Acute Ischemic Stroke in a Young Woman with the Thiamine-Responsive Megaloblastic Anemia Syndrome

Valeria Villa, Angela Rivellese, Francesco Di Salle, Ciro Iovine, Vincenzo Poggi and Brunella Capaldo

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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We report the case of a 20-yr-old girl with thiamine-responsive megaloblastic anemia (TRMA) associated with diabetes mellitus and bilateral sensorineural deafness (1, 2). Megaloblastic anemia was diagnosed at 7 months and was successfully treated with multiple vitamin preparations. Diabetes was diagnosed at age 2 yr and was treated with insulin for 6 months at a dose of 0.5 IU/kg BW. The diagnosis of TRMA syndrome was clinically confirmed when bilateral sensorineural deafness was detected. Thereafter, thiamine treatment was started (50 mg/day), and insulin was discontinued because of frequent episodes of hypoglycemia. At age 9 yr, due to reoccurrence of hyperglycemia, the patient underwent glibenclamide treatment (2.5 mg/day), which was replaced by insulin at menarche. Glycemic control was satisfactory, as evidenced by hemoglobin A1c (HbA1c) values between 7.5–8%. Laboratory parameters, including coagulation factors, were in the normal range.

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 (30–35 IU/24 h), and the average HbA1c levels had been between 7.1–7.3% 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. 1Go). 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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Figure 1. Time of flight MR angiography showing absent flow in the distal carotid arteries (solid arrows) with slight hypertrophy of the basilar artery (solid arrowhead) and marked stenosis of the middle cerebral artery on the right (large open arrowhead). A narrowing of the proximal anterior cerebral artery on the left is also present (small open arrowhead).

 

    Discussion
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Over the last 30 yr, 17 patients with the TRMA syndrome have been described in the literature, most of whom were born from consanguineous parents (1, 2, 3, 4, 5). Our patient’s parents were not consanguineous, but were both affected by reduced glucose tolerance. Her mother underwent splenectomy at age 19 yr because of thrombocytopenia of unknown origin. A maternal uncle had bilateral deafness for high frequencies and type 1 diabetes from the age of 18 yr.

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 Givre’s area in right eye, three Givre’s 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) {alpha}-ketoglutarate dehydrogenase, and 3) branched chain keto-acid dehydrogenase. Based on the finding of reduced {alpha}-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 23.2–1q 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 (Wernicke’s 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
 

  1. Poggi V, Longo G, De Vizia B, et al. 1984 Thiamin-responsive megaloblastic anemia: a disorder of thiamin transport? J Inher Metab Dis. 7(Suppl 2):153–154.
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  8. Stagg AR, Fleming JC, Baker MA, Sakamoto M, Cohen N, Neufeld EJ. 1999 Defective high-affinity thiamine transporter leads to cell death in thiamine-responsive megaloblastic anemia syndrome fibroblasts. J Clin Invest. 103:723–729.[Abstract/Free Full Text]
  9. Neufeld EJ, Mandel H, Raz T, et al. 1997 Localization of the gene for thiamine-responsive megaloblastic anemia syndrome, on the long arm of chromosome 1, by homozygosity mapping. Am J Hum Genet. 61:1335–1341.[CrossRef][Medline]
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  13. Fleming JC, Tartaglini E, Steinkamp MP, Schorderet DF, Cohen N, Neufeld EJ. 1999 The gene mutated in thiamine-responsive anemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter. Nat Genet. 22:305–308.[CrossRef][Medline]




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