Departments of Clinical and Experimental Medicine and Biomorphological and Functional Sciences (F.D.S.), Federico II University Medical School, Ospedale Pausillipon (V.P.), 80131 Naples, Italy
Address all correspondence and requests for reprints to: Brunella Capaldo, M.D., Dipartimento di Medicina Clinica e Sperimentale, Università Federico II, Via Pansini 5, 80131 Naples, Italy. E-mail: brucapal{at}unina.it
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Introduction |
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At age 17 yr, because of secondary amenorrhea and echographic findings
of small ovarian cysts, the patient was diagnosed as having polycystic
ovary syndrome and was treated with estro-progestins (12 cycles/yr of
ciproterone, ethinyl estradiol). One year later, at age 18 yr, the
patient developed motor seizures initially involving the left leg, then
rapidly extending to the whole body, followed by unconsciousness. On
admission, left hemiplegia was observed. Arterial blood pressure and
plasma lipid concentrations were normal (100/60 mm Hg; total
cholesterol, 147 mg/dL; total triglycerides, 84 mg/dL). The patient was
receiving insulin therapy (3035 IU/24 h), and the average
HbA1c levels had been between 7.17.3% during
the previous year. A computed tomography scanning revealed a small area
of edema at the right cerebral hemisphere; 24 h later an ischemic
area involving the territory of the right middle cerebral artery became
manifest. One month later, during antiepileptic and ticlopidine
therapy, the patient developed clonic movements of the left leg
followed by generalized coreic movements and unconsciousness. Brain
magnetic resonance (MR) imaging and angiography showed severely reduced
blood flow in the right middle cerebral artery, with a large ischemic
area in the corresponding territory, absence of flow in the distal
internal carotid arteries, and slight compensatory hypertrophy of the
basilar artery (Fig. 1). X-Ray digital
arteriography confirmed MR findings and showed narrowing of the left
superficial femoral and popliteas arteries. Hemostasis tests revealed
high fibrinogen levels (612 mg/dL), whereas prothrombin,
APTT, antithrombin III, and protein S were normal.
Anticardiolipin (IgG and IgM) and lupus anticoagulant antibodies were
also normal. In contrast, a low activity of protein C (60%
vs. 98 ± 15%) was found, which reverted to
normal after a year. Further investigation for a hypercoagulable state
showed negative factor V Leiden and a homocysteine concentration in the
normal range. In addition, screening for prothrombin gene G20210A
mutation and mutations of two enzymes involved in homocysteine
metabolism, i.e. C677T in the coding region for
N5,N10-methylenetetrahydrofolate
reductase and cystathionine ß-synthase 844INS68, gave negative
results. On hospital discharge, the patient had left-sided hemiparesis.
Oral anticoagulant and antiepileptic drugs were prescribed together
with insulin and thiamine, which induced satisfactory glycemic control
and resumption of menses. During the 1-yr follow-up the patient
progressively recovered upper limb motility and is now independent with
regard to everyday life needs.
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Discussion |
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In addition to the cardinal clinical manifestations of the syndrome (thiamine-responsive megaloblastic anemia, diabetes mellitus, and sensorineural deafness), some patients may show congenital heart disease and/or arrythmias, backwardness, situs viscerum inversus as well as abnormalities of the retina and optic nerve (3, 4). Retinic abnormalities (one Givres area in right eye, three Givres areas in left eye) were also present in our patient.
Thiamine administration is reported to correct megaloblastic anemia but to be ineffective for sensorineural deafness. With regard to diabetes, 8 of the 17 TRMA patients showed no improvement of glycemic control after thiamine administration, 5 patients were able to temporarily reduce their insulin dose, and the remaining 4 showed an improvement of their diabetes. Two of the latter, among whom was our patient, were noninsulin requiring for a long period. Puberty appears to be a determinant in deteriorating the metabolic control and generally requires the reinstitution of insulin therapy.
