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Deficient transport of dehydroascorbic acid in the glucose transporter protein syndrome.

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Deficient Transport of
Dehydroascorbic Acid in
the Glucose Transporter
Protein Svndrome
4
Jorg Klepper, MD,* Juan Carlos Vera, PhD,t
and Darryl C. De Vivo, MD*
The glucose transporter protein syndrome (GTPS) is
caused by defective transport of glucose across the bloodbrain barrier via the glucose transporter GLUT1, resulting in hypoglycorrhachia, infantile seizures, and developmental delay. Recent reports indicated that GLUTl is a
multifunctional transporter. We investigated the transport of vitamin C in its oxidized form (dehydroascorbic
acid) via GLUTl into erythrocytes of 2 patients with
GTPS. In both patients, uptake of oxidized vitamin C
was 61% of the mothers’ values. Our findings are consistent with recent observations that vitamin C is transported in its oxidized form via GLUTl. We speculate
that impaired transport of this substrate and perhaps
other substrates in GTPS might contribute to the pathophysiology of this condition.
Klepper J, Vera JC, De Vivo DC. Deficient
transport of dehydroascorbic acid in the
glucose transporter protein syndrome.
Ann Neurol 1998;44:286-287
Glucose transport into the brain is mediated by the
GLUTl transporter protein. In 1991, we reported 2
patients with hypoglycorrhachia, infantile seizures, and
developmental delay.’ Since that report, we have studied 14 additional patients and defined the molecular
basis for this novel clinical syndrome.2 This condition,
now recognized as the glucose transporter protein syndrome (GTPS),3 is presumably caused by decreased
transport of glucose at the blood-brain barrier and
across astroglial cell membranes. Recently, there has
been increasing evidence that GLUTl is multifunctional, transporting galactose, H,O, glycopeptides, and
dehydroascorbic a ~ i d . ~
In. ~the GTPS, a multifunctional GLUTl deficiency could have important consequences. Therefore, we investigated the uptake of
From the *Neurological Institute, Columbia University, and ?Memorial Sloan-Kettering Cancer Center, New York, NY.
Received Dec 22, 1997, and in revised form Mar 11, 1998. Accepted for publication Mar 19, 1338.
Address correspondence to Dr De Vivo, Neurological Institute, Columbia University, 710 West 168th Street, New York, NY 10032.
286
3-0-methylglucose and dehydroascorbic acid into
erythrocytes as d e ~ c r i b e d ~in. ~2 male patients with
GTPS (ages 6 and 11 years) and their mothers (ages 35
and 45 years).
Uptake values for 3-0-methylglucose and dehydroascorbic acid were decreased in both patients, with
their mothers serving as intraassay controls. O u r studies have shown no differences in glucose uptake between the parents and healthy controls. 3-0methylglucose uptake values in Patients 1 and 2 were
43% and 47%. These values were well within the
range observed in 16 patients with the GTPS (46 t
8%, mean 5 SD; unpublished data). Dehydroascorbic
acid uptake was 61% in both patients compared with
the intraassay controls (Fig).
The reduced transport of dehydroascorbic acid observed in the GTPS patients may have a significant impact on intracerebral vitamin C homeostasis. Vitamin
C is highly concentrated in the brain and may exert
profound effects on nervous system function as a neuromodulator or neuroprotective agent. The erythrocyte
transports dehydroascorbic acid preferentially. In brain,
several reports suggest that transport of ascorbate occurs via an active sodium-dependent transport system.‘
However, this hypothetical transporter remains to be
characterized at the molecular level. Recent evidence
indicates that dehydroascorbic acid crosses the bloodbrain barrier via GLUTl and is rapidly reduced to
ascorbate and thus trapped within the brain.4 This
trapping mechanism may contribute to the high vitamin C levels in the brain without the participation of
an active transport mechanism. The significance of this
pathway is currently unclear because of the much lower
serum concentration, the chemical instability, and the
possible toxicity of dehydroascorbic acid.
Our data provide further evidence that the GLUTl
protein is a multifunctional transporter. In the GTPS,
the deficient transport of substrates other than glucose
might contribute to the pathophysiological mechanisms of the disease. Further investigations including
the measurement of vitamin C concentrations in the
cerebrospinal fluid and kinetic studies are in progress
to answer these questions.
This study was supported in part by the Colleen Giblin Charitable
Foundation for Pediatric Neurology Research, the Will Foundation,
and the Deutsche Forschungsgemeinschaft.
We are especially grateful for the helpful discussions with Jorge
Fischbarg, M D , Departments of Physiology and Cellular Biophysics
and Ophthalmology, Columbia Presbyterian Hospital, and for the
skillful assistance of Pamela Kranz-Eble in the laboratory.
Copyright 0 1998 by the American Neurological Association
Patient 1
3-OMG uptake
0
10
Patient 1
DHA uptake
20
40
30
0
0
-0.2
=
g -0.4
u
$
E:
-0.1
U
-0.6
-.
-= -0.8
r
Y
3
$
.
*. 0
43%
-1
-=
r
C
control
-1.2
time (see)
-0.2
-0.3
61%
-0.4
time (see)
Patient 2
3-OMG uptake
0
10
Patient 2
DHA uptake
20
40
30
0
20
10
30
40
0
I
- -+. .-+. .
-4 patient
= -0.1
Q)
0
-0.2
control
=
E -0.3
i=r
-1.2
1
61%
J
-0.4
time (sec)
~
time (sec)
.
control
Fig. For dehydroascorbic acid (DHA) uptake, preparations of '-I4C-1abeled ascorbic acid were oxidized to '-l4C-labeled dehydroascorbic acid (4 pmol/L, 8 pCi/ml in 0.9%phosphate-buffered saline) by the addition of ascorbate oxidase and measured by
high perfomance liquid chromatography as described4 Afzpr the immediate incubation of 100 pl of erythrocyte suspension with
50 p1 of '-'4C-labeled dehydroascorbic acid solution, the uptake was terminated at 5-second intervals (5-3060 seconds). The same
conditions were applied for uptake of 3-0-methylglucose (3-OMG) (0.5 mmol/L, 1 pCi/ml in 0.9% phosphate-buffered saline) as
de~cribed.~
The data ofpatients (+I and their mothers serving as controls ( 0 ) (two determinations per data point) were expressed as
the natural logarithm of intracellular radioactivity at time t and at equilibrium versus time (seconds).
References
1. De Vivo DC, Trifiletti RR, Jacobson RI, et al. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay.
N Engl J Med 1991;1325:703-709
2. Seidner G, Garcia-Alvarez M, Yeh JI, et al. Glut-1 deficiency
syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. Nat Gen 1998;18:1-4
3. De Vivo DC, Garcia-Alvarez M, Ronen G, Trifiletti R. Glucose
transport protein deficiency: an emerging syndrome with therapeutic implications. Int Pediatr 1995;10:51-56
4. Agus DB, Garnbhir SS, Pardridge WM, et al. Vitamin C
crosses the blood-brain barrier in the oxidized form through the
glucose transporters. J Clin Invest 1997;100:2842-2848
5. Vera JC, Rivas CI, Fischbarg J, Golde DW. Mammalian facilitative hexose transporters mediate the transport of dehydroascorbic acid. Nature 1993;364:79- 82
6. Spector R. Vitamin homeostasis in the central nervous system.
N Engl J Med 1977;296:1393-1398
Brief Communication: Klepper et al: Dehydroascorbic Acid in GTPS
287
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acid, syndrome, dehydroascorbic, transport, deficiency, protein, glucose
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