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Letters |
1
Department for Neuropediatrics and Inherited Metabolic Diseases, University Children’s Hospital, Deutschhausstrasse 12, D-35033 Marburg, Germany
2
Department of Internal Medicine, and Cardiology, University Hospital, Baldingerstrasse, D-35033 Marburg, Germany
a Address correspondence to this author at: c/o Dr. R. Surtees, Institute of Child Health, University College London, The Wolfson Centre, Mecklenburgh Square, GB-London WC1N 2AP, United Kingdom. Fax 44-171-833-9469; e-mail Verena_Peters{at}med.uni-heidelberg.de
To the Editor:
We report the observation of abnormal protein glycosylation in a
patient with achondroplasia in whom known causes of impaired
glycosylation could not be found. Automated isoelectric focusing (IEF)
was performed in our laboratory for the investigation of glycosylation
disturbances of transferrin (1)(2). All
procedures were carried out in accordance with the Helsinki Declaration
of 1975 as revised in 1996. We used surplus serum samples as controls,
and surprisingly, in one of those, IEF revealed a moderate increase in
disialotransferrin and a slight increase in asialotransferrin (Fig. 1
, lane 1) compared with control serum (Fig. 1
, lane 2). A
similar IEF pattern has been described, e.g., in alcohol abuse
(3) or in carbohydrate-deficient glycoprotein (CDG) syndrome
(4). The patient’s isotransferrin pattern had been
stable in different blood samples for more than 3 years. The
hypoglycosylation of transferrin was confirmed by an increased
carbohydrate-deficient transferrin (CDT) concentration of 44
units/L (upper reference limit, 20 units/L) determined by the
CDTect assay (Pharmacia & Upjohn).
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Clinically, the patient was a 41-year-old man in good general health. His past history included well-controlled arterial hypertension (treated with low-dose ß-blockers) and two generalized seizures at the ages of 35 and 37 years. His height was 142 cm, his weight was 57 kg, and his head circumference was 62 cm (75th centile for achondroplasia). He had shown the stigmata of achondroplasia from the neonatal period, and his motor milestones were slightly delayed, which is usual in subjects with achondroplasia. Mental development had been normal. Detailed neurological examination was normal, including the absence of any tremor. Typical skeletal features of achondroplasia were present on radiological examination. Heterozygosity for a g1138a transition leading to a Gly380Arg substitution in the gene coding for fibroblast growth factor receptor 3 confirmed the clinical and radiological diagnosis. This is the most common mutation causing this disorder (5). The patient had worked as an optician for the same small company for 20 years, and continues to do so.
The most obvious suspicion in an adult with increased CDT values is
alcohol abuse (3)(6). This had been thoroughly
investigated. The clinical findings, history, interview of the patient,
and the history given by his relatives gave no evidence of alcohol
abuse. Conventional biochemical markers of alcohol abuse (7)
determined in this patient were within the reference interval:
-glutamyltransferase, mean corpuscular volume, aspartate
aminotransferase, alanine aminotransferase, and aspartate
aminotransferase/alanine aminotransferase ratio. Additionally,
we tested for apolipoprotein AI, an additional marker of alcohol abuse
(8), which was within the reference interval as well. After
carbamazepine therapy for seizures, -glutamyltransferase,
HDL-cholesterol, and apolipoprotein AI were moderately increased, a
known consequence of anticonvulsant medication (9). In
addition to negative biochemical markers and history, working for the
same small company for 20 years in a job requiring good fine motor
skills seems a strong argument against the hypothesis of alcohol abuse.
There is a theoretical possibility that low-dose treatment with a
ß-blocker can cause disturbed glycosylation. We found one study
investigating CDT values in treated hypertensive men >50 years with at
least one of the following additional problems: tobacco smoking,
diabetes mellitus, and/or hypercholesterolemia (10).
Increased CDT values were reported to be overrepresented in patients
receiving calcium antagonists but not in those receiving ß-blockers
or diuretics. Meerkerk et al. (11) could not confirm this
observation in their study and reported unaffected specificity for CDT
concentrations when investigating the possible influence of several
common diseases and common medications individually. In the group with
false-positive CDT tests, they found more and heavier smokers as well
as statistically higher mean corpuscular volumes. Our patient did not
smoke.
The patient’s isotransferrin band pattern was also similar to CDG
syndrome type I, albeit mild. Various skeletal abnormalities, including
dysplasia (12), have been described in patients with CDG
syndromes, all of which were different from the typical findings in
achondroplasia. The patient’s professional and private activities are
incompatible with known CDG syndromes. Furthermore, the biochemical
markers that may suggest CDG syndromes, such as albumin,
thyroid-stimulating hormone, factor XII, and proteins C and S had been
within the appropriate reference values on more than one
occasion. Similarly, other biochemical markers known to be pathological
in patients with various CDG syndromes were within reference values.
Phosphomannomutase and phosphomannose isomerase activities, measured in
leukocytes and fibroblasts according to the method described by Van
Schaftingen and Jaeken (13), were within reference values.
Other well-documented causes of transferrin hypoglycosylation or
increased CDT concentrations, such as biliary cirrhosis or chronic
active hepatitis (3), fructosemia (14),
galactosemia (15), and reduced ferritin concentrations
(16) could be ruled out clinically or by routine laboratory
analyses. Genetic transferrin D variants known to cause increased
CDT values (3) were excluded by IEF after neuraminidase
treatment of serum samples. In addition to abnormal transferrin
glycosylation, the altered IEF pattern of
1-antitrypsin (data not shown) hinted at a
generalized disturbance of N-glycosylation of proteins. We also studied
the O-glycosylation of apolipoproteins E and C III by IEF according to
Hackler et al. (17) and Noll et al. (18), which
did not reveal abnormalities.
To elucidate whether there is a causal link between achondroplasia and disturbed N-glycosylation of proteins, the investigation of additional patients and studies of the glycosylation pathways in cultured fibroblasts are necessary. The CDT test currently is the most specific biochemical marker of alcohol abuse, with a specificity of >90% (11). However, laboratories involved in the interpretation of increased CDT values or screening for CDG patients should be aware of the existence of glycosylation disturbances that may not be caused by alcohol abuse or other known reasons. When alcohol abuse is considered, conventional biochemical markers must also be determined as well as a detailed clinical investigation. This is particularly important when the wrong interpretation of increased CDT values could have an impact on the social lives of individuals. Additional investigations of false-positive CDT test results may in the future lead to new insights in the biology of protein glycosylation.
Acknowledgments
We are grateful for the mutation analysis performed in the Department of Metabolic and Molecular Genetics, University Children’s Hospital, Zurich, Switzerland, Dr. Superti-Furga. We also acknowledge the Department of Clinical Chemistry and Pathobiochemistry, University Hospital Marburg, Germany, for the determination of CDT concentrations, and thank Dr. Robert Surtees for reading the manuscript and helpful discussions.
Footnotes
Address as of June 2000: Department for General Pediatrics, Metabolic Diseases, Gastroenterology and Nephrology, Metabolic Laboratory, University Children’s Hospital, Im Neuenheimer Feld 150, D-69120 Heidelberg, Germany. Fax 49-6221-56-43-88.
References
The following articles in journals at HighWire Press have cited this article:
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  B. Wuyts, J. R. Delanghe, I. Kasvosve, A. Wauters, H. Neels, and J. Janssens Determination of Carbohydrate-deficient Transferrin Using Capillary Zone Electrophoresis Clin. Chem., February 1, 2001; 47(2): 247 - 255. [Abstract] [Full Text] [PDF]
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