With regard to the mechanisms underlying thiamine deficiency, in
vitro studies of human intestinal cells have shown that thiamine
uptake may take place through two pathways: 1) active transport by
means of a saturable, high affinity carrier; and 2) passive uptake by a
low affinity carrier. A similar pattern has been seen in human
erythrocytes (1, 6, 7). Once taken up by the cells, intracellular
thiamine is converted into the active form, i.e. thiamine
pyrophosphate (TPP), which is incorporated into four mammalian enzymes:
the pentose phosphate shunt enzyme transketolase and three
multienzymatic complexes involved in oxidative decarboxylation
reactions: 1) pyruvate dehydrogenase, 2) -ketoglutarate
dehydrogenase, and 3) branched chain keto-acid dehydrogenase. Based on
the finding of reduced
-ketoglutarate dehydrogenase in the
lymphocytes of a patient with TRMA, Abboud et al. proposed
that defective TPP binding to the enzyme was implicated in the genesis
of the syndrome (5). Poggi et al. first noted a low TPP
content in TRMA erythrocytes and postulated that the lack of high
affinity thiamine transporter might be associated with the syndrome (1, 7). This hypothesis has recently been confirmed by Stagg et
al., who documented the absence of the high affinity thiamine
transporter on fibroblasts of TRMA patients and demonstrated that a low
thiamine concentration may cause cell death by apoptosis (8). Thus, to
date, the primary abnormality of the TRMA syndrome is probably ascribed
to a defect in intracellular thiamine transport, although the factor(s)
linking the three components of the syndrome remains unknown. Very
recently, genetic studies performed in four families with the TRMA
syndrome have shown linkage of the TRMA gene to a 16-centimorgan region
on 1q 23.21q 23.3 between D1S194-D1S2786 markers (9), which has been
further refined to a narrow 1.4-centimorgan interval (10). In this
region a new gene has been identified, the SLC19A2 (11, 12), which
encodes the high affinity, saturable transporter of thiamine, the first
identified in complex eukaryotes (13). Mutations in this gene have been
found in all TRMA patients examined (11). On the basis of the TRMA
phenotype, it is reasonable to presume that this carrier may play a
crucial role in facilitating the transport of thiamine not only into
hemopoietic but also into pancreatic islet and auditory apparatus
cells.
Among documented cases of patients with TRMA, ours is the only one who suffered from ischemic stroke. Thiamine deficiency may induce neurological manifestations characterized by ataxia, loss of righting, opisthotonos, and drowsiness (Wernickes disease), which rapidly and fully reverse with thiamine administration, indicating that the neurological damage is reversible and metabolic in nature. The mechanism responsible for the neurological syndrome is probably related to the low activity of two oxidative decarboxylation enzymes, with a consequent dysfunction in the Krebs cycle and decreased mitochondrial energy production.
It is important to underline that our patient had been treated with estro-progestins for 1 yr before the thrombotic event. The association between the use of oral contraceptives and the thromboembolic disease is well known in the general population, especially in women with high cardiovascular risk. No data are available to date in patients with the TRMA syndrome. Although there is no clear evidence of a causal relationship between the use of oral contraceptives and the severe thrombotic disease in our patient, the temporal relation between the two events and the lack of such complication in other patients with TRMA suggest that estro-progestins should be considered as the most likely cause.
A new insight into this potential association comes from the genetic findings discussed above. It is worth noting that human coagulation factor V and antithrombin III precursor also map between D1S194-D1S2786 markers. Thus, an intriguing question arises as to whether a complex mutational event in this region may also involve coagulation cascade genes, causing susceptibility to thrombosis. If this were true, a thrombogenic stimulus such as estro-progestins, acting on a predisposing ground, could precipitate an acute thrombotic event. Although this hypothesis needs to be proven, it is advisable to avoid estro-progestins in patients with the TRMA syndrome.
Received September 21, 1999.
Revised November 9, 1999.
Accepted November 17, 1999.
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References |
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