Clinical Chemistry -- eLetters for Durand and Seta, 46 (6) 795-805

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Geneviève Durand and Nathalie Seta
Protein Glycosylation and Diseases: Blood and Urinary Oligosaccharides as Markers for Diagnosis and Therapeutic Monitoring
Clin Chem 2000; 46: 795-805 [Abstract] [Full text] [PDF]

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PROTEIN GLYCOSYLATION AND DISEASES: S Vivekanandan (13 September 2000)

PROTEIN GLYCOSYLATION AND DISEASES 13 September 2000

S Vivekanandan,
Clinical Scientist
Department of Chemical Pathology, Guy's & St.Thomas' Hospitals, London SE1 7EH
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Re: PROTEIN GLYCOSYLATION AND DISEASES

s.vivekanandan{at}kcl.ac.uk S Vivekanandan

In the review article "Blood and Urinary oligosaccharides as Markers for Diagnosis and therapeutic Monitoring" (1) the authors did not mention what to do if the serum transferrin isoform (TfI) by isoelectric focussing (IEF) is negative in a patient with high pretest probability referred by an experienced clinician. The abnormal serum TfI pattern, the most characteristic biochemical abnormality of congenital disorders of glycosylation (CDG), remains the test of choice using mostly serum and occasionally other body fluids. In IEF, a marked decrease of sialic acid rich tetrasialotransferrin and increase in sialic acid deficient di- and asialofractions is unique in type I. A positive screen from IEF is confirmed by the demonstration of decreased cell enzymes (Phosphomannose mutase 2 [PMM2] for CDG type Ia and phosphomannose Isomerase [PMI] for CDG type IB using cultured fibroblasts or leukocytes from the affected patient). The IEF of CDT isoforms has a high positive predictive value but a negative result does not exclude CDG(2), for which also cellular studies should be carried out. Recently a pitfall in the diagnosis of CDG-Ia using fibroblasts alone has been reported and rectified using leukocytes in addition to fibroblasts for confirmation (3). Awareness of this limitation is highly essential as some of these types are treatable by mannose administration. The genetic screening (2) and coupled mass spectrometry of TfI4 hold promise as a future screening strategy.
Secondly, the authors did not mention diseases in which this typical CDGS serum IEF pattern is encountered, for the differential diagnosis as well as their potential application in the management of these hypoglycosylation diseases. Clinically, CDG type I and galactosemia have some symptoms in common. These glycoprotein abnormalities in galatosemia are important for pathogenesis and in treatment control. Serum transferrin isoform pattern similar to that seen in CDGS particularly type I, is obtained in galactosaemics (5) and also in hereditary fructose intolerance (HFI) (6). Galactosaemia and HFI should be excluded before a diagnosis of CDGS is made (2). HFI occurs due to the metabolic deficiency of fructose-1-phosphate aldolase results in the accumulation of fructose-1-phosphate, which in turn reported to inhibit phosphomannomutase 2 (PMM2). As PMM2 is a key enzyme in the generation of substrate for glycosylation, this enzyme deficiency causes CDGS type I a (a most common CDGS subtype). Galactosemia, HFI and CDGS are all autosomal recessive inherited metabolic diseases, which display the same tissue and circulatory glycoproteins hypoglycosylation pathology exhibiting altered tissue and circulatory glycoproteins including transferrin and recently FSH.7 Currently the diagnosis of galactosemia is not without difficulty, especially in transfused patients. This hypoglycosylation tool offers much scope in these situations. A recent report describes this strategy to be useful in screening (8) and to monitor dietary compliance (surrogate marker) in HFI as well since 1997 (9). There is a good scope for this strategy to be followed globally. Also abnormal transferrin isoforms revert to normal after 4- 6 months of conventional treatment in these patients.
References:
1. Durand G, Seta N. Protein glycosylation and diseases: Blood and Urinary Oligosaccharides as Markers for Diagnosis and Therapeutic Monitoring. Clin Chem 2000; 46: 795 – 805.
2. Imtiaz F, Worthington V, Champion M, et al.. Genotypes and phenotypes of patients in the UK with Carbohydrate- deficient glycoprotein syndrome type1. J Inherit Metab Dis 2000; 23: 162 – 174
3. Grunewald S, Schollen E, Berghenouse G et al. Partial deficiency of phosphomannomutase: A possible pitfall in the diagnosis of CDG-Ia. J Inherit Metab Dis 2000; 23(Suppl.1): 181
4. Lacey JM, Magera MJ, Matern D et al. A method for the rapid determination of transferrin isoforms by immunoaffinity liquid chromatography-mass spectrometry. J Inherit Metab Dis 2000;23(suppl.1): 178-179.
5. Ornstein KS, McGuire EJ, Berry GT et al. Abnormal galactosylation of complex carbohydrates in cultured fibroblasts from patients with galactose-1- phosphate uridyltransferase deficiency. Pediatr Res 1992; 31: 508 – 511.
6. Adamowicz M, Pronicka E. Carbohydrate deficient glycoprotein syndrome-like transferring isoelectric focussing pattern in untreated fructosuria. Eur J paed 1996; 155: 347 – 8.
7. Prestoz LLC, Couto AS, Shin YS, Petry KG. Alternate follicle stimulating hormone isoforms in female galactosaemics. Eur J Pediatr 1997; 156: 116-120.
8 . Pronicka E, Sykut-Cegielska J, Adamowicz M et al. Isoelectric focussing transferrin glycoforms pattern as a method to detect galactosaemia and fructosaemia. J Inherit Metab Dis 2000; 23 (Suppl.1): 179.
9 . Pronicka E, Adamowicz M, Rogaszewska M et al. Decreased transferrin glycosylation as a possible marker of insufficient compliance of fructose restricted diet in young patients with inherited fructose intolerance