterocytes Contributes to Protein-Losing Enteropathy in a Congenital Disorder of Glycosylation

Reduced Heparan Sulfate Accumulation in Enterocytes Contributes to Protein-Losing Enteropathy in a Congenital Disorder of Glycosylation

Protein losing enteropathy in children

Paediatric gastroenterology 1966–2000

